HK1050365A - Nicotinamide benzofused-heterocyclyl derivatives useful as selective inhibitors of pde4 isozymes - Google Patents

Description

Nicotinamide benzo-fused heterocyclic derivatives useful as selective inhibitors of PDE4 isozymes

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1.0 reference to related applications

See pending international application with application number PCT/IB98/00315 and U.S. applications based thereon, both filed 10/3/1998 (agency Docket No. PC9762A), and published at 15/10/1998 in WO98/45268, claiming priority to application 60/043403 (agency Docket No. PC9762), filed 4/1997, which has been disclaimed now; it discloses nicotinamide derivatives having inhibitory activity on the PDE4 isoenzyme and can therefore be used for the treatment of inflammatory, respiratory and allergic diseases and conditions. The above applications do not disclose teachings to one of ordinary skill in the relevant art how to obtain the novel compounds of the present invention, or their unexpectedly high inhibitory selectivity for the PDE4 isoenzyme.

See also pending application No. 09/345,185, 30.6.1999 (agency Docket No. PC10096A) which claims priority to application No. 60/105,120, 21.10.1998 (agency Docket No. PC10096) which discloses N-substituted nicotinamide derivatives and methods of making the compounds, but the disclosed compounds and methods are different from the present invention.

Further reference is made to related applications filed on even date herewith, attorney Docket numbers PC10523, PC10546, PC10690, PC10691, PC10698 and PC11848, which relate to other types of nicotinamide derivatives useful as inhibitors of isoenzymes of PDE4, the disclosures of all of which are hereby incorporated by reference in their entirety.

2.0 background of the invention

The 3 ', 5' -cyclic nucleotide Phosphodiesterases (PDEs) comprise a large class of enzymes, at least divided into eleven distinct families, which differ significantly from each other structurally, biochemically and pharmacologically. Enzymes within the same family are generally referred to as isoenzymes or isoenzymes. A total of more than fifteen gene products are included in this family, with further differences due to specific splicing and post-translational processing of these gene products. The present invention relates to four gene products of the PDE fourth family, namely PDE4A, PDE4B, PDE4C and PDE4D, whose inhibitory effects include the selective inhibition of PDE 4D. These enzymes are collectively referred to as isomerases or subtypes of the PDE4 isozyme family. The genomic organization, molecular structure and enzymatic activity, specific splicing, translational regulation and phosphorylation, distribution and expression, and selective inhibition of the PDE4 isozyme subtype are discussed in detail below.

PDE4 is characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3 ', 5' -cyclic monophosphate (cAMP), and sensitivity to rolipram inhibition. A number of selective inhibitors of PDE4 have been discovered in recent years, and the beneficial pharmacological effects of such inhibition have been shown in various disease models, see, for example, Torphy et al, environ. health Perfect.102Suppl.10, 79-84, 1994; duplantier et al, j.med.chem.39120-125, 1996; schneider et al, Pharmacol, biochem, Behav, 50211-217, 1995; banner and Page, Br.J.Pharmacol.11493-98, 1995; barnette et al, j.pharmacol.exp.ther.273674-679, 1995; wright et al, "a selective phosphodiesterase 4 inhibitor, CP-80633 differential in bronchial relaxation in vitro and in vivo" Can.J. physiol Pharmacol.751001-1008, 1997; manabe et al, "a phosphodiesterase 4 and 1 inhibitor, the anti-inflammatory and bronchodilatory properties of KF 19514)," eur.j.pharmacol.33297-107, 1997; and Ukita et al, "new, potent and selective phosphodiesterase 4 inhibitors as antiasthmatic agents: synthesis and biological activity of a series of 1-pyridylnaphthalene derivatives, "J.Med.chem.421088-1099, 1999. Accordingly, there has been considerable interest in the art in finding more potent selective inhibitors of PDE 4.

The invention also relates to the use of selective PDE4 inhibitors for the improved treatment of a wide range of inflammatory, respiratory and allergic diseases, but is particularly useful in the treatment of asthma, Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis, emphysema and bronchiectasis, chronic rhinitis and chronic sinusitis.However, to date, the first treatment options in the art for asthma and other known obstructive airways diseases are the non-selective PDE inhibitors theophylline, and pentoxifylline and IBMX, which can be represented by the formulae (0.0.1), (0.0.2) and (0.0.3), respectively:

theophylline, which targets PDE as one of its biochemical targets, in addition to having a well-characterized bronchodilating effect, also increases pulmonary arterial pressure to affect the patient's vasculature, inhibits inflammatory cell responses, and induces apoptosis of neutrophils. However, the adverse effects of theophylline, most commonly cardiac dysrhythmia and nausea, are also mediated by PDE inhibition, which has led to the search for more selective inhibitors of PDEs that inhibit immune cell function in vitro and allergic lung inflammation in vivo, with improved side effects. In the trachea of patients with asthma and other obstructive airways diseases, PDE4 is the most important PDE isoenzyme targeted as a drug because it is distributed in airway smooth muscle and inflammatory cells. Several PDE4 inhibitors used in the art to date have been assigned an improved therapeutic index with respect to the cardiovascular, gastrointestinal and central nervous system side effects of the above-mentioned non-selective xanthines.

Airway obstruction and airway inflammation are features of asthma, and COPD, the prominent feature of bronchial asthma is eosinophilic inflammation, while neutrophils play a major role in the pathogenesis of COPD. PDE is involved in smooth muscle relaxation and is found in both eosinophils and neutrophils, and therefore, it may be an essential element of the progression of both diseases. The PDEs involved included PDE3 and PDE4, and it was found that bronchodilator inhibitors were selective PDE3 inhibitors and dual selective inhibitors of PDE 3/4. Examples are milrinone, a selective PDE3 inhibitor, and zadavalin and phenicol, both of which are dual selective inhibitors of PDE3/4, which may be represented by formulas (0.0.4), (0.0.5) and (0.0.6), respectively

However, with administration by inhalation, phenicol only causes bronchodilation whereas zadavirin only causes moderate short-term bronchodilation, milrinone is a cardiotonic, causes short-term bronchodilation and produces a mild protective effect on induced bronchoconstriction, but it has significant side effects, e.g. tachycardia and hypotension. The weakly selective PDE4 inhibitor, sulfanilast, and the selective PDE5 inhibitor, zaprinast, also give unsatisfactory results and can be represented by the formulae (0.0.7) and (0.0.8), respectively:

With the discovery and development of selective PDE4 inhibitors, more relevant successful advances have been made in the art.

In vivo, PDE4 inhibitors reduce eosinophil influx into the lungs of allergen-challenged animals, while also reducing bronchoconstriction and the elevated bronchial response that occurs after allergen challenge. PDE4 inhibitors also inhibit immune cell activity, including CD4⁺T-lymphocytes, monocytes, mast cells and basophils; reduce pulmonary edema; inhibiting excitatory, non-adrenergic, non-cholinergic neurotransmission (eNAC); potentiating inhibitory, non-adrenergic, non-cholinergic neurotransmission (iNANC); reducing mitogenesis of tracheal smooth muscle, and reducing bronchiectasis. PDE4 inhibitors also inhibit the activity of a number of inflammatory cells associated with COPD pathophysiology, including monocytes/macrophages, CD8⁺T-lymphocytes and neutrophils. PDE4 inhibitors also reduce mitogenesis of vascular smooth muscle and strongly interfere with the ability of airway epithelial cells to produce pro-inflammatory mediators. Neutrophils, by releasing neutral proteases and acid hydrolases from their granules, and generating reactive oxygen species, produce chronic inflammation-related damage to tissues and are further implicated in the pathology of some conditions, such as emphysema.

Combinations have been found to dateTherapeutically advantageous PDE4 inhibitors include SB-207,499, identified under the trademark ARIFLO , which may be represented by formula (0.1.9):

in a study involving a large number of patients, SB-207,499 was administered orally at doses of 5, 10 and 15mg b.i.d., with a significant increase in FEV1 trough (trough) (forced expiratory volume of 1 second) already at week 2 compared to the placebo group. Another potent and selective PDE4 inhibitor, CDP840, showed inhibition of late phase reactions to inhaled allergens 9.5 days after oral administration at doses of 15 and 30mg in the bronchial asthma patient population. CDP840 may be represented by formula (0.0.9):

PDEs have also been investigated as a potent treatment for lung obstructive diseases, including COPD. In a large study of SB-207,499 on COPD patients, the group of patients receiving the 15mg b.i.d. dose experienced FEV compared to the 160mL placebo group₁The trough gradually improved, reaching a maximum mean difference at week 6, which represents an increase of 11%. See Compton et al, "second generation oral PDE4 inhibitor, efficacy of Ariflo (SB207499) on COPD patients," am.j.respir.crit.care med.159, 1999. It has been observed that severe COPD patients have pulmonary hypertension and that in clinical conditions, a reduction in mean pulmonary arterial pressure can be achieved by oral administration of the selective PDE3 inhibitors milrinone and enoximone. Enoximone also reduces airway resistance in COPD hospitalized patients with metabolic disorders. See Leeman et al, Chest 91662-6, 1987. Using the selective PDE3 inhibition of motapidone and the selective PDE5 inhibition of zaprinast, it has been demonstrated that the combined inhibition of PDE3 and 5 produces a relaxation effect on the pulmonary artery loop, which corresponds broadly to the PDE isozyme pattern found in the pulmonary artery smooth muscle, see Rabe et al, am.j. physio.266(LCMP 10): L536-L543, 1994. The structures of milrinone and zaprakast are shown in formulas (0.0.4) and (0.0.8) above, respectively. The structures of enoximone and motapidone can be represented by formulas (0.0.10) and (0), respectively. 0.11) represents:

the efficacy of PDE4 inhibitors on different inflammatory cell responses may serve as a basis for the description and selection of inhibitors for further study. These include elevation of cAMP and inhibition of peroxide production, degranulation, chemotaxis and tumor necrosis factor alpha (TNF α) release in eosinophils, neutrophils and monocytes. PDE4 inhibitors can cause emesis, namely nausea and vomiting, which, as predicted, is a side effect. When PDE4 inhibitors were first used in studies of CNS indications (e.g., depression), and rolipram and denbufylline were used in clinical trials, the vomiting side effects became apparent and rolipram and denbufylline may be represented by formulas (0.0.12) and (0.0.13), respectively:

the mechanism by which PDE4 inhibitors can strongly cause emesis is uncertain. However, one study of the PDE4 inhibitor Ro-20-1724 suggested that nausea and vomiting are mediated, at least in part, by the centers of emesis in the brain. Gastrointestinal side effects can be caused by local effects, for example rolipram is a powerful stimulator of acid secretion by gastric parietal cells, and gastrointestinal disorders can be exacerbated by excess acid produced by producing local stimulation. Ro-20-1724 can be represented by formula (0.0.14):

Efforts to reduce or eliminate the above-mentioned side effects sometimes associated with PDE4 inhibitors include preparing inhibitors that do not have a penetrating effect on the central nervous system, and administering PDE4 inhibitors by inhalation instead of orally.

For PDE4 isoforms A, B, C and D, PDE4C has been found to be generally less sensitive to all inhibitors, however, for isoforms A, B and D there is no clear evidence for inhibitor specificity, defined as IC₅₀The values differ by a factor of 10. Although most inhibitors, especially RS-25,344 against PDE4D is more potent, but this is not equal to selectivity. RS-25,344 may be represented by the formula (0.0.15):

on the other hand, in various cells, there is a stereoselective effect on the cAMP elevation, which is demonstrated in the results of studies on CDP840 as shown in formula (0.0.9) and its less active enantiomer, CT-1731, which can be represented by formula (0.0.16):

it is now known that rolipram interacts with a high affinity binding site on the meninges, and this high affinity binding site (S) for rolipram has been subsequently identified in the art_r) Is distinctly different from catalytic site (S)_c) It is present in both the truncated recombinant PDE4A and the full-length recombinant PDE 4B. Recently, S has been found on all four PDE4 subtypes _rSee Hughes et al, Drug discovery today2(3)89-101, 1997. S_rHave profound effects on the ability of some inhibitors, such as rolipram and RS-25,344, to inhibit the isozyme catalytic activity of PDE 4.

Also noteworthy is the effect of the residue on inhibitor binding, and it has been demonstrated that a substitution of only one amino acid (alanine for aspartic acid) in the catalytic region of PDE4B is crucial for the inhibitory effect of rolipram, and this shows a class of effects, since the relevant inhibitors RP-73,401 and Ro-20-1724 likewise lose potency with respect to the mutant enzyme. However, for elevation of cAMP and suppression of cellular response, the inhibitor is on S_cOr S_rThe binding effect of (c) is not yet fully understood.

In guinea pig studies, RP-73,401 was found to be active in the following respects: (1) inhibiting antigen-induced lung eosinophilia and eosinophil peroxidase (EP0), Banner, k.h., "effect of selective phosphodiesterase inhibitors on guinea pig intratracheal antigen-induced eosinophilia as compared to other anti-asthma drugs", palmcol.837-42, 1995; (2) antigen-induced bronchoalveolar lavage (BAL) eosinophilia, Raeburn et al, "novel selective phosphodiesterase type IV inhibitor, anti-inflammatory and bronchodilator properties of RP 73401", br.j.pharmacol.1131423-1431, 1994; (3) antigen-induced eosinophilia and Platelet Activating Factor (PAF) -and ozone-induced Airway Hyperresponsiveness (AHR), Karlsson et al, "anti-inflammatory action of a novel phosphodiesterase type IV inhibitor RP 73401", int. arch. allergy immunol.107425-426, 1995; and (4) IL-5 induced pleuropyneogranulocytosis. The development of RP-73,401, piclamilast, has been discontinued. Piclamilast can be represented by formula (0.0.17):

Representative of the related series are RPR-132294 and RPR-132703, which have been found to have inhibitory activity against antigen-induced bronchospasm in murine studies; escott et al, "pharmacological profile of phosphodiesterase 4(PDE4) inhibitors and treatment rate analysis for mice and dogs", br.j.pharmacol.123(proc.suppl.) -40P, 1998; and Thuuraratam et al, "summary of biological Activity and side effects of RPR-132294 and RPR-132703-novel PDE4 inhibitors", XV^thEFMC iht.symp.med.chem., 1998. The structure of RPR-132294 can be represented by formula (0.0.18):

another compound that has been discontinued is WAY-PDA-641, filaminast, which has been found to have an inhibitory effect on bronchoconstriction caused by 5-hydroxytryptamine (seriatonin) in a study in dogs. Filamast can be represented by formula (0.0.19):

it has been proposed in the art to use S_rPDE4 inhibitors with high affinity may be associated with emesis and increased gastric acid secretion. RS-23,544, RP-73,401 and CP-80,633 cause emesis and contrast with S_rHas high affinity. CDP840 and SB-207,499 vs S_rHas a relative lowBut CDP840 at S_cHas significantly higher efficacy than SB-207,499. CDP840 has been shown to have significant suppression of the post-phase response in the treatment of asthma without any nausea or headache side effects. Another PDE4 inhibitor with nausea and vomiting side effects is BRL-61,063, also known as cipamfylline, described further below.

The development of CDP840 has been discontinued, and CP-80,633, atizoram, is under continued development. CP-80,633 and BRL-61,063 may be represented by formulas (0.0.20) and (0.1.12), respectively:

another compound under development is LAS-31025, arofylline, which has been found to have inhibitory effects on antigen-induced bronchoconstriction in guinea pig studies, Beleta, b.j., a characterization of LAS 31025: a novel selective PDEIV inhibitor for bronchial asthma ", 3 rd international conference on cyclic nucleotide phosphodiesterases: from gene to therapy, Glasgow, UK, 1996, abstract 73. LAS-31025, aroxylline, may be represented by formula (0.0.21):

many PFE4 inhibitors have also been shown to have enhanced effects on in vitro TNF release and PHA-induced lymphocyte proliferation under LPS-stimulation in a randomized, double-blind placebo-controlled study, which found that an oral dose of 300mg was effective in reducing TNF levels and lymphocyte proliferation, landalls et al, "Phosphodiesterase (PDE)4 inhibitors," oral administration of V11294A inhibited agonist-induced cell activation in vitro, "eur.resp.j.12 (suppl.28)362s, 1998, and Gale et al," Phosphodiesterase (PDE)4 inhibitors, "pharmacodynamic-pharmacokinetic (PD/PK) profile of V11294A in volunteer human subjects," am.j.respir.crit.care.159a 611, 1999.

In a single escalating dose, randomized, placebo-controlled phase I study, compound D4418 pairs have been administeredAdministration was performed in healthy volunteers, Montana et al, "novel Phosphodiesterase (PDE)4 inhibitor, D4418 role in asthmatic cells and animal models and in early clinical studies", am.j.respir.crit.care med.159 a108, 1999. D4418 is a moderately potent PDE4 inhibitor, IC₅₀Was 200 nM. It has good oral absorption effect, and can obtain blood C of 1.4 μ g/ml at a dose of 200mg_max. D4418 has been discontinued due to its moderate potency and was replaced by candidate compound D4396 in preclinical development.

V-11294A and D4418 can be represented by formulas (0.0.22) and (0.0.23), respectively:

another compound, CI-1018, has been tested in 54 subjects and found to have no side effects at doses up to 400mg, Pruniaux et al, "novel Phosphodiesterase (PDE)4 inhibitor CI-1018 inhibits antigen-induced pulmonary eosinophilia in sensitized brown mice-in contrast to rolipram", Inflammation S-04-6, 1999. CI-1018 has been shown to have good oral bioavailability (57% in rats) and good oral efficacy, ED in the same species ₅₀It was 5 mg/kg. CI-1018 is a relatively weak PDE4 inhibitor, IC in U937 cells₅₀At 1.1. mu.M. CI-1018 has been identified as, or structurally closely related to, PD-168787, and studies in mice have demonstrated that PD-168787 has an inhibitory effect on antigen-induced eosinophilia, Pascal et al, "4-oxo-1-phenyl-3, 4, 6, 7-tetrahydro- [1, 4]-diaza  o [6, 7, 1-hi]Indoline: synthesis and Structure-Activity relationship for novel PDE4 inhibitors ", 215^thACS, Dallas, USA, MEDI50, 1998. The deduced structures of CI-1018 and PD-168787 are of the diaza  ketone class, whose parent nucleus can be represented by formula (0.0.24):

the above compounds have been tested in animal models disclosing PDE4 inhibitory activity, e.g., they have been testedV-11294A was found to have inhibitory activity on bronchoconstriction in guinea pig studies, Cavalla et al, "novel phosphodiesterase 4(PDE4) inhibitors, role of V11294A in asthma cells and animal models", amer.j.respir.crit.care Med, 155a660, 1997. It has been found that D4418 has inhibitory activity against antigen-induced early and late phase bronchoconstriction and BAL eosinophilia in guinea pig experiments, Montana, et al, supra. It has been found that CI-1018 has inhibitory activity against antigen-induced eosinophilia in murine assays, Burnouf et al, "pharmacology of the novel phosphodiesterase type 4 inhibitor CI-1018", 215 ^thACS Nat.Meeting，MEDI 008，1998。

Other compounds in development enhancement stage include CDC-3052, D-22888, YM-58997 and roflumilast, which can be represented by formulas (0.0.27), (0.0.28), (0.0.29) and (0.0.30), respectively:

CDC-3052 has been discontinued, but has been superseded by very potent PDE4 inhibitors, compounds of formula (0.0.31), anti-inflammatory compounds of formula (0.0.32), respectively:

the compounds of formula (0.0.32) are reported to have IC's of 42pM and 130nM as PDE4 inhibitors and TNF production inhibitors, respectively₅₀Values, Muller et al, "N-phthaloyl β aryl- β -amino derivatives: potent TNF-alpha and PDE4 inhibitors "217^thAmerican chemical Society, Annheim, Germany, MEDI200, 1999, and Muller et al, "thalidomide analogs and PDE4 inhibition", bioorg. Med. chem. letters.82669-2674, 1998.

CDC-801 is derived from a series of compounds based on thalidomide and was first developed to ameliorate the TNF- α inhibitory effects of thalidomide in the treatment of autoimmune diseases. Thalidomide may be represented by formula (0.0.33):

CDC-801 has also been studied in the treatment of Crohn's disease, a chronic granulomatous inflammatory disease of unknown etiology, often involving the terminal ileum, with scarring and thickening of the intestinal wall, often leading to ileus and the formation of intestinal fistulas and abscesses. Crohn's disease has a high rate of recurrence after treatment.

YM-58997 has an IC of 1.2nM for PDE4₅₀Value, Takayama et al, "synthetic studies of Selective phosphodiesterase type IV (PDEIV) inhibitors", 214^thAmerican chemical Society, Las Vegas, USA, MEDI245, 1997. YM-58997 has the structure of 1, 8-naphthyridin-2-one, like YM-976.

Roflumilast has been studied for the treatment of COPD and asthma; it has an IC of 3.5nM in a standard in vitro guinea pig model of asthma₅₀The value is obtained. The use of Roflumilast and surfactants in the treatment of Adult Respiratory Distress Syndrome (ARDS) has been described.

AWD-12,281 (now known as loteprednol) has been shown to be active in an animal model of allergic rhinitis, as described in the section below relating to allergic rhinitis and treatment with PDE4 inhibitors. AWD-12,281 can be represented by formula (0.0.34):

compounds structurally related to CDP840 (as shown above in formula (0.0.9)) include L-826, 141, which is reported to be active in murine models of bronchitis, Gordon et al, "anti-inflammatory effects of PDE4 inhibitors in murine models of model bronchitis," am.j.respir.crit.caremed.159 a33, 1999. Another such compound is structurally related to the compounds reported by Perrier et al, see "substituted furan compounds as inhibitors of the isoenzyme PDE 4", bioorg, med, chem, letters, 9323-326, 1999, which is represented by formula (0.0.35):

Other compounds which have been found to be very potent inhibitors of PDE4 are compounds represented by formulae (0.0.36), (0.0.37) and (0.0.38):

compounds have been produced which have both PDE4 and Matrix Metalloproteinase (MMP) inhibitory activity within a single molecule; groneberg et al, "dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by arylsulfonyl hydroxamic acid templates", J.Med.chem.42(4)541-544, 1999. Two examples of such compounds can be represented by formulas (0.0.39) and (0.0.40):

IC of Compounds of formula (0.1.36) and (0.1.37) Using guinea pig macrophage PDE4 assay₅₀Values were 1nM and 30nM, respectively.

It has been demonstrated that the compounds KF19514 and KF17625 have the following inhibitory activities in guinea pig experiments: histamine-and antigen-induced bronchoconstriction; PAF-induced eosinophilia and antigen-induced BAL eosinophilia and neutrophilia, acetylcholine (ACh) -induced AHR; PAF-induced eosinophilia and antigen-induced BAL eosinophilia and neutrophilia, and AHR; antigen-induced bronchospasm; and allergic bronchoconstriction; fujimura et al, "bronchoprotective effects of KF-19514 and cilostazol in guinea pig in vitro tests", Eur.J. Pharmacol.32757-63, 1997; manabe et al, supra; manabe et al, "phosphodiesterase 4 and 1 inhibitors KF19514 inhibit PAF-induced pulmonary inflammatory responses in guinea pig trials by inhalation administration", int. arch. allergy 114389-399, 1997; suzuki et al, "novel bronchodilators: 3. imidazo [4, 5-c) ][1，8]Naphthyridin-4 (5H) -one ", j.med.chem.354866-4874, 1992; matsuura et al, "substituted 1, 8-naphthyridine (naphthyridine) -2(1H) -ones as selective phosphodiesterase IV inhibitors", biol. pharm. Bull.17(4)498-503, 1994; and Manabe et al, "New BranchBronchodilators, pharmacological properties of KF17625 ", jpn.j. pharmacol.58(suppl.1)238P, 1992. KF19514 and KF17625 may be represented by formulas (0.0.41) and (0.0.42):

the reported potency performance and absence of emetic side effects of the series 2, 3-dihydro-1, 3-indandione (indandione) suggests that the hypothesis of correlating side effects such as emetic with the affinity ratio for the PDE4 enzyme and for the High Affinity Rolipram Binding Site (HARBS) is erroneous. These 2, 3-dihydro-1, 3-indandiones can be represented by formulas (0.0.43) and (0.0.44):

r is benzyloxy (0.0.43)

R ═ 1, 4 '] -piperidinyl-1' -carbonyloxy (0.0.44)

The PDE4 inhibitors that have been invented to date can be divided into many different classes according to their chemical structures. These types can be viewed as derivatives of phenanthridines and naphthyridines. One class of PDE4 inhibitors are lignans such as T-440, which have been shown to have the following inhibitory activity: early bronchoconstriction induced by antigen, histamine, LTD4, U-46619, Ach, neurokinin A and endothelin-1; antigen-induced early and late bronchoconstriction and BAL eosinophilia; ozone-induced AHR and tracheal epithelial injury. Optimization of the PDE4 inhibitory potency of these compounds led to the discovery of T-2585, one of the most potent PDE4 inhibitors reported to date, which has an IC for guinea pig pulmonary PDE4 ₅₀The value was 0.13 nM. T-440 and T-2585 may be represented by formulas (0.0.45) and (0.0.46):

another class of PDE4 inhibitors consists of benzofurans and benzothiophenes, specifically, the substitution of the pharmacophore cyclopentyl ether of rolipram with furan and chroman rings, an example of which is structurally distinct from BAY19-8004A related compound, which may be represented by formula (0.0.47):

another benzofuran-type compound is reported to have an IC of 2.5nM₅₀The value, may be represented by equation (0.0.48):

a compound of related structure, but not a benzofuran, can be described by a fused dioxacin ring, reported to produce almost complete inhibition of canine tracheal PDE4 at 100nM, and can be represented by formula (0.0.49):

quinones and quinolones are another class of structures of PDE4 inhibitors that replace the catechol structure of rolipram, and the compounds and two structurally similar compounds may be represented by formulas (0.0.50), (0.0.51) and (0.0.52):

the purine, xanthine and pteridine classes also represent another class of compounds to which PDE4 inhibitors have been reported in the art to date, and the above compound V-11294A represented by formula (0.0.22) is a purine which is a PDE4 inhibitor of xanthine compounds to which theophylline belongs and is described in the art; montana et al, "PDE 4 inhibitors, novel xanthine analogs", bioorg. Med. chem. letters.82925-2930, 1998. The xanthine compound may be represented by formula (0.0.54):

It has been shown that a potent PDE4 inhibitor belonging to the pteridine class of compounds has an IC of 16nM for tumour cell derived PDE4₅₀And inhibit tumor growth at large molarity; merz et al, 7-benzylamino-6-chloro-2-piperazin-1-yl-4-pyrrolidinyl-pteridine and the synthesis of novel derivatives free of positional isomers,cAMP-specific phosphodiesterase and potent inhibitors of malignant cell growth, J.Med.chem.41(24) 4733-. The pteridine PDE4 inhibitor may be represented by formula (0.0.55):

triazines represent another class of compounds to which PDE4 inhibitors have been described to date in the art. Two triazine compounds are described to exhibit bronchodilator activity in a guinea pig tracheal model and are potent relaxants. These compounds can be represented by the following formulae (0.0.56) and (0.0.57), which are also moderately potent PDE4 inhibitors with IC's of 150 and 140nM, respectively₅₀The value:

a triazine compound having a putative structure closely related to formulae (0.0.56) and (0.0.57) is UCB-29936, which has been shown to be active in a murine model of septic shock; danhaive et al, "UCB 29936, selective inhibitor of phosphodiesterase type IV: potent treatment of endotoxic shock ", am.j.respir.crit.care.med.med.159 a611, 1999.

Efforts have also been made in the art to improve the selectivity of PDE4 inhibitors for the above-mentioned subtypes A-D. There are currently four known PDE4 isozyme isoforms (subtypes), including 7 splice variants, as described above. The mRNA of PDE4D isoforms is expressed in inflammatory cells, such as neutrophils and eosinophils, and it has been suggested in the art that D-selective inhibitors of PDE4 give good clinical results with reduced side effects. The inhibition of the PDE4D isoform by nicotinamide derivatives shows selectivity and has been described in WO 98/45268; naphthyridine derivatives have also been reported as selective inhibitors of PDE4D in WO 98/18796. These compounds may be represented by formulas (0.0.58) and (0.0.59), respectively:

another nicotinamide compound is described in the art, which can be used for the treatment of CNS disorders, such as multiple sclerosisScleroderma, GB-2327675; the art describes a rolipram derivative which is a PDE4 inhibitor which binds to both the catalytic site and the HARB site on human PDE4B2B with equal affinity, Tian et al, "(R, R) - (+/-) -methyl-3-acetyl-4- [3- (cyclopentyloxy) -4-methoxyphenyl-]Double inhibition of the human phosphodiesterase type IV isoform by methyl 3-methyl-1-pyrrolidinecarboxylate, Biochemistry37(19)6894-6904, 1998. These nicotinamide derivatives and rolipram derivatives may be represented by formulae (0.0.60) and (0.0.61), respectively:

Further information on background relating to selective PDE isozymes may be found in prior publications in the art, e.g., Norman, "PDE 4 inhibitor, 1999", exp. Opin. Ther. Patents9(8)1101-1118, 1999(Ashley published Co., Ltd.); and Dyke and Montana, "therapeutically potent PDE4 inhibitors", exp. opin. invest. drugs8(9) 1301-.

3.0 State of the Art

WO98/45268(Marfat et al), published in 1998 at 10/15, discloses active nicotinamide derivatives as selective inhibitors of the PDE4D isozyme, which are represented by the formula (0.1.1):

US4,861,891(Saccomano et al), issued 8/29 in 1989, discloses nicotinamide compounds of formula (0.1.2) which can be used as antidepressants as calcium-independent c-AMP phosphodiesterase inhibitors:

the nicotinamide core of the typical compounds disclosed in this patent is directly bound to R¹A group defined by 1-piperidinyl, 1- (3-indolyl) ethyl, C₁-C₄Alkyl, phenyl, 1- (1-phenylethyl) or benzyl, optionally mono-substituted with methyl, methoxy, chloro or fluoro; r²The substituent being bicyclo [2.2.1]Hept-2-yl or a group of the formula: Wherein Y is H, F or Cl; and X is H, F, Cl, OCH₃、CF₃、CN、COOH、-C(＝O)(C₁-C₄) Alkoxy, NH (CH)₃) C (═ O) - (methylcarbamoyl) or N (CH)₃)₂C (═ O) - (dimethylcarbamoyl).

US4,692,185(Michael et al) discloses herbicides of formula (0.1.3):

wherein R is (C)₁-C₄) Alkyl, (C)₁-C₄) Haloalkyl or halogen. EP550900(Jeschke et al) discloses herbicides and plant nematicides of formula (0.1.4)

(0.1.4) wherein n is 0-3; r¹Selected from a large number of radicals, but generally H, 6-CH₃Or 5-CI; r²Is alkyl, alkenyl, alkynyl, aryl or aralkyl; r1 and R2 are halogen, CN, NO₂Alkyl, haloalkylalkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy or arylthio; and R is⁴Is an alkyl group.

EP500989(Mollner et al) discloses ACE inhibitors of formula (0.1.5):wherein n is 0 to 3; r is OH, SH, COOH, NH₂Halogen, OR₄、SR₄、COOR₄、NHR₄Or N (R)₄)₂Wherein R is₄Is lower alkyl, optionally substituted aryl or acyl; r₁Is OH, lower alkoxy, optionally substituted aryl lower alkoxy, aryloxy or di-substituted amino; r₂Is lower alkyl or amino lower alkyl; and R1 and R2 are halogen, NO₂Lower alkyl, halogenated lower alkyl, Aryl lower alkyl or aryl. Particular embodiments disclosed include compounds of formula (0.1.6):

FR2.140.772(Aries) discloses compounds of formula (0.1.7) claimed to have analgesic, sedative, antipyretic, anti-inflammatory and antirheumatic effects:wherein R is 1 or 2 substituents selected from the group consisting of lower alkyl, trihalomethyl, alkoxy and halogen; r' is H or alkyl; r' is hydrogen or alkyl.

JP 07304775 (Otsuka et al) discloses 1, 5-naphthyridine and pyridopyrazine derivatives which have anti-inflammatory, immunomodulatory, analgesic, antipyretic, antiallergic and antidepressant effects. Also disclosed are intermediates of formula (0.1.8):wherein X may be CH and R' are each lower alkyl. With respect to the disclosure of the above patents and published patent applications, it is to be understood that only the disclosure of WO98/45268(Marfat et al) relates to the inhibition of the PDE4 isozyme. The state of the art also includes information about compounds which are completely different in chemical structure from the compounds of formula (1.0.0) of the present invention, but which, on the other hand, have biological activity similar to that of the compounds of formula (1.0.0). Representative patents and published patent applications disclosing the above information are set forth below.

US5,552,438, US5,602,157 and US5,614,540 (both inventors Christensen) share the same priority date, 1992, 4/2, and all relate to a therapeutic agent called ARIFLO  which is a compound of formula (0.1.9) and is named as follows:

ARIFLO  cis- [ 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl)

Cyclohexane-1-carboxylic acid (0.1.9)

Compounds of formula (0.1.9) fall within the scope of US5,552,438, which discloses a class of compounds of formula (0.1.10):wherein R is₁＝-(CR₄R₅)_rR₆Wherein R is 0 and R₆-C_3-6A cycloalkyl group; x ═ YR₂Wherein Y is O, R₂＝-CH₃；X₂＝O；X₃＝H；X₄A group of the partial formula (0.1.10.1):wherein X₅H; s is 0; r1 and R2 ═ CN; z ═ C (O) OR₁₄Wherein R is₁₄H. The disclosures of US5,602,157 and US5,614,540 differ from US5,552,438 and are each other with respect to the group R₃Also differently defined, in the ARIFLO  compound is CN. A preferred salt form of the disclosed ARIFLO  compound is the tris (hydroxymethyl) methylammonium salt.

US5,863,926(Christensen et al) discloses analogues of compounds of ARIFLO , for example compounds of formula (0.1.11):

WO99/18793(Webb et al) discloses a process for the preparation of ARIFLO  and related compounds. WO95/00139(Barnette et al) claims compounds which bind with high affinity to the IC of the PDE IV-catalyzed form of rolipram (rolipram) ₅₀Divided by IC in the form of rolipram binding with low affinity₅₀The resulting IC₅₀A ratio of about 0.1 or greater; however, in the dependent claims, the scope is defined as a compound that is not known to be a PDE4 inhibitor until 21.6.1993.

WO99/20625(Eggleston) discloses a polymorphic form of cipamfylline of formula (0.1.12) for use in the treatment of PDE4 and TNF mediated diseases:

WO99/20280(Griswold et al) discloses a method of treating pruritus by administering an effective amount of a PDE4 inhibitor, such as a compound of formula (0.1.13):

US5,922,557(Pon) discloses the inhibition of the CHO-K1 cell line, which stably expresses high levels of full-length low-Km cAMP specific PDE4A enzyme, which in turn was used to test for effective PDE4 enzyme inhibitors and to compare their ability to inhibit phosphodiesterase activity in a fragmented cell preparation to compare their level of efficacy in raising cAMP in whole cell preparations. Furthermore, it is said that it has been found that the measurement of the inhibitory effect of soluble enzymes described in the prior art does not reflect the action behaviour of the inhibitor in vivo. An improved whole cell assay for soluble enzymes has been disclosed which is said to reflect the action of inhibitors in vivo. In addition, the presence of at least four different isoforms or subtypes of PDE4 is disclosed, and it has been demonstrated that each isoform forms a number of splice variants that exhibit different cellular localization and affinity for inhibitors.

With respect to the disclosure of the above patents and published patent applications, it is understood that the compounds referred to have the same biological activity as the compounds of formula (1.0.0), but at the same time the skilled artisan will observe that the chemical structures of the above compounds disclosed in the prior art are not only different from each other, but also from the structures of the novel compounds of the present invention. The state of the art also includes the information on compounds that differ in chemical structure from the compound of formula (1.0.0) and do not have PDE4 inhibitor activity similar to the compound of formula (1.0.0). Nevertheless, these compounds disclosed in the prior art are often used for therapeutic utility similar to the compounds of formula (1.0.0), i.e. for the treatment of inflammatory, respiratory and allergic diseases. In particular, this applies to certain enzyme inhibitors and antagonists of the so-called leukotriene pathway receptor, especially for leukotriene LTB₄And LTD₄The situation (2). Thus, representative patents and published patent applications disclosing further such intelligence are described belowPlease note.

Arachidonic acid is metabolized by cyclooxygenase-1 and 5-lipoxygenase, and the 5-lipoxygenase channels lead to the production of Leukotrienes (LTs) which elicit an inflammatory response through their effects on neutrophil aggregation, degranulation and chemotaxis, vascular permeability, smooth muscle contractility, and on lymphocytes. Cysteinyl leukotrienes, LTC ₄、LTD₄And LTE₄Plays an important role in the pathogenesis of asthma. The composition of leukotriene channels provides a target for therapeutic intervention, as illustrated in the following figures:

thus, agents that intervene in the 5-lipoxygenase pathway at any step provide therapeutic opportunities. An example of such an agent is the 5-lipoxygenase inhibitor zileuton (zileuton), a therapeutic agent identified as ZYFLO , which can be represented by formula (0.1.14):

another such agent is LTD₄The receptor antagonist zafirlukast, a therapeutic agent identified as ACCOLATE , which may be represented by formula (0.1.15):

another LTD₄The receptor antagonist is montelukas, a therapeutic agent identified as singulir , which can be represented by formula (0.1.16):

another class of such therapeutic target targets is LTB₄A receptor, an example of an antagonist of the receptor being BIIL-260, a therapeutic agent that can be represented by formula (0.1.17):

LTB₄another example of a receptor-antagonizing therapeutic agent is CGS-25019c, which may be represented by formula (0.1.18):

the above-mentioned state of the art does not disclose or suggest to the skilled person the novel compounds of the present invention or their PDE4 inhibitory activity, as well as the therapeutic utility and therapeutic index resulting in significant improvements in the treatment of inflammatory, respiratory and allergic diseases and conditions.

4.0 summary of the invention

The present invention relates to novel compounds having the biological activity of inhibitors of phosphodiesterase, the so-called "type IV" isozyme (PDE4 isozyme). Some embodiments of the novel compounds of the present invention are effective as nonselective inhibitors of the PDE4 isozyme, while other embodiments of the compounds are specific for PDE4 isozyme substrates, particularly the D subtype. Said novel compounds having activity as non-selective or D-selective PDE4 inhibitors are generally useful in the treatment of a variety of inflammatory, allergic and respiratory diseases and conditions, and in particular they provide significant improvements in the treatment of obstructive respiratory diseases, especially asthma and Certain Obstructive Pulmonary Diseases (COPD).

The present invention relates to compounds of formula (1.0.0) or a pharmaceutically acceptable salt thereof:

wherein

-m is 0, 1 or 2;

-n is 1 or 2;

-W is-O-; -S (═ O)_t-, where t is 0, 1 or 2; or-N (R)³)-，R³Have the meanings as described below;

-Y is ═ C (R)^E) -, or- [ N → (O)]-；

Wherein

--R^ESelected from-H, -F, -Cl, -CN, -NO₂、-(C₁-C₄) Alkyl, (C)₂-C₄) Alkynyl, fluoro-(C₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, fluoro (C)₁-C₃) Alkoxy, -OH and-C (═ O) NH₂；

-R^AAnd R^BEach independently selected from-H, -F, -CF ₃、-(C₁-C₆) Alkyl, - (C)₃-C₇) Cycloalkyl, phenyl, benzyl; and a heterocyclic group selected from: pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl and thiadiazolyl; wherein said alkyl, cycloalkyl, phenyl, benzyl or heterocyclyl is each independently substituted with 0-3 substituents R¹⁰Substituted;

with the proviso that for R^AAnd R^BThe above meanings of and R^AAnd R^BAll other meanings apply as R^AOr R^BR of a substituent¹⁰having-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³In the meaning of (A), the said-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³And means OR¹²The positional relationship of Z of (a) is not vicinal;

wherein

--R¹⁰Selected from-F, -Cl, -CF₃、-CN、(C₁-C₂) Alkyl, OR¹²、-C(＝O)OR¹²、-O-C(＝O)R¹³、-C(＝O)NR¹²R¹³、-O-C(＝O)NR¹²R¹³、-NR¹²R¹³、-NR¹²C(＝O)R¹³、-NR¹²C(＝O)OR¹³、-NR¹²S(＝O)₂R¹³、-S(＝O)₂NR¹²R¹³；

Wherein

--R¹²And R¹³Each independently selected from-H, - (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, (C)₃-C₆) Cycloalkyl, phenyl, benzyl, and monocyclic heterocyclyl, including (C) in which the nitrogen heteroatom replaces one carbon atom₃-C₆) Cycloalkyl, a 5-or 6-membered heterocyclyl optionally substituted at a second nitrogen heteroatom by a second carbon atom and a 5-or 6-membered heterocyclyl further optionally substituted at an oxygen heteroatom by a third carbon atom; wherein said alkyl, alkenyl, cycloalkyl, phenyl, benzyl, or mono-heterocyclyl is substituted with 0-3 substituents selected from F and Cl;

-or-

Under the condition that m is 1, -R^AAnd R^BTogether form a spiro group of formula (1.1.0):

wherein

-r and s are independently 0 to 4, with the proviso that the sum of r + s is at least 1 but not more than 5;

-and-

--Q^AIs selected from-CH₂-、-CHF、-CF₂、-NR¹²-, -O-, and-S (═ O)_t-, where t is 0, 1 or 2; any one or more carbon atoms of said spiro group, including Q^ADefinition of middle-CH₂Carbon atom of (A) by 0 to 3 substituents R¹⁰Is substituted in which R¹⁰And R¹²Having the meaning defined above with the proviso that for R^AAnd R^BThe above meanings of and R^AAnd R^BAll other meanings apply as R^AOr R^BR of a substituent¹⁰having-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³In the meaning of (A), the said-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³And means OR¹²The positional relationship of Z of (a) is not vicinal;

-R^Cand R^DHaving the above-mentioned R^AAnd R^BMeaning defined, only R^CAnd R^DAt least one must be H; they are independent of one another and are selected from R^AAnd R^B；

-Q is phenyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, oxazolyl, monocyclic (C)₅-C₇) Cycloalkyl, monocyclic (C) ring selected from cyclopentenyl, cyclohexenyl and cycloheptenyl₅-C₇) Cycloalkenyl, bicyclic- (C)₇-C₁₀) Cycloalkyl or- (C)₇-C₁₀) Cycloalkenyl, preferably norbornyl, norbornenyl, bicyclo [2.2.2 ]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.0]Octyl, bicyclo [2.2.2]Oct-5-enyl, bicyclo [2.2.2]Oct-7-enyl, bicyclo [3.3.1]Nonyl and adamantyl;

-R¹and R²Each independently selected from-H, -F, -Cl, -R¹²、-OR¹²、-S(＝O)_pR¹²、-C(＝O)OR¹²、-OC(＝O)R¹²、-CN、-NO₂、-C(＝O)NR¹²R¹³、-OC(＝O)NR¹²R¹³、-NR¹⁴C(＝O)NR¹⁶R¹²、-NR¹⁴C(＝NR¹⁴)NR¹⁵R¹²、-NR¹⁴C(＝NCN)NR¹⁵R¹²、-NR¹⁴C(＝N-NO₂)NR¹⁵R¹²、-C(＝NR¹⁴)NR¹⁵R¹²、-OC(＝NR¹⁴)NR¹⁵R¹²、-OC(＝N-NO₂)NR¹⁵R¹²、-NR¹⁵R¹²、-CH₂NR¹⁵R¹²、-NR¹⁴C(＝O)R¹²、-NR¹⁴C(＝O)OR¹²、-NR¹⁴S(＝O)_pR¹³(ii) a and-S (═ O)_pNR¹²R¹³(ii) a Wherein p is 0, 1 or 2; r¹²And R¹³Have the meaning as defined above; and R is¹⁴And R¹⁵Have the meaning defined below;

-R³is-H, - (C)₁-C₃) Alkyl, - (C)₁-C₃) Alkoxy, -OH, phenyl or benzyl;

-R⁴is a group independently selected from the following groups: - (a) -H, -F, -CI, - (C)₂-C₄) Alkynyl, -R¹²、-OR¹²、-S(＝O)_pR¹²、-C(＝O)OR¹²、-OC(＝O)R¹²、-CN、-NO₂、-C(＝O)NR¹⁵R¹²、-OC(＝O)NR¹⁵R¹²、-NR¹⁴C(＝O)NR¹⁵R¹²、-NR¹⁴C(＝NR¹⁴)NR¹⁵R¹²、-NR¹⁴C(＝NCN)NR¹⁵R¹²、-NR¹⁴C(＝N-NO₂)NR¹⁵R¹²、-C(＝NR¹⁴)NR¹⁵R¹²、-OC(＝NR¹⁴)NR¹⁵R¹²、-OC(＝N-NO₂)NR¹⁵R¹²、-NR¹⁵R¹²、-CH₂NR¹⁵R¹²、-NR¹⁴C(＝O)R¹²、-NR¹⁴C(＝O)OR¹²、-NR¹⁴S(＝O)_pR¹³(ii) a and-S (═ O)_pNR¹⁵R¹²(ii) a and-CH₂C(＝NR¹⁴)NR¹⁵R¹²Wherein p is 0, 1 or 2; r¹²Have the meaning as defined above;

wherein

-R¹⁴Is selected from-H, -CH₃and-CH₂CH₃；

-R¹⁵Independently selected from-H, -C (═ O) OR¹²、-C(＝O)NR¹²R¹³、-(C₁-C₄) Alkyl, - (C)₂-C₄) Alkenyl, - (C)₁-C₂) Alkoxy, - (C)₃-C₇) Cycloalkyl and phenyl; wherein R is¹²And R¹³Have the meaning as defined above; the alkyl group, the alkenyl group; alkoxy, cycloalkyl and phenyl substituted by 0-2 substituents R²¹Substituted;

wherein

-R²¹Independently selected from-F, -CI, -C (═ O) OR²³Wherein R is²³And R²⁴Has the meaning defined as-OH, -CN, -C (═ O) NR²³R²⁴、-NR²³R²⁴、-NR²³C(＝O)R²⁴、-NR²³C(＝O)OR²⁴、-NR²³S(＝O)_pR²⁴and-S (═ O)_pNR²³R²⁴Wherein p has the meaning as defined above, - (C)₁-C₄) Alkyl (including dimethyl) and- (C)₁-C₄) An alkoxy group; wherein said alkyl and alkoxy groups are each independently substituted with 0-3 substituents independently selected from the group consisting of: -F and-CI, - (C) ₁-C₂) Alkoxycarbonyl, - (C)₁-C₂) Alkanoyl and- (C)₁-C₂) An alkylcarbonyloxy group;

wherein

R²³And R²⁴Independently is-H or- (C)₁-C₂) An alkyl group;

-R⁴further (b) is independently selected from- (C)₁-C₄) Alkyl and- (C)₁-C₄) An alkoxy group; wherein said alkyl and alkoxy are each independently substituted with 0-3 substituents-F or-Cl; or by 0 or 1 substituents (C)₁-C₂) Alkoxycarbonyl-, (C)₁-C₂) Alkylcarbonyl-or (C)₁-C₂) Alkylcarbonyloxy-substituted;

-R⁴yet further- - (c) an aryl or heterocyclic group independently selected from: phenyl, benzyl, furyl, tetrahydrofuryl, oxetanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, pyrazolyl, pyrazolidinyl, oxadiazolyl, thiadiazolyl, imidazolyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, triazolyl, triazinyl, tetrazolyl, pyranylAlkyl, azetidinyl, morpholinyl, p-thiazinyl, indolyl, indolinyl, benzo [ b ]]Furyl, 2, 3-dihydrobenzofuryl, 2-H-benzopyranyl, chromanyl, benzothienyl, 1-H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, 2, 3-naphthyridinyl, quinazolinyl, quinoxalinyl, and purinyl;

Wherein the alkyl, alkoxy, aryl and heterocyclyl are each independently substituted with 0-3 substituents R¹⁰Is substituted in which R¹⁰Have the meaning as defined above;

-R⁵and R⁶Together form a group selected from the group consisting of the radicals of the partial formulae (1.1.1) to (1.1.5):

wherein

-R⁷And R⁸Each independently is-H, -CH₃、-OR¹⁴Wherein R is¹⁴Have the meaning as defined above; or they are absent, in which case the dotted line- - - -represents a double bond;

-and-

-Z is independently selected from-OR¹²、-C(＝O)R¹²and-CN, wherein R¹²Have the meaning as defined above.

The present invention also relates to a method of treating a patient having a disease mediated by the isozyme of PDE4, which has a regulatory effect on the degranulation and activation of human eosinophils, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (1.0.0) as described above. Similarly, the invention also relates to a pharmaceutical composition for use in the above treatment comprising a compound of formula (1.0.0) above and a pharmaceutically acceptable carrier.

The present invention relates to PDE4 isozyme inhibitors containing a compound of the formula (1.0.0) above, for use in the treatment or prevention of one or more of the following diseases, disorders or conditions:

-asthma of any type, etiology or pathogenesis, or asthma selected from: atopic asthma, non-atopic asthma, allergic asthma, atopic, bronchial asthma, IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, intrinsic asthma caused by a pathophysiological disorder, extrinsic asthma caused by an environmental factor, idiopathic asthma of unexplained or nondominant etiology, nonatopic asthma, bronchial asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infection, non-allergic asthma, asthma primordial, infantile asthma syndrome;

Chronic or acute bronchoconstriction, chronic bronchitis, fine airway obstruction, and emphysema;

-an obstructive or inflammatory airway disease of any type, etiology or pathogenesis, or selected from the following: asthma, pneumoconiosis, chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), including COPD caused by chronic bronchitis, emphysema or dyspnea associated therewith, COPD characterized by irreversible, progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), and secondary exacerbation of airway hyperreactivity to other drug therapy;

-pneumoconiosis of any type, etiology or pathogenesis, or selected from the following: bauxite or aluminous diseases, charcoal or coal mining asthma, asbestos or steam pipework asthma, chalicosis or flint disease, ostrich pneumoconiosis caused by inhalation of ostrich smut, iron pneumoconiosis caused by inhalation of iron dust, silicosis or abrasionproof diseases, cotton scurf or cotton dust asthma, and talc pneumoconiosis;

-bronchitis of any type, etiology or pathogenesis, or selected from the group consisting of: acute bronchitis, laryngeal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal infectious bronchitis, and alveolar bronchitis;

-any type, etiology or pathogenesis of bronchiectasis, or bronchiectasis selected from: cylindrical bronchiectasis, cystic bronchiectasis, fusiform bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis;

-seasonal allergic rhinitis, perennial allergic rhinitis or sinusitis of any type, etiology or pathogenesis, or of sinusitis selected from the following: purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary or sphenoid sinusitis;

-rheumatoid arthritis of any type, etiology or pathogenesis, or selected from the following rheumatoid arthritis: acute arthritis, acute gouty arthritis, chronic arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, and spondyloarthritis;

-gout, fever and pain associated with inflammation;

-an eosinophil-related disorder of any type, etiology or pathogenesis, or selected from the following: eosinophilia, pulmonary infiltrative eosinophilia, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopulmonary aspergillosis, Aspergillus, eosinophil-containing rheumatic granuloma, allergic granulomatous vasculitis or Churg-Strauss syndrome, polyarticular nodules (PAN), and necrotizing systemic vasculitis;

-atopic dermatitis or allergic dermatitis, or allergic or atopic eczema;

-urticaria of any type, etiology or pathogenesis, or selected from the following: immune-mediated urticaria, complement-mediated urticaria, urticaria mediated by urticaria-causing substances, urticaria caused by physical agents, urticaria caused by stress reactions, idiopathic urticaria acute, chronic urticaria, angioedema (angioedema), cholinergic urticaria, autosomal dominant urticaria cold or acquired urticaria cold, contact urticaria, giant urticaria, and papular urticaria;

-conjunctivitis of any type, etiology or pathogenesis, or selected from the group consisting of: actinic conjunctivitis, acute catarrhal conjunctivitis, acute contagious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, suppurative conjunctivitis, and vernal conjunctivitis;

-uveitis of any type, etiology or pathogenesis, or of uveitis selected from: inflammation of all or part of the uvea, anterior uveitis, iritis, cyclitis, iridocyclitis, granulomatous uveitis, non-granulomatous uveitis, phakic uveitis, posterior uveitis, choroiditis, and choroidal retinitis;

-psoriasis;

-multiple sclerosis of any type, etiology or pathogenesis, or selected from the following multiple sclerosis diseases: primary progressive multiple sclerosis, and remission of recurrent multiple sclerosis;

-autoimmune/inflammatory diseases of any type, etiology or pathogenesis, or selected from the following: autoimmune blood diseases, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, polychondritis, scleroderma, Wegner's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, primary sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, endocrine eye disease, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, juvenile diabetes or type I diabetes, anterior uveitis, granulomatosis or posterior uveitis, keratoconjunctivitis, epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, psoriatic arthritis, glomerulonephritis with or without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy; inflammatory/hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, benign familial pemphigus, pemphigus erythematodes, pemphigus foliaceus, and pemphigus vulgaris;

-prevention of allograft rejection after organ transplantation;

-Inflammatory Bowel Disease (IBD) of any type, etiology or pathogenesis, or selected from the following inflammatory bowel diseases: ulcerative Colitis (UC), collagenous colitis, polypoidal colitis, transmural colitis, and Crohn's Disease (CD);

-septic shock of any type, etiology or pathogenesis, or selected from the following: renal failure, acute renal failure, cachexia, malaria cachexia, pituitary cachexia, uremic cachexia, cardiac cachexia, adrenal cachexia or Addison's disease, cancer cachexia, and cachexia resulting from infection by Human Immunodeficiency Virus (HIV);

-liver damage;

pulmonary hypertension, and pulmonary hypertension due to hypoxia;

-bone loss disease, primary osteoporosis, and secondary osteoporosis;

-a central nervous system disorder of any type, etiology or pathogenesis, or a central nervous system disorder selected from the group consisting of: depression, Parkinson's disease, cognitive and memory impairment, tardive dyskinesia, drug dependence, arteriosclerotic dementia, and dementia with Huntington's chorea, Wilson's disease, parkinsonism, and thalamotricity;

Infections, especially viral infections, wherein such viruses increase the production of TNF- α in their host or are susceptible to upregulation of TNF- α in the host, whereby their replication or other activity is adversely affected; comprising a virus selected from the group consisting of: HIV-1, HIV-2 and HIV-3, cytomegalovirus, CMV, influenza, adenovirus, and herpes viruses, including herpes zoster and herpes simplex;

-yeast and fungal infections sensitive to or causing the production of TNF- α up-regulation in a host, e.g. fungal meningitis, especially in order to combat systemic yeast and fungal infections, when other drugs are selected for co-administration, including but not limited to polymyxins (such as polymyxin B), imidazoles (such as clotrimazole, econazole, miconazole and ketoconazole), triazoles (such as fluconazole and itraconazole), and amphotericins (such as amphotericin B and liposomal amphotericin B);

-ischemia reperfusion injury, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infection, lupus erythematosus, kidney and ureter diseases, genitourinary and gastrointestinal diseases, and prostate diseases;

In particular, the compounds of formula (1.0.0) are useful in the treatment of: (1) an inflammatory disease or disorder, comprising: arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis and Crohn's disease; (2) respiratory diseases and disorders, including: asthma, acute respiratory distress syndrome, chronic lung inflammatory disease, bronchitis, chronic obstructive airways disease and silicosis; (3) infectious diseases and disorders, including: sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, fever and muscle pain from bacterial, viral or fungal infections, and influenza; (4) immune diseases and disorders, including: autoimmune diabetes, systemic lupus erythematosus, graft-versus-host reactions, allograft rejection, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) other diseases and disorders, including: bone resorption diseases, reperfusion injury, cachexia secondary to infection or malignancy, cachexia secondary to Acquired Immune Deficiency Syndrome (AIDS) in humans, Human Immunodeficiency Virus (HIV) infection or AIDS related syndrome (ARC), formation of leucoderma tumors, formation of leucoderma tissues, type I diabetes and leukemia.

The present invention still further relates to the combination of a compound of formula (1.0.0) with one or more agents selected from the group consisting of: (a) leukotriene biosynthesis inhibitor: a 5-lipoxygenase (5-LO) inhibitor and a 5-lipoxygenase activating protein (FLAP) antagonist selected from the group consisting of zileuton, ABT-761, fenleuton, tiposalin, Abbott-79175; abbott-85761, the N- (5-substituted) thiophene-2-alkylsulfonamides of formula (5.2.8), the 2, 6-di-tert-butylphenol hydrazones of formula (5.2.10), the methoxytetrahydropyrans including Zeneca ZD-2138 of formula (5.2.11), the compound SB-210661 of formula (5.2.12) and its class of compounds, the pyridyl-substituted 2-cyanonaphthalenes of L-739,010, the 2-cyanoquinolines of L-746,530, the indoles and quinolines of MK-591, MK-886 and BAYx 1005; (b) leukotriene LTB₄、LTC₄、LTD₄And LTE₄A receptor antagonist selected from: phenothiazine-3-ones to L-651,392, amidinates to CGS-25019c, benzoxazolamines to onazolast, benzamidines to BIIL284/260, and zafirlukast, arlukast, montelukast, pranlukast, villukast (MK-679), RG-12525, Ro-245913, ilakast (CGP45715A), and BAYx 7195; (c) PDE4 inhibitors, including isozyme PDE4D inhibitors; (d) a 5-lipoxygenase (5-LO) inhibitor, or a 5-lipoxygenase activating protein (FLAP) antagonist; (e) a dual inhibitor of 5-lipoxygenase (5-LO) and a Platelet Activating Factor (PAF) antagonist; (f) including LTB ₄、LTC₄、LTD₄And LTE₄Leukotriene antagonists (LTRAs) including antagonists; (g) antihistaminic H₁Receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, and,Nitrogen  statin and chlorpheniramine maleate; (h) stomach protection H₂A receptor antagonist; (i) alpha is alpha₁-and α₂-an adrenergic receptor agonist, a vasoconstrictor, a sympathomimetic agent for oral or topical administration for decongestion, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethyl norepinephrine hydrochloride; (j) alpha for use in combination with 5-lipoxygenase (5-LO) inhibitors₁-and α₂-an adrenergic receptor agonist; (k) anticholinergic agents including ipratropium bromide, tiotropium bromide, oxitropium bromide, perenzapine, and telenzepine; (l) Beta is a₁-β₄-adrenergic agonists including metaproterenol, isoproterenol, albuterol, salbutamol, formoterol, salmeterol, terbutaline, metaproterenol, bitolterol mesylate, and pirbuterol; (m) methylxanthines, including theophylline and aminophylline; (n) cromolyn sodium; (o) muscarinic receptor (M1, M2, and M3) antagonists (p) COX-1 inhibitors (NSAIDs), COX-2 selective inhibitors including rofecoxib, and nitroxide NSAIDs; (q) insulin-like growth factor type I (IGF-1) mimetics; (r) ciclesonide; (s) inhaled glucocorticoids with reduced systemic side effects including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate; (t) tryptase inhibitors; (u) Platelet Activating Factor (PAF) antagonists; (v) monoclonal antibodies active against endogenous inflammatories; (w) IPL 576; (x) Anti-tumor necrosis factor (TNF α) agents including Etanercept, Infliximab, and D2E 7; (y) DMARDs including leflunomide; (z) a TCR peptide; (aa) Interleukin Converting Enzyme (ICE) inhibitors; (bb) IMPDH inhibitors (cc) adhesion molecule inhibitors, including VLA-4 antagonists; (dd) cathepsin; (ee) MAP kinase inhibitors; (ff) glucose-6 phosphate dehydrogenase inhibitors; (gg) kinin-B ₁-and B₂-a receptor antagonist; (hh) gold in the form of a aurothioylene group having various hydrophilic groups; (ii) immunosuppressants such as cyclosporine, azathioprine and methotrexate; (jj)Anti-gout agents, such as colchicine; (kk) xanthine oxidase inhibitors, such as allopurinol; (II) uricosuric agents, for example, probenecid, sulindac, and benzbromarone; (mm) antineoplastic agents, especially antimitotic agents, including vinca alkaloids, such as vinblastine and vincristine; (nn) growth hormone secretagogues; (oo) matrix metalloproteinase inhibitors (MMPs), i.e., stromelysin, collagenase and gelatinase, and aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11); (pp) transforming growth factor (TGF β); (qq) Platelet Derived Growth Factor (PDGF); (rr) fibroblast growth factors, e.g., basic fibroblast growth factor (bFGF); (ss) granulocyte macrophage colony stimulating factor (GM-CSF); (tt) capsaicin emulsifiable concentrate; (uu) tachykinin NK-1, NK-1/NK-2, NK-2 and NK-3 receptor antagonists, including NKP-608C, SB-233412(talnetant) and D-4418; (vv) elastase inhibitors, including UT-77 and ZD-0892; and (ww) adenosine A2a receptor agonists.

Detailed Description

5.0 Compounds

The present invention relates to compounds of formula (1.0.0):in section 4.0 of the summary of the invention, the maximum range of the compounds of the invention is defined, and further description is given below of said compounds and of specific embodiments capable of displaying and exemplifying the characteristics of the compounds of formula (1.0.0), according to the different types of specific groups. Preferred and more preferred embodiments of the compounds are also set forth, but it should be understood that these preferred embodiments are listed without in any way limiting the scope of the compounds of the present invention.

The term "- (C) as used herein₁-C₃) Alkyl- "- (C)₁-C₄) Alkyl "and" - (C)₁-C₆) Alkyl "and equivalent variations of the same meaning include both branched and straight chain configurations of these aliphatic groups, and thus, the above terms are intended to be other than straightThe chain includes, in addition to methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl, branched iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl (2-methylbutane), 2-methylpentane, 3-methylpentane, 1-ethylpropane and 1-ethylbutane. The meanings of the above terms apply equally regardless of whether they are in substituted or unsubstituted form. Thus, "fluoro-substituted- (C) ₁-C₃) Alkyl "includes the various fluoro forms of the aliphatic groups n-propyl and iso-propyl.

As used herein, for compounds of formula (1.0.0) and related other formulae and subformulae, one or more of the nitrogen atoms therein is represented as N [ → (O)]It or an optional nitroxide form thereof comprising the nitrogen atom. In the case where there is more than one form of nitroxide, they are selected independently of each other. Further, it should be understood that the above-described nitroxide forms can also be expressed as "[ N → (O)_u]", wherein u is 0 or 1.

Preferred embodiments of the present invention include compounds wherein m is 1 and n is 1; r^AAnd R^Bis-H, -F, -CF₃Or by 0 or 1-F, -Cl, -CF₃、-CN、-NH₂Or C (═ O) NH₂Substituted- (C)₁-C₆) Alkyl, or together form a substituted or unsubstituted radical of 0 or 1-F, -Cl, -CF₃or-CN substituted spiro- (C)₃-C₆) A cycloalkyl group; r^cAnd R^DOne is-H, the other is-H, - (C)₁-C₄) Alkyl or phenyl, each of which is substituted by 0 or 1-F, -Cl or-CN; w is-O-; y is ═ C (R)^E) Wherein R is^Eis-H, -F, -Cl, -CN, -CH₃or-OCH₃；R¹And R²is-H, -F, -Cl, -CN, -NO₂、-OH、-CH₃、-OCH₃、-OCHF₂Or OCF₃；R³is-H or-CH₃；R⁴is-H, -F, -CN, -NO₂、-OH、-CH₃or-OCH₃；R⁵And R⁶Together form a group of the sub-formula (1.1.1), the sub-formula (1.1.4) or the sub-formula (1.1.5), which In, R⁷And R⁸In each of said formulae is absent, -H or-CH₃(ii) a Q is phenyl, norbornyl, furyl, thienyl, pyrimidinyl or cyclohexyl; z is OR¹²or-C (═ O) R¹²Wherein R is¹²is-H, -CH₃、-CH₂CH₃or-C (CH)₃)₃(ii) a Or Z is-CN.

In these preferred embodiments, particular mention is made of compounds in which R^AAnd R^BAre all-CH₃Or one is-CH₃And the other is-CH (CH)₃)₂or-C (CH)₃)₃Or one is-H and the other is-CH₃or-CF₃Or together form a spirocyclopropyl or spirobutyl; r^cAnd R^DOne is-H and the other is-H or-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H, -F or-Cl; r¹And R²is-H, -F or-Cl; r³is-H; r⁴is-H; r⁵And R⁶Together form a group of the sub-formula (1.1.1) or the sub-formula (1.1.4), wherein R⁷And R⁸Are not present; q is phenyl, thienyl or cyclohexyl; z is OR¹²Wherein R is¹²is-H, or Z is-C (═ O) R¹²Wherein R is¹²is-H or-CH₃Or Z is-CN.

In these preferred embodiments, inter alia, compounds are included wherein R^AAnd R^BAre all-CH₃Or together form a spirocyclopropyl group; r^cAnd R^DOne is-H and the other is-H or-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H, -F or-Cl; r¹And R²is-H, -F or-Cl; r ³is-H; r⁴is-H; r⁵And R⁶Together form a group of the formula (1.1.1), wherein R⁷And R⁸Are not present; z is OR¹²Wherein R is¹²is-H.

Of the class of compounds just mentioned, a more preferred embodiment includes compoundingIn which R is^AAnd R^BAre all-CH₃；R^cAnd R^DAre all-H; y is ═ C (R)^E) Wherein R is^Eis-H; r¹And R²One is-H and the other is-F.

Among the compounds of the type just mentioned, a more preferred embodiment also includes compounds wherein Y is ═ C (R)^E) Wherein R is^Eis-F; r¹And R²Are all-H.

In a preferred embodiment of the compounds of formula (1.0.0), particular mention is made of compounds in which R is⁵And R⁶Together form a group of the sub-formula (1.1.4), and wherein R^AAnd R^BAre all-CH₃Or one is-H and the other is-H or-CH₃Or together form a spirocyclopropyl group; r^cAnd R^DOne of which is-H and the other is H or-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H or-F; r¹And R²is-H, -F or-Cl; r³is-H; r⁴is-H; r⁷And R⁸Are not present; q is phenyl, norbornyl, furyl, thienyl, pyrimidinyl or cyclohexyl; z is OR¹²Wherein R is¹²is-H.

Among the compounds of the type immediately above, particularly preferred embodiments include compounds wherein R is ^AAnd R^BAre all-CH₃；R^cAnd R^DOne is-H and the other is-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H; r¹And R²Are all-H; r³is-H; r⁴is-H; q is phenyl, thienyl or cyclohexyl; z is OR¹²Wherein R is¹²is-H.

In another group of preferred embodiments of the compounds of formula (1.0.0), compounds are included wherein m is 1, n is 1; r^AAnd R^Bis-H, -CF₃Or by 0 or 1-F, -Cl, -CF₃、-CN、-NH₂or-C (═ O) NH₂Substituted- (C)₁-C₆) Alkyl, or together form a substituted or unsubstituted radical of 0 or 1-F, -Cl, -CF₃or-CN substituted spiro- (C)₃-C₆) A cycloalkyl group; r^cAnd R^DOne is-H, the other is-H, - (C)₁-C₄) Alkyl or phenyl, each of which is substituted by 0 or 1-F, -Cl or-CN; w is-O-; y is ═ C (R)^E) Wherein R is^Eis-H, -F, -Cl, -CN, -CH₃or-OCH₃；R¹And R²is-H, -F, -Cl, -CN, -NO₂、-OH、-CH₃、-OCH₃、-OCHF₂Or OCF₃；R³is-H; r⁴is-H, -F, -CN, -NO₂、-OH、-CH₃or-OCH₃；R⁵And R⁶Together form a group of the partial formula (1.1.5), wherein R⁷is-H or-CH₃(ii) a Q is phenyl, norbornyl, furyl, thienyl, pyrimidinyl or cyclohexyl; z is OR¹²or-C (═ O) R¹²Wherein R is¹²is-H, -CH₃、-CH₂CH₃or-C (CH)₃)₃Or Z is-CN.

In these preferred embodiments, particular mention is made of compounds in which R^AAnd R^BAre all-CH ₃Or one is-CH₃And the other is-CH (CH)₃)₂or-C (CH)₃)₃Or one is-H and the other is-CH₃or-CF₃Or together form a spirocyclopropyl or spirobutyl; r^cAnd R^DOne is-H and the other is-H or-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H, -F or-Cl; r¹And R²is-H, -F or-Cl; r³is-H; r⁴is-H; q is phenyl, thienyl or cyclohexyl; z is OR¹²Wherein R is¹²is-H, or Z is-C (═ O) R¹²Wherein R is¹²is-H or-CH₃Or Z is-CN.

The core nucleus (core nucleus) of formula (1.0.0) is nicotinamide derived from nicotinic acid and represented by the sub-formula (1.0.1):the core is formed by defining the group Y as ═ C (R)^E) -or- [ N → (O)]And are explained in detail. Has a chemical formula of- [ N → (O) at Y]In the case of the meaning of-the compounds according to the invention are pyrimidinyl compounds, the pyrimidine radical of the compounds of the formula (1.0.0) being an important part of the scope of the invention. Nevertheless, preferred compounds of formula (1.0.0) have the Y group defined as ═ C (R)^E) -, wherein the substituent R^ESelected from-F, -Cl, -CN, -NO, in addition to-H₂、-(C₁-C₃) Alkyl, fluoro- (C)₁-C₃) Alkyl, - (C)₁-C₃) Alkoxy, fluoro- (C)₁-C₃) Alkoxy, -OH and-C (═ O) NH₂. Preferably R^EThe substituents have the meaning of-F, -Cl, -CH₃or-OCH ₃(ii) a More preferably R^Eis-F or-H, i.e. in these R^EIn the-H embodiment, the 5-position of the nicotinamide occupied by the group Y is unsubstituted.

In certain embodiments of the compounds of formula (1.0.0), wherein Y is ═ C (R)^E) The group Q is phenyl, and the substituent at the 5-position of the nicotinamide core and the substituent at the 2' -position of the phenyl to which the amide moiety is attached are selected from the same group definitions, although their selection is provided independently. The substituents involved can be illustrated by the following formula (1.0.2):

the substituents R in the 5-and 2' -position being referred to their pharmacological, pharmacokinetic properties, such as potency and substrate specificity (selectivity) and physicochemical properties^EAnd R¹The same property modification function is possessed for all the compounds of the formula (1.0.0). In such preferred embodiments of the compounds of the present invention, R^EAnd R¹The substituents each have the following meanings: -H and-H, -H and-F, -F and-H, and-F.

5.1 linking groups (W) and R⁴substituted-R⁵/R⁶Bicyclic heterocycles with fused benzene rings

By reacting the carbon atom in the 2-position of the pyridine or pyrimidine ring of the nucleus of formula (1.0.1) with a radical R⁴The substituted benzene ring forms an ether, thioether or amine linkage, and the parent nucleus of nicotinamide is more detailed. Substituent R ⁴Can be attached to any of the available carbon atoms and have the same meaning as defined above. More significantly, the benzene ring and its substituent R⁵And R⁶Form a bicyclic heterocycle fused to the phenyl ring, this result constituting R directly⁵And R⁶That is, together form a group selected from the group represented by the partial formulae (1.1.1) to (1.1.5):

accordingly, further groups represented by the partial formulae (1.0.3), (1.0.4), (1.0.5), (1.0.6) and (1.0.7) are obtained:wherein W has the meaning-O-, -S (═ O)_t-, where t is 0, 1 or 2; or-N (R)³) -. In the preferred compounds of formula (1.0.1), and thus for formula (1.0.0), W has the meaning of-O-, the ether linkage thus created connects the phenyl ring fused bicyclic heterocycle to the nicotinamide parent nucleus.

In still other preferred embodiments of the compounds of formula (1.0.0), R⁷And R⁸None are present. It can be determined that: r⁷And R⁸In the absence of any, the dotted line- - -represents a double bond, and the resulting phenyl moiety in the benzene ring-fused bicyclic heterocycle represented by the sub-formulae (1.0.3), (1.0.5), (1.0.6) and (1.0.7) cannot have all of the double bonds in the sub-formula because the pentavalent carbon atom is forbidden in the phenyl moiety.

Accordingly, R ⁷And R⁸In the absence, the compound obtained is characterized by the structures shown in the sub-formulae (1.0.8) and (1.0.9):

in still other preferred embodiments of the compounds of formula (1.0.0), the bicyclic heterocycle having a fused phenyl ring is of formula (1.0.3)The meaning of the groups is shown. This condition and other preferable conditions of the compound of formula (1.0.0) are selected simultaneously, resulting in obtaining a group represented by the sub-formula (1.0.10)

In other embodiments of the invention W has the meaning of-S-, or it may have the meaning of-N (R)³) The meaning of (A) wherein R³preferably-H, whereby ether or thioether bonds, or amine bonds, are formed. If a sulfur bond is selected, and R⁷And R⁸None are present, a further embodiment of the compounds of the present invention is obtained, which may be represented by the sub-formula (1.0.11)

Accordingly, as to the substituents R on the bicyclic heterocyclic ring whose benzene ring is fused, represented by the partial formulae (1.1.1), (1.1.2), (1.1.3), (1.1.4) and (1.1.5) and the partial formulae (1.0.3), (1.0.4), (1.0.5), (1.0.6) and (1.0.7)⁷And R⁸In each of the above formulae, R⁷And R⁸Each independently is-H, -CH₃、-OCH₃Or absent, in which case the dotted line- - -represents a double bond, provided that the phenyl portion of the bicyclic heterocycle to which the phenyl ring is fused does not have a pentavalent carbon atom.

The pharmaceutical chemist will understand that the effect of these substituents on the lipophilicity and physicochemical properties of the overall molecule formed will influence the choice of such substituents. Based on the above-mentioned choice of substituents and the corresponding potency testing of the resulting molecules in the following rapid in vitro assay methods, the state of the art offers the possibility to rapidly and conveniently synthesize a large number of compounds of very similar chemical nature. The current combinatorial chemical synthesis and analysis approaches in the art further expand the number of combinations of substituents one can quickly assess. The information obtained using these techniques allows reasonable prediction of certain preferred embodiments of the various embodiments of the present invention, which are described in detail below.

When R is⁵And R⁶Together form a radical of sub-formulae (1.1.1), (1.1.2), (1.1.3), (1.1.4) and (1.1.5), and R⁷And R⁸As defined herein, benzofurazan and similar groups and substituted derivatives thereof are formed, including in particular the following groups of the subformulae (2.1.1) to (2.1.23):wherein in the sub-formulae (2.1.3), (2.1.4), (2.1.5), (2.1.7), (2.1.21) and (2.1.22) in the absence of an oxygen atom attached to the respective nitrogen atom, the dotted line represents a double bond; in the case where one oxygen atom is bonded to the nitrogen atom, the dotted line represents a single bond.

Those of ordinary skill in the synthesis of organic molecules will understand that for compounds of formula (1.0.0), wherein R is⁵And R⁶When the groups represented by the above partial formulae (2.1.2), (2.1.10), (2.1.11), (2.1.13), (2.1.15), (2.1.17) and (2.1.23) are formed together, tautomeric forms exist, and each group of the partial formulae has a tautomer. These tautomers are associated with a shift in hydrogen and one or more * -bonds. The skilled person will be able to identify or determine which tautomer is present or most stable, if desired.

Thus, carbonyl tautomers of compounds of formula (1.0.0) are generally more stable than the corresponding iminoalcohol counterparts. Any compound of formula (1.0.0) having an alpha-hydrogen, carbonyl and iminoalcohol tautomers thereof described herein are within the scope of the present invention.

5.2 R^C/R^DRadical (I)

After describing group Q, the group- [ R ] is described further below^A-C-R^B]_m-, which is located at the end of the compound of formula (1.0.0) near the right half. This sequence is detailed from left to right for the compound of formula (1.0.0). Para radical- [ R^C-C-R^D]_n-and- [ R^A-C-R^B]_mThe description herein has been made in a similar manner, but in no way limits the independent choice of the meanings of the two groups. In the immediately following paragraph, pair Group- [ R ]^C-C-R^D]_n-carrying out the description.

The ether, thioether or linked nicotinamide moiety of the left half of the molecule of the compound of formula (1.0.0) above is characterized by the linking group to the moiety R¹And R²A substituted group Q, which may be represented by the sub-formula (1.1.9):wherein n is 1 or 2. In a more preferred embodiment of the compounds of the invention, n is defined as the integer 1. When n is 1, the group- [ R ]^C-C-R^D]_nIs present, wherein R^CAnd R^DEach independently selected from-H, -F, -CF₃、-(C₁-C₆) Alkyl, - (C)₃-C₇) Cycloalkyl, phenyl, benzyl, or a heterocyclyl selected from: pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl and thiadiazolyl, wherein the alkyl, cycloalkyl, phenyl, benzyl and heterocyclyl are each independently substituted with 0-3 substituents R¹⁰Substituted; with the proviso that^CAnd R^DAt least one must be hydrogen. Preferred embodiments of the compounds of formula (1.0.0) often include R therein^CAnd R^DAll are hydrogen compounds.

For R^CAnd R^DAlkyl and heterocyclyl radicals in the definitions, R¹⁰Is an optional substituent selected from phenyl and benzyl substituted with 0, 1 or 2 of: -F, -CH ₃、-OCH₃、-CF₃OH, -CN or-NH₂(ii) a And said R is¹⁰The group is further selected from-F, -Cl, -CF₃、-CN、(C₁-C₂) Alkyl, -C (═ O) OR¹²、-O-C(＝O)R¹³、-C(＝O)NR¹²R¹³、-O-C(＝O)NR¹²R¹³、-NR¹²R¹³、-NR¹²C(＝O)R¹³、-NR¹²C(＝O)OR¹³、-NR¹²S(＝O)_tR¹³and-S (═ O)_tNR¹²R¹³Wherein t is 0, 1 or 2. Secondary substituent R¹²And R¹³Selected from-H, - (C)₁-C₄) Alkyl and- (C)₃-C₆) Cycloalkyl, wherein the alkyl and cycloalkyl are substituted with 0-3 substituents selected from the group consisting of-F and-Cl.

In some preferred embodiments of the invention, R^CAnd R^DAre all-H, thereby forming a methylene bridge which is to be substituted by R¹And R²The substituted group Q is separated from the left half of the compound of formula (1.0.0). In other preferred embodiments, R^COr R^DOne must be-H and the other is methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyrrolyl, imidazolyl, pyridyl, oxazolyl, thiazolyl or oxadiazolyl, each of which is optionally substituted with one substituent R¹⁰And (4) substituting.

Thus, according to the above description, sub-formula (1.1.9):representative embodiments of linking groups include, but are not limited to, groups represented by the partial formulae (2.2.1) - (2.2.41):

in the compounds of the invention, R is¹And R²The linking group of the substituted group Q to the group Z may be represented by the partial formula (1.1.10): Wherein R is^A、R^BAnd m has the same meaning as defined above. However, it should be understood that in the alternative R^AAnd R^BWhen R is^CAnd R^DThe meaning of a particular choice is not a necessary factor, at least not a prerequisite factor; likewise subscript m is chosen independently of subscript n.

5.3 R^A/R^BRadical (I)

In the compounds of the invention, R is¹And R²The linking group of the substituted group Q to the group Z may be represented by the partial formula (1.1.10):wherein R is^A、R^BAnd m has the following meanings. As already indicated, in the selection of R^AAnd R^BWhen R is^CAnd R^DThe specific choice is not a necessary factor, i.e., is not a prerequisite factor; similarly, the subscript m is chosen to be independent of the intake value chosen for the subscript n.

For the group- [ R ]^A-C-R^B]_m-, where the subscript m is 1 or 2. In a preferred most embodiment of the compounds of the invention, m has the meaning 1.

When m is 1, R^AAnd R^BAll may be-H, thereby forming a methylene bridge. In the most preferred compounds of formula (1.0.0.) R^AAnd R^BAre all methyl. When m is 1, R is also preferred^AAnd R^BOne is-H and the other is-CH₃. In other embodiments, R^AAnd R^Bis-H and the other is selected from their further definitions, including- (C) ₁-C₆) Alkyl and- (C)₃-C₇) A cycloalkyl group. As defined herein for other alkyl-containing substituents, it may be a straight or branched aliphatic radical, correspondingly, in- (C)₁-C₄) In the case where the alkyl group is branched, R^AAnd R^BMeaning isopropyl, sec-butyl and tert-butyl. When m is 1, R^AAnd R^BPreferred meanings of (A) are-H or methyl; and R is^AAnd R^BMay be both-H or methyl. Particular preference is given to R^AAnd R^BIs simultaneously-CH₃。

At R^AAnd R^BHas a radical of formula (C)₁-C₆) Alkyl or- (C)₃-C₇) In the meaning of cycloalkyl, the alkyl or cyclopentyl group may be substituted by 0 to 3 substituents R¹⁰Is substituted byWherein R is¹⁰is-F, -Cl, -CF₃、-CN、(C₁-C₂) Alkyl, OR¹²、-C(＝O)OR¹²、-O-C(＝O)R¹³、-C(＝O)NR¹²R¹³、-OC(＝O)NR¹²R¹³、-NR¹²R¹³、-NR¹²C(＝O)R¹³、-NR¹²C(＝O)OR¹³、-NR¹²S(＝O)₂R¹³or-S (═ O)₂NR¹²R¹³。

At R^AAnd/or R^BBy R¹⁰Is substituted and R¹⁰Is defined as-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³In the case of (A), the resulting substituents obey the proviso that for the above case or R^AAnd R^BAll other applicable meanings of (A), said-OR¹²、-O-C(＝O)R¹³or-C (═ O) NR¹²R¹³And the meaning is-OR¹²The positional relationship of the Z groups of (A) is not vicinal. In other words, when Z has the meaning of OR¹²For the group- [ R ]^A-C-R^B]_m-, m is 1 and R^AAnd/or R^Bis-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³In the case of (2), the resulting Z and R¹⁰Substituent(s): (1) -OR¹²，(2)-OR¹²、-O-OC(＝O)R¹³or-C (═ O) NR¹²R¹³Each not linked, i.e. not in a vicinal position, to an adjacent carbon atom.

The precondition applies to R^AAnd R^BAll applicable meanings, whether exemplary or defined as discussed herein — (C)₁-C₆) Alkyl or- (C)₃-C₇) Cycloalkyl is also a spiro group of formula (1.1.0) formed together in the examples discussed below. It is to be understood that R^AAnd R^BAs phenyl, benzyl or heterocyclyl, the meanings do not apply to the above prerequisites.

R¹²And¹³are independently selected from-H, - (C)₁-C₄) Alkyl group (a)C₂-C₄) Alkenyl, (C)₃-C₆) Cycloalkyl, phenyl, benzyl, and monocyclic heterocyclyl radicals comprising a nitrogen atom replacing a carbon atom₃-C₆) Cycloalkyl and optionally a 5-or 6-membered said heterocyclyl with a second nitrogen atom replacing a second carbon atom; wherein said alkyl, alkenyl, cycloalkyl, phenyl, benzyl, or monocyclic heterocyclyl is substituted with 0-3 substituents selected from-F and-Cl.

In a preferred embodiment, R^AAnd R^BIn definition of- (C)₁-C₄) Alkyl, (C)₃-C₆) Having R on cycloalkyl¹⁰Substituents, preferably the substitution is single, and the single substituent is-F, -Cl or-CF₃。

The most preferred embodiment of the compound of formula (1.0.0) is that R^AAnd R^BAre all-CH₃And R is^CAnd R^DAll the meanings of (A) are-H.

R^AAnd R^BAlso having the meaning of a heterocyclic group selected from pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl and thiadiazolyl, wherein said heterocyclic group is substituted with 0-3 substituents R ¹⁰And (4) substituting. Accordingly, R^AAnd R^BFor example, it may be 3- [ O-C (═ O) NH₂]-pyridin-4-yl.

R^AAnd R^BAnd also have the meaning of together forming a spiro group of formula (1.1.0):

of course, R^AAnd R^BThis means that m in the formula (1.0.0) is 1. For the radical of the formula (1.1.0), r and s can be from 0 to 4, provided that the sum r + s is at least 1 but not more than 5. In a preferred embodiment, one of r and s is 0 and the other is 1, or both r and s are 1, or one of r and s is 1 and the other is 2.Group Q^AIs selected from-CH₂-、-CHF-、-CF₂-、-NR¹²-, -O-and-S (═ O)_t-, where t is 0, 1 or 2, but preferably Q^Ais-CH₂-。

In the preferred meaning of r and s, a spirocycloalkyl group is obtained, i.e.cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The spiro group is preferably substituted by 0 to 1 substituent R¹⁰Is substituted in which R¹⁰is-F and-CH₃. As already indicated, when Z has the meaning OR¹²And R is^AAnd/or R^Bis-OR¹²、-O-C(＝O)R¹³or-C (═ O) NR¹²R¹³In the case of (3), the final Z and R¹⁰Substituent(s): are respectively (1) -OR¹²，(2)-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³Not linked to an adjacent carbon atom, i.e. not in a vicinal position. The precondition applies to R^AAnd R^BAll applicable meanings include spiro groups of formula (1.1.0) together formed as exemplified in the discussion herein.

In addition to the foregoing, a number of preferred R's are described^CAnd R^DThe meanings of the radicals including the meanings of the invention in relation to R^AAnd R^BPreferred embodiments of (1). These meanings are not repeated here in a corresponding manner, but are incorporated by reference in their entirety as if reiterated. Radical R^AAnd R^BThe preferred meanings of (A) are expressed by the partial formulae (2.6.1) to (2.6.22):

5.4 radicals Q

The group Q includes phenyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, oxazolyl, monocyclic- (C)₅-C₇) Cycloalkyl, monocyclic C₅-C₇) Cycloalkenyl selected from cyclopentenyl, cyclohexenyl and cycloheptenyl, or bicyclo- (C)₇-C₁₀) Cycloalkyl, bicyclo- (C)₇-C₁₀) Cycloalkenyl, preferably selected from norbornyl, norylBornylene, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.0]Octyl, bicyclo [2.2.2]Oct-5-enyl, bicyclo [2.2.2]Oct-7-enyl, bicyclo [3.3.1]Nonyl, cyclodecyl and adamantyl. All of these Q groups are R as detailed below¹And R²And (4) substituting. Preferred Q are phenyl, norbornyl, thienyl and cyclohexyl; however, important embodiments of further compounds of the formula (1.0.0) include those in which Q has the meaning pyrrolyl, furanyl, pyridyl, pyrimidyl, imidazolyl and cyclohexyl.

It is to be understood that Q is a divalent radical which is bonded to the linking group R^A/R^BAnd R^C/R^DThe connection points may vary from one another. Thus, for example, where Q is phenyl, the points of attachment may be in ortho-, meta-, or para-relationship to each other, although para-relationship is preferred.

In addition to cyclohexyl, the Q group can be cyclopentyl or cycloheptyl. In which the radical Q is monocyclic- (C)₅-C₇) In the case of cycloalkenyl, the meaning is selected from cyclopentene, cyclohexene, and cycloheptene. At the Q group is bicyclic- (C)₇-C₁₀) Cycloalkyl, bicyclo- (C)₇-C₁₀) In the case of cycloalkenyl, preferred embodiments include the Q group as norbornyl, norbornenyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.0]Octyl, bicyclo [2.2.2]Oct-5-enyl, bicyclo [2.2.2]Oct-7-enyl, bicyclo [3.3.1]Nonyl and adamantyl. The Q group in these preferred meanings can be represented by the partial formulae (1.1.11) to (1.1.21):

in the monocyclic ring described above- (C)₅-C₇) Of the cycloalkenyl groups, the moiety (1.1.12), cyclohexene, is preferred in embodiments of the compound of formula (1.0.0).

5.5 R¹And R²Substituent group

The Q group being located at a linking group- [ R ] as detailed above^C-C-R^D]_n-and- [ R^A-C-R^B]_m-and the aforementioned Q group is substituted by a substituent R ¹And R²Substituted, R¹And R²Each independently selected from-H, -F, -Cl, -R¹²、-OR¹²、-S(＝O)_pR¹²、-C(＝O)OR¹²、-OC(＝O)R¹²、-CN、-NO₂、-C(＝O)NR¹²R¹³、-OC(＝O)NR¹²R¹³、-NR¹⁴C(＝O)NR¹⁵R¹²、-NR¹⁴C(＝NR¹⁴)NR¹⁵R¹²、-NR¹⁴C(＝NCN)NR¹⁵R¹²、-NR¹⁴C(＝N-NO₂)NR¹⁵R¹²、-C(＝NR¹⁴)NR¹⁵R¹²、-OC(＝NR¹⁴)NR¹⁵R¹²、-OC(＝N-NO₂)NR¹⁵R¹²、-NR¹⁵R¹²、-CH₂NR¹⁵R¹²、-NR¹⁴C(＝O)R¹²、-NR¹⁴C(＝O)OR¹²、-NR¹⁴S(＝O)_pR¹³and-S (═ O)_pNR¹²R¹³(ii) a Wherein p is 0, 1 or 2; and R is¹²、R¹³、R¹⁴And R¹⁵Have the same meaning as given above.

In particular, embodiments of the present invention have a single substituent, namely R¹And R²One being-H and the other having the above-mentioned meaning, the single substituent being preferably selected from the group consisting of-H, -F, -Cl, (C)₁-C₃) Alkyl, fluoro (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, fluoro (C)₁-C₃) Alkoxy, -CN, -NO₂-OH and-C (═ O) NH₂。

These of the invention having a single substituent R¹Or R²Preferably in the 2-position, i.e. the Q group with the linker- [ R ]^C-C-R^D]_n-has the substituent in the ortho position to the point of attachment. This is particularly true where the Q group is phenyl. In the formula (1)0.0) preferred embodiment of the compounds of formula (I), R¹Or R²Is defined as-F, fluoro (C)₁-C₃) Alkyl or fluoro (C)₁-C₃) An alkoxy group. Of these preferred embodiments of the compounds of formula (1.0.0), R is particularly preferred¹Or R²A compound which is-F.

At R¹Or R²In the case where it is other than-H, in embodiments of the compounds of formula (1.0.2), the substituted Q group is phenyl, preferably with a halogen substituent at its 2' -end. Notably, R¹Or R²Preferably small lipophilic groups, e.g. -F, fluoro (C) ₁-C₃) Alkyl or fluoro (C)₁-C₃) An alkoxy group. Thus, said R¹Or R²Substituents and definitions include-F, fluoro (C)₁-C₃) Alkyl or fluoro (C)₁-C₃) Other substituents of alkoxy compounds of formula (1.0.0) are selected from the following groups:

-F -CH₂F -CHF₂ -CF₃ -CH₂CH₂F

-CH₂CHF₂ -CH₂CF₃ -CHFCH₂F -CHFCHF₂ -CHFCF₃

-CF₂CF₂CF₃ -O-CH₂F -O-CHF₂ -O-CF₃ -O-CH₂CH₂F

-O-CH₂CHF₂ -O-CH₂CF₃ -O-CHFCH₂F -O-CHFCHF₂ -O-CHFCF₃

-O-CF₂CH₂F -O-CF₂CHF₂ -O-CF₂CF₃

with such groups as R1 or R2, selectivity of the whole molecule can be achieved, possibly due to conformational alignment of lipophilic groups to the corresponding lipophilic regions of the PDE4 enzyme matrix, and possibly due to changes in the overall lipophilicity of the resulting molecule. All such embodiments are within the scope of the present invention, regardless of the actual mechanism by which such selectivity is achieved.

5.6Z radicals and their reaction with- [ R ]^A-C-R^B]_mRelation of-radicals

As already described above, the group- [ R ]^A-C-R^B]_m-is a linking group joining together groups Q and Z in the compounds of the invention. Thus, Z and the group- [ R ]^A-C-R^B]_mAdjacent, as discussed above, preferably m is 1. This relationship can be represented by the equation (1.1.7):

wherein "-" is a symbol representing the point of attachment of the group of sub-formula (1.1.7) to the group Q in the remainder of the compound of formula (1.0.0).

5.7 terminal groups Z

Z is independently selected from-OR¹²、-C(＝O)R¹²and-CN, wherein R¹²Have the same meaning as defined herein.

To further illustrate the significance of Z in characterizing other embodiments of the compounds of formula (1.0.0), the following description describes the groups of formulae (3.0.1) - (3.0.24), which represent different meanings within the scope of formulae (1.1.7):

if R is^AAnd R^BIs substituted by 1 or 2 substituents R¹⁰Substituted- (C)₁-C₆) Alkyl, Z is-OR¹²、-C(＝O)R¹²and-CN, wherein R¹²Is H, - (C)₁-C₄) Alkyl or phenyl, the resulting group falling within the range of the sub-formula (1.1.7),and include further embodiments of compounds of formula (1.0.0) as described in sub-formulae (3.0.20) - (3.0.24) below. As already indicated, the meaning at Z is OR¹²And R is^AAnd/or R^Bis-OR¹²、-O-C(＝O)R¹³or-C (═ O) NR¹²R¹³In the case of (2), the resulting Z and R¹⁰Substituent(s): are respectively (1) -OR¹²，(2)-OR¹²、-O-C(＝O)R¹³or-C (═ O) NR¹²R¹³Not linked to an adjacent carbon atom, i.e. not in a vicinal position. The precondition applies to R^AAnd R^BAll applicable meanings.

R^AAnd R^BTogether also form a spiro structure represented by the sub-formula (1.1.0):wherein r and s are independently 0 to 4, provided that the sum of r + s is at least 1 but not more than 5, and Q^AIs selected from-CH₂-、-CHF-、-CF₂-、-NR¹²-, -O-and-S (═ O)_p-wherein p is 0, 1 or 2; the spiro group includes Q at any one or more of its carbon atoms^AIn definition of-CH₂With 0 to 3 substituents R¹⁰Is substituted in which R ¹⁰And R¹²Have the same meaning as given above.

In the group R¹⁰is-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³In the case of (2), it is to be understood that the-OR is¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³with-OR as meaning of Z¹²The positional relationship of the groups must be non-vicinal. It should also be understood that Q^Agroup-CH in the definition₂By 0 to 3 substituents R¹⁰Is substituted, and R¹⁰May be-F. Accordingly, due to Q^AIs defined as-CHF-or-CF₂The meaning of-has already been given, it being understood that R¹⁰In the case of-F, by 1 or 2R¹⁰substituted-CH₂Not applicable。

The resulting groups fall within the scope of sub-formula (1.1.7) above, and include further embodiments of compounds of formula (1.0.0), as described in sub-formulae (4.0.1) - (4.0.37):

in the above description, preferred embodiments of various aspects of the compound of formula (1.0.0) have been proposed. As an illustration of the contents and scope of the present invention, specific compounds of formula (1.0.0) are given, including but not limited to the following compounds of formulae (5.5.1) - (5.5.66):

Detailed Description

6.0 Process for preparing Compounds of formula (1.0.0)

Preparation of a Compound of formula (1.0.0), wherein the group Q is in particular phenyl, and R₅And R₆Together form a group of partial formula (1.1.1), (1.1.4) or (1.1.5):

A suitable method is described in the synthesis scheme (10.0.0) below.

Synthetic line (10.0.0)Wherein R is a carboxyl protecting group, especially a lower alkyl ester; q¹is-O-, -S-or-N (R)⁷)-；R^A、R^B、R^C、R^D、R¹、R²、R⁴Z, m and n have the same meaning as defined herein; THF is tetrahydrofuran; DMF is dimethylformamide; EDCI is 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride; HOBT is 1-hydroxybenzotriazole hydrate.

In step 1 of the synthesis line (10.0.0), 5-hydroxybenzofurazan, i.e. 5-hydroxy-benzo [2, 1, 3]Oxadiazole treatment of protected 2-chloronicotinic acid to prepare Q¹A compound which is-O-. Accordingly, Q is to be prepared¹Compounds of formula-S-employing 5-hydroxybenzo [1, 3, 2]A thiadiazole; and with 5-hydroxybenzo [1, 2, 3 ]]Preparation of triazole Q¹is-N (R)⁷) -and R⁷A compound which is-H. The carboxyl group of the starting 2-chloronicotinic acid is protected, for example, in the form of the alkyl ester employed, other commonly used carboxyl protecting groups also being suitable.

In step 1, protected nicotinic acid is added to cesium carbonate Cs₂CO₃With 5-hydroxybenzofurazan in the presence of anhydrous N, N-Dimethylformamide (DMF) as solvent, a known process for the preparation of asymmetric esters, by the aryloxy-chloro-displacement mechanism. Other strong bases, e.g. NaOH, KOH, NaH, tBuOK (potassium tert-butoxide) or K ₂CO3 may also be used in place of Cs₂CO₃. Other aprotic polar solvents may be used instead of dimethylformamide, for example, acetone, nitromethane, acetonitrile, sulfolane, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), methyl ethyl ketone (2-butanone), or Tetrahydrofuran (THF). The most preferred solvent is N, N-Dimethylformamide (DMF).

After the reaction mixture is formed, it is heated to 70 ℃ to 110 ℃, typically 80 ℃ to 100 ℃, and at most 90 ℃. At the lower above-mentioned temperatures it is necessary to heat the reaction mixture for a considerable period of time, from 1 to 6 days, preferably from 2 to 5 days, most preferably from 3 to 4 days. At higher temperatures as described above, the reaction proceeds faster and takes less time, 1/2-5 days, usually 3/4-3 days, most often 1-2 days.

In step 2 of the synthesis scheme (10.0.0), the protected 2- (benzo [2, 1, 3] oxadiazol-5-yloxy) nicotinic acid, e.g. methyl ester, prepared in step 1 is deprotected and treated with a milder base such as lithium hydroxide, LiOH, in an aprotic solvent, e.g. 1, 4-dioxane, Dimethoxyethane (DME) or Tetrahydrofuran (THF), preferably Tetrahydrofuran (THF). The reaction is carried out at room temperature for 8 to 24 hours, usually 10 to 20 hours, more usually 12 hours.

In step 3 of the synthetic route (10.0.0), 2- (benzo [2, 1, 3] oxadiazol-5 yloxy) nicotinic acid prepared in step 2, which constitutes the left half of the compound of formula (1.0.0), is reacted with a compound constituting the right half of the compound of formula (1.0.0), which is in the form of an amine, with the result that an amide bond is formed linking the two halves constituting the compound of formula (1.0.0). This reaction was carried out using a mixture of the coupling reagents 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole Hydrate (HOBT). Other coupling reagents such as Dicyclohexylcarbodiimide (DCCI), N' -carbonyldiimidazole and benzotriazol-1-yl diethyl phosphate may also be used.

The coupling reaction is carried out in an aprotic solvent, such as acetone, nitromethane, N-Dimethylformamide (DMF), acetonitrile, sulfolane, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) or methyl ethyl ketone (2-butanone), preferably N, N-Dimethylformamide (DMF). The reaction is carried out at room temperature to slightly above room temperature for 8-24 hours, usually 10-20 hours, more usually 12 hours.

Detailed Description

7.0 pharmaceutically acceptable salts and other forms

The compounds of the invention described above may be used in the form of acids, esters or other chemical species falling within the scope of the compounds. These compounds may also be used within the scope of the present invention, i.e. in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases according to methods well known in the art.

Pharmaceutically acceptable salt forms of the compounds of formula (1.0.0) are most likely prepared by conventional methods. When the compound of formula (1.0.0) contains a carboxylic acid group, suitable salts thereof may be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Examples of such bases are alkali metal hydroxides including potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. Also included are aluminum salts of the compounds of formula (1.0.0).

For certain compounds of formula (1.0.0), these compounds may be treated with pharmaceutically acceptable organic and inorganic acids to form acid addition salts, for example, hydrohalic salts such as the hydrochloride, hydrobromide, hydroiodide; other inorganic acids and their corresponding salts such as sulfates, nitrates, phosphates, etc.; alkyl-and monoaryl sulfonates such as ethane sulfonate, toluene sulfonate, and benzene sulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like.

Thus, pharmaceutically acceptable acid addition salts of compounds of formula (1.0.0) include, but are not limited to, acetate, adipate, alginate, arginine, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, lauryl sulfate, ethanesulfonate, fumarate, mucate (galactarate) (made from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isobutyrate, salts of compounds of formula (1.0.0), Lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate.

Further, base salts of the compounds of the present invention include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Among the above salts, ammonium salts, sodium and potassium alkali metal salts and calcium and magnesium alkaline earth metal salts are preferred. Salts of compounds of formula (1.0.0) derived from pharmaceutically acceptable non-toxic organic bases include, but are not limited to, salts with primary, secondary and tertiary amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, chitosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, and mixtures thereof, Tripropylamine, and tris- (hydroxymethyl) -methylamine (tromethamine).

Compounds of the invention comprising basic nitrogen-containing groups may be quaternized with such agents, e.g. (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; sulfuric acidTwo (C)₁-C₄) Alkyl esters such as dimethyl sulfate, diethyl ester and diamyl ester; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl- (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. These salts can make water-soluble and oil-soluble compounds of the invention.

Among the above pharmaceutically acceptable salts, preferred include, but are not limited to, acetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiolate, tosylate and trimethylamine.

The acid addition salts of the basic compounds of formula (1.0.0) can be prepared by contacting the free base form with a sufficient amount of the acid required for salt formation in a conventional manner. The free base can be regenerated by contacting the salt form with a base in a conventional manner and then isolating the free base. The free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, these salts are otherwise equivalent to their corresponding free base forms.

As mentioned above, the pharmaceutically acceptable base addition salts of the compounds of formula (1.0.0) are formed by reaction with metals or amines, such as alkali and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

Base addition salts of the acidic compounds of the invention may be prepared by contacting the free acid form with a sufficient amount of the base required to form the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and then isolating the free acid in a conventional manner. The free acid forms differ somewhat from their corresponding salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, these salts are otherwise equivalent in their corresponding free acid forms.

When the compounds of the present invention contain more than one group capable of forming such pharmaceutically acceptable salts, double salt forms are also included within the scope of the present invention. Examples of typical double salt forms include, but are not limited to, ditartrate, diacetate, difumarate, diglucamine, diphosphate, disodium and trihydrochloride.

In light of the above, it will be understood that the term "pharmaceutically acceptable salt" as used herein is meant to include active ingredients of the compounds of formula (1.0.0) used in their salt form, especially in these salt forms, i.e. they are capable of imparting improved pharmacokinetic properties to the active ingredient compared to the free form of the active ingredient or some other salt form of the active ingredient used previously. The pharmaceutically acceptable salt form of the active ingredient may also initially impart to the active ingredient beneficial pharmacokinetic properties not previously possessed by the active ingredient, and which may even positively influence the pharmacokinetics of the active ingredient with respect to its in vivo therapeutic activity.

The pharmacokinetic properties of the active ingredients that can be favorably influenced include, for example, the way in which the active ingredients are transported across the cell membrane, which in itself can directly and positively influence the absorption, distribution, biotransformation and excretion of the active ingredients. While the route of administration of the pharmaceutical composition is important, and various anatomical, physiological and pathological factors can have a significant impact on bioavailability, the solubility of the active ingredient generally depends on the nature of the particular salt form used. Furthermore, as is known to those skilled in the art, aqueous solutions of the active compounds will enable the active ingredient to be absorbed most rapidly into the body of the patient to be treated, whereas lipid solutions and suspensions, as well as solid dosage forms, do not enable the active ingredient to be absorbed rapidly.

Oral intake of the active ingredient of formula (1.0.0) is the most preferred route of administration for reasons of safety, convenience and economy, but absorption of such oral dosage forms can be adversely affected by physical properties such as polarity, vomiting due to irritation of the gastrointestinal mucosa, destruction by digestive enzymes and low pH, irregular absorption or propulsion in the presence of food or other drugs, and enzymatic metabolism of the mucosa, intestinal flora or liver. Formulating the active ingredient into different pharmaceutically acceptable salt forms is effective in overcoming or alleviating one or more of the above-mentioned problems encountered with absorption of oral dosage forms.

The compound of formula (1.0.0) prepared according to the process described herein may be isolated from the reaction mixture which is ultimately produced by any conventional method known to chemists skilled in the art of the preparation of organic compounds. After isolation, the compound is purified by known methods. Various methods and techniques can be used as methods of separation and purification, and include, for example, distillation; recrystallizing; column chromatography; ion exchange chromatography; gel chromatography; affinity chromatography; preparing thin-layer chromatography; and solvent extraction.

7.1 stereoisomers

The constituent atoms of a compound within the range of formula (1.0.0) although having the same connectivity can be arranged in two or more different ways spatially. As a result, the compounds can exist in stereoisomeric forms. The cis-trans isomerism is only a stereoisomerism. When the stereoisomers are mirror images of each other that cannot overlap, they are enantiomers with chirality due to the presence of one or more asymmetric carbon atoms in their constituent structures. Enantiomers are optically active and are identifiable because they enable the plane of polarized light to be rotated equally in opposite directions.

When two or more asymmetric carbon atoms are present in a compound of formula (1.0.0), there are two possible configurations for each of the carbon atoms. For example, when two asymmetric carbon atoms are present, there are four possible stereoisomers. In addition, the four possible stereoisomers may be arranged in six possible pairs of stereoisomers that are different from each other. In order for pairs of molecules with more than one asymmetric carbon to be enantiomers, they must have different configurations on each asymmetric carbon. These diastereomeric relationship pairs have different stereochemical relationships (referred to as diastereomeric relationships). Stereoisomers of diastereomers are referred to as diastereomers, and are commonly referred to as diastereomers.

All these known aspects of the stereochemistry of the compounds of formula (1.0.0) are considered to be part of the present invention. Thus included within the scope of the present invention are compounds of formula (1.0.0) which are stereoisomers, wherein these stereoisomers are enantiomers, single enantiomers, racemic mixtures and artificial mixtures of said enantiomers, i.e. manufactured mixtures wherein the ratio of said enantiomers is different from the ratio of said enantiomers in the racemic mixture. When a compound of formula (1.0.0) includes stereoisomers which are diastereomers, within the scope of the compound are included single diastereomers as well as mixtures of two or more of the diastereomers in any ratio.

For example, in the presence of a single asymmetric carbon atom in the compound of formula (1.0.0), the (-) R and (+) (S) enantiomers are formed; included within the scope of the compounds are all pharmaceutically acceptable salt forms, prodrugs and metabolites thereof that are therapeutically active and useful in the treatment or prevention of the conditions further described herein. When the compounds of formula (1.0.0) are present in the form of the (-) (R) and (+) (S) enantiomers, the (+) (S) enantiomer alone, or the (-) (R) enantiomer alone, is likewise included within the scope of the compounds, in which case all, substantially all or most of the therapeutic activity belongs to only one of the enantiomers, and/or the adverse side effects belong to only one of the enantiomers. In the case where there is no substantial difference in the biological activity of the two enantiomers, the (+) (S) enantiomer and the (-) (R) enantiomer are further included within the scope of the compound of formula (1.0.0) as a racemic mixture or as a non-racemic mixture in any suitable amount ratio, present together.

For example, in the presence of the pair of enantiomers of formula (1.0.0), its unique biological activity and/or physicochemical properties suggest that a certain proportion of said enantiomers can be used to constitute the final therapeutic product. By way of example, where enantiomeric pairs are present, they may be used in different ratios, for example 90% (R) to 10% (S); 80% (R) to 20% (S); 70% (R) to 30% (S); 60% (R) to 40% (S); 50% (R) to 50% (S); 40% (R) to 60% (S); 30% (R) to 70% (S); 20% (R) to 80% (S); and 10% (R) to 90% (S). After evaluating the properties of the various enantiomers (when present) of the compound of formula (1.0.0), the proportional amount of one or more of said enantiomers having each desired property constituting the final therapeutic product can be determined in a simple manner.

7.2 isotope

Also further included within the scope of compounds of formula (1.0.0) are isotopically labeled forms thereof. Isotopically-labelled forms of the compounds of formula (1.0.0) are identical to those recited, except that one or more atoms in the compound are replaced by an atom having an atomic mass or atomic number different from the atomic mass or atomic number usually found in nature. Examples of commercially available isotopes which can be incorporated into compounds of formula (1.0.0) in known manner include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example respectively²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of formula (1.0.0), prodrugs thereof, or pharmaceutically acceptable salts of both, containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.

Isotopically-labeled formula (1.0.0) can be effectively used in various aspects. For example, isotopically-labelled compounds of formula (1.0.0), e.g. doped with a radioactive isotope such as³H and¹⁴c, useful in drug and/or substrate tissue distribution assays. These isotopes are tritium (A), (B), (C), (³H) And carbon-14 (¹⁴C) Particularly preferred for ease of preparation and detection. The incorporation of heavier isotopes such as deuterium (i.e., deuterium) into compounds of formula (1.0.0)²H) To obtain certain therapeutic advantages, based on isotopic labelling The compound has higher metabolic stability. Higher metabolic stability is directly manifested by an increased half-life in vivo or a reduced dosage requirement, which in most cases constitutes a preferred embodiment of the invention. Isotopically labeled compounds of formula (1.0.0) are generally prepared by following the procedures disclosed in the synthetic schemes herein and in the associated descriptions, examples and preparations, by substituting a readily available isotopically labeled reagent for its corresponding non-isotopically labeled reagent.

Deuterium²H can also be incorporated into the compound of formula (1.0.0) for manipulating the oxidative metabolic processes of the compound by first order kinetic isotope effects. The first order kinetic isotope effect refers to the rate change of the chemical reaction initiated by the replacement isotope core, which in turn is caused by the change in ground state energy required to form covalent bonds after the substitution by the isotope. Substitution of heavier isotopes generally results in a reduction in the ground state energy required for chemical bonds, thereby causing a reduction in the rate of the rate-limiting bond cleavage step. If the bond rupture occurs at or near the saddle point region in accordance with the coordinates of the multi-product reaction, the product split ratio may change significantly. For example, when tritium is bound to a carbon atom at a non-exchangeable site, the typical rate difference K _M/K_D2-7. This rate difference applies successfully to oxidatively unstable compounds of formula (1.0.0) and can significantly affect the in vivo distribution of the compounds, resulting in improved pharmacokinetic properties.

In the discovery and development of therapeutic agents, practitioners are seeking to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to speculate that many compounds with poor pharmacokinetic profiles have the disadvantage of oxidative metabolic instability. The in vitro liver microsome assay now available provides valuable information on this oxidative metabolism, so that deuterated compounds of formula (1.0.0) with improved stability by tolerating this oxidative metabolism can be rationally designed. Thereby obtaining a significantly improved pharmacokinetic profile of the compound of formula (1.0.0) and allowing for a maximum therapeutic effect with an in vivo half-life (t/2)Concentration (C) of_max) Increase in area under the dose response curve (AUC) and F, and decrease in clearance, dose and cost of goods are quantified.

By way of example above, compounds of formula (1.0.0) having multiple sites of oxidative metabolic potential (e.g., a benzylic hydrogen atom and a hydrogen atom alpha to the nitrogen atom) are made into a series of analogs in which various combinations of hydrogen atoms are replaced with deuterium atoms, resulting in the replacement of some, most, or all of the hydrogen atoms with deuterium atoms. The half-life period measurement provides a simple and accurate method for measuring the improvement degree of antioxidant metabolism. It has been determined in this way that the half-life of the parent compound can be extended by up to 100% as a result of this deuterium-hydrogen substitution.

Deuterium-hydrogen substitution of the compound of formula (1.0.0) may also be used to obtain a favourable change in the metabolite distribution of the parent compound as a way of reducing or eliminating harmful toxic metabolites. For example, where toxic metabolites are produced by oxidative carbon-hydrogen (C-H) cleavage, deuterated analogs are expected to substantially reduce or eliminate undesirable metabolite production, even in the case of specific oxidation non-rate-determining steps.

Further information on deuterium-hydrogen substitution prior art can be found, for example, in Hanzlik et al, J.org.chem.553992-3997, 1990; reider et al, J.org.chem.523326-3334, 1987; foster, adv. drug res.141-40, 1985; gillette et al, Biochemistry 33(10) 2927-; and Jarman et al, Carcinogenesis16(4)683-688, 1993.

Detailed Description

8.0 therapeutic applications and clinical Final Condition

The following description relates to the therapeutic use of the compounds of formula (1.0.0), where appropriate to explain the clinical end-points associated with such therapeutic use. The contents of various in vitro assays and animal model tests are also described, thereby providing sufficient information to demonstrate and demonstrate the therapeutic utility of the compound of formula (1.0.0).

The therapeutic utility of the compounds of formula (1.0.0) is applicable to patients or hosts suffering from the diseases or conditions described herein and in need of such treatment. Either administered to an animal or a human will produce beneficial therapeutic results. The term "animal" as used herein is intended to refer to humans as opposed to other species of animals. The compounds of formula (1.0.0) have therapeutic utility in the treatment of mammals, particularly humans. As described herein, when referring to a subject, all major subclasses of mammalian species are included within the scope of the invention. Mammals, such as pets, are important to humans and, therefore, may be subjects. This applies in particular to canine and feline mammals. Other mammals are estimated to be domestic animals, but their treatment according to the invention is unlikely to be useful for the treatment of the diseases and conditions described herein, given the poor economic results. This applies in particular to equine, bovine, porcine and ovine mammals.

The compounds of formula (1.0.0) are capable of inhibiting the PDE4 isozyme and thus have broad therapeutic utility as described below, since the PDE4 isozyme family plays an important role in the physiology of all mammals. The enzymatic action performed by the PDE4 isozyme is intracellular hydrolysis of adenosine 3 ', 5' -monophosphate (cAMP) in proinflammatory leukocytes. cAMP itself is a major factor mediating the action of various hormones in vivo, and as a result, inhibition of PDE4 plays an important role in various physiological processes. There is a lot of literature in the art describing the effects of PDE inhibitors on various inflammatory cell responses, including inhibition of superoxide generation, degranulation, chemotaxis and the release of Tumor Necrosis Factor (TNF) in eosinophils, neutrophils and monocytes, in addition to cAMP elevation.

PDE4 was first identified in 1985 by Nemoz et al (biochem. pharmacol.342997-3000, 1985), and the PDE4 inhibitors rolipram and denbufylline were previously studied in clinical trials for CNS indications such as depression. PDE4 was later determined to be the major phosphodiesterase in inflammatory leukocytes. The four subtypes of PDE4, PDE4A, PDE4B, PDE4C, and PDE4D, are widely distributed in human tissues as measured by the presence of their mRNAs. PDE4D is expressed in kidney, thymus, small intestine and colon tissues, and is strongly expressed in brain, lung, skeletal muscle, prostate, and Peripheral Blood Leukocyte (PBL) tissues. Expression was weak only in heart, placenta, liver pancreas, spleen, testis, and ovary tissues. PDE4A and PDE4B were also strongly expressed in brain and skeletal muscle tissue, but were weakly expressed in placenta, liver and ovary tissue. PDE4C is also strongly expressed in skeletal muscle tissue, but is also weakly expressed in ovarian tissue. PDE4C is not generally detectable in most of the above tissues.

The PDE4 isozyme family is the predominant phosphodiesterase form found in cell types associated with chronic inflammatory diseases, and in bone marrow derived cell types, only platelets do not express PDEs. PDE4 is the major cAMP-metabolizing enzyme in immune and inflammatory cells, and is one of the two major cAMP-metabolizing enzymes in airway smooth muscle. PDE4 is present only in neutrophils, eosinophils, basophils and monocytes, whereas PDE3 and PDE1 activity has been shown in macrophages and PDE7 activity in T lymphocytes. PDE inhibitors have been demonstrated to have beneficial anti-inflammatory effects in vitro and have been confirmed to inhibit peroxide production in human monocytes, eosinophils and neutrophils; inhibiting mediator release in basophils, macrophages and neutrophils; and inhibiting the release of TNF α in monocytes and macrophages. PDE inhibitors also inhibit inflammatory cells such as monocytes and monocyte-derived macrophages, lung mast cells, T-lymphocytes, B-lymphocytes, lung macrophages and eosinophils.

Also, beneficial anti-inflammatory effects have been observed in vivo, including inhibition of microvascular leakage into the lungs of sensitized guinea pigs, reduction of bronchial hyperreactivity and eosinophilia in cynomolgus monkeys after reducing antigen repeat challenge. PDE4 inhibitors have also been shown to be potent in inhibiting TNF α release from monocytes.

8.1 asthma

One of the most important respiratory diseases that can be treated with PDE4 inhibitors of the compound type of formula (1.0.0) is asthma, a chronic, increasing common disease worldwide, characterized by intermittent reversible airway obstruction, airway hyperresponsiveness and inflammation. The cause of asthma has not been identified to date, but the most common pathological manifestation of asthma is airway inflammation, which is equally evident in the airways of patients with mild asthma. From bronchial biopsy and lavage studies, it has been clearly shown that asthma is associated with infiltration of mast cells, eosinophils and T-lymphocytes into the airways of patients. Bronchoalveolar lavage (BAL) of allergic asthma says that the activation of Interleukins (IL) -3, IL-4, IL-5 and granulocyte/macrophage colony stimulating factor (GM-CSF) suggests the presence of a T-helper 2(Th-2) -like population of T-cells.

The compounds of formula (1.0.0) inhibit PDE4 in human eosinophils and are therefore useful in the treatment of allergic or non-allergic asthma. The term "atopic" refers to a genetic predisposition to develop type I (immediate) hypersensitivity to antigens commonly found in the environment. The most common clinical manifestations are allergic rhinitis, paroxysmal bronchial asthma, atopic dermatitis and occasional food allergies. Thus, the term "allergic asthma" as used herein is synonymous with "allergic asthma", i.e. bronchial asthma, i.e. the allergic manifestations of the sensitized population. The term "non-allergic asthma" as used herein refers to all other kinds of asthma, especially basic or "real" asthma, which are induced by various factors including intense exercise, irritant particles, psychological stress.

The use of the compounds of formula (1.0.0) for the treatment of allergic asthma or non-allergic asthma can be determined and demonstrated using the PDE inhibition model, inhibition of eosinophil activation and bronchodilator model described below.

Inhibition of PDE isozymesThe ability of the compounds of formula (1.0.0) to selectively inhibit PDE4 was demonstrated using a human PDE inhibition assay. In this test, all isoenzyme preparations were derived from human sources. Use of the advantage of the PDE3 isozyme in platelets and the advantage of the PDE4 isozyme in neutrophils to obtain PDE3 and PDE4 preparations . The following procedure was used. Citrated human blood was collected and neutrophils were isolated by dextran sedimentation, density gradient centrifugation and hypotonic lysis of erythrocytes. Using PBS (NaCl 140mM, KCl 2.7mM, KH)₂PO₄ 1.5mM，Na₂HPO₄8.1mM, pH7.4) human platelets from the same source. Neutrophils and platelets were suspended in 10ml of buffer (0.24M sucrose, 1M MEDTA, 1mM dithiothreitol, 10mM trisHCI, ph7.4) containing the following protease inhibitors: 5 μ l/ml phenylmethylsulfonyl fluoride (7mg/ml 2-propanol), 1 μ/ml leupeptin and pepstatin A (1mg/ml, ethanol). After sonication at 4 ℃ for 15 seconds, the homogenate was centrifuged (2200 g). The pellet was resuspended in 10ml buffer and sonication repeated. The supernatants were pooled and stored at-20 ℃.

Other isozymes were partially purified by chromatography as described in the prior art, where PDE1 and PDE5 were obtained from human lungs, and PDE2 was obtained from human platelets. PDE activity is determined using the ion exchange column method described by Thompson et al (Nucleotide Res., 10, 69-92, 1979) in the presence or absence of variable concentrations of a test substance of formula (1.0.0), using 1. mu.M³H]Cyclic AMP as a substrate (PDE3 and PDE4), or 0.5. mu.M calcium, 0.125. mu.M calmodulin and 1.0. mu.M [ alpha ] ³H]Cyclic AMP (PDE1), or 100. mu.M [ solution ]³H]Cyclic AMP (PDE2), or 1.0. mu.M [, ]³H]Cyclic GMP (PDE 5).

In this test method, the compound of formula (1.0.0) inhibits mainly PDE4 isozyme, with a relatively low inhibitory effect on PDE1, PDE2, PDE3 and PDE 5.

The selective PDE4 inhibitory activity of the compound of formula (1.0.0) can also be determined using a panel of five different PDE isozymes according to methods known in the art. Tissues used as sources of different isozymes may include the following: PDE 1B-porcine aorta; PDE 1C-guinea pig heart; PDE 3-guinea pig heart; PDE 4-human monocytes; and PDE 5-canine bronchiole. PDE1B, 1C, 3, and 5 were partially purified by conventional chromatographic methods; torphy and Cieslinski, mol. Pharmacol.37206-214, 1990. PDE4 was purified to kinetic purity using anion exchange sequentially after heparin-Sepharose chromatography; torphy et al, J.biol.chem.2671798-1804, 1992.PDE Activity was determined using the Torphy and Cieslinski method described in the above-mentioned article.

The ability of PDE4 inhibitor compounds of formula (1.0.0) to increase cAMP accumulation in intact tissues can also be evaluated using U-937 cells, a human monocyte cell line that has been shown to contain large amounts of PDE 4. To determine the level of PDE4 inhibitory activity in intact cells, undifferentiated U-937 cells (approximately 10) ⁵Cells/reaction tubes) were incubated with different concentrations (0.01-1000. mu.M) of PDE4 inhibitor for 1M, followed by 1. mu.M prostaglandin E₂Incubate for 4 minutes. After the reaction was initiated by adding 17.5% perchloric acid, the cells were lysed for 5 minutes, and 1M KCO was added₃The pH was adjusted to a neutral level and the cAMP content was measured with RIA. General protocols for this assay are described in Brooker et al, "radioimmunoassays of cyclic AMP and cyclic GMP," adv. cyclic Nucleotide Res.101-33, 1979.

Bronchodilator activityVarious isozyme-selective PDE inhibitors have been identified which cause effective relaxation of airway smooth muscle in the human airways, and PDE1, 2, 3, 4, and 5 enzyme activity has been measured in these tissues and cells. Selective inhibitors of PDE3 and PDE4 have been shown to cause bronchial ring relaxation under a variety of conditions. In addition, cAMP is not only associated with relaxation of airway smooth muscle, but also exerts a general inhibitory effect on the proliferation of airway smooth muscle. Airway smooth muscle hypertrophy and hyperplasia are regulated by cAMP, and these symptoms are common features of chronic asthma morphology. The combination of PDE3 with a PDE4 inhibitor has been shown to have a significant inhibitory effect on proliferation. Several families of PDE isozymes, including PDE4, have been found in human pulmonary arteries, and selective PDE inhibitors have been shown to produce an effect in relaxing the pulmonary artery rings.

Relaxation of human bronchial tubesHuman lung samples cut in cancer surgery were obtained within 3 days after resection. The small bronchi (internal diameter ≈ 2-5mm) were excised, cut into several portions, and placed in 2ml of a liquid nitrogen storage ampoule containing Fetal Calf Serum (FCS) containing 1.8M Dimethylsulfoxide (DMSO) and 0.1M sucrose as cryoprotectants. Putting the ampoule into a containerPlaced in a polystyrene box (11X 22cm) and slowly frozen in a refrigerator maintained at-70 ℃ at an average cooling rate of about 0.6 ℃/m. After 3-15 hours, the ampoules were transferred to liquid nitrogen (-196 ℃) and stored until use. Before use, the tissue is placed at-70 deg.C for 30-60m, and then the ampoule is placed in a 37 deg.C water bath to be thawed within 2.5 m. The bronchial segment was then placed in Krebs-Henseleit solution (μ M: NaCl118, KCl 4.7, MgSO 2) containing 37 deg.C₄ 1.2，CaCl₂ 1.2，KH₂PO₄ 1.2，NaHCO₃25, glucose 11, EDTA 0.03), and then cut into circumferential strips, suspended in a 10ml organ bath, and recorded under an approximately 1g preload for an equal volume (isometric) of tension. Concentration-response curves were plotted by cumulative addition, with each concentration addition occurring when the previous concentration produced the greatest effect. Addition of papaverine (300. mu.M) at the end of the concentration response curve induced complete relaxation of the bronchial rings. This effect is considered to be 100% relaxation.

In the above assay model, the compound of formula (1.0.0) produces concentration-dependent relaxation in human bronchial preparations at concentrations ranging from 0.001 to 1.0. mu.M, and in a preferred embodiment, the compound is active at concentrations ranging from 5.0nM to 50 nM.

Inhibition of Bombesin (Bombesin) -induced bronchoconstrictionMale Dunkin-Hartley guinea pigs (400-800g) were selected, fed and drunk freely before the trial, anesthetized with sodium phenobarbital (100mg/kg i.p.) and sodium pentobarbital (30mg/kg i.p.), and then paralyzed with bisabolomine (10mg/kg i.m.). The animals were kept 37 ℃ with a hot plate (controlled with a rectal thermometer) and ventilated with a mixture of air and oxygen (45: 55v/v) through a tracheal tube (approximately 8ml/kg, 1 Hz). Ventilation was monitored at the trachea using a pneumotachograph connected to a differential pressure transducer (with a respiratory pump in series). The pressure difference between the trachea and the thorax can be measured and displayed using a differential pressure transducer to directly monitor intra-thoracic pressure changes through an intra-thoracic cannula. From these measurements of airflow and transpulmonary pressure, the airway resistance (R) per respiratory cycle is calculated using a digital electronic breath analyzer₁cmH₂O/l/s)And compliance (Cd) _dyn). The pressure transducer was used to record the blood pressure and heart rate of the carotid artery.

When the values of basal resistance and compliance were stable, continued bronchoconstriction was induced by continuous intravenous infusion of bombesin (100 ng/kg/min). Bombesin was dissolved in 100% ethanol and diluted with phosphate buffered saline. The test compound of formula (1.0.0) was administered when the response to bombesin was strongest and stable (calculated as 2 minutes after the start of the infusion of bombesin). Reversal of bronchoconstriction was assessed 1 hour after intratracheal or intraduodenal instillation or intravenous bolus (bolus). Bronchial spasmolytic activity the strongest resistance (R) was initiated following infusion of bombesin_D) The% inhibition is expressed. ED (electronic device)₅₀Values represent doses that resulted in a 50% reduction in bombesin-induced resistance. Duration of action is defined as the time required to reduce bronchoconstriction by 50% or more, in minutes. Effect on Blood Pressure (BP) and Heart Rate (RT) with ED₂₀Value characterisation, i.e. the dose required to reduce BP and HR 20% was measured 5 minutes after dosing.

The test compound of formula (1.0.0) may be administered in the form of a solution or, in the case of intratracheal or intraduodenal instillation, in the form of an aqueous suspension containing 0.5% gum tragacanth, in which case the test compound does not dissolve completely. The suspension was sonicated for 5 minutes prior to dosing to obtain a fine particle size. 2-4 doses (n-3-4/dose) were tested per drug. Appropriate amounts of controls (5-6) were used.

In the above test model, the compound of formula (1.0.0) shows bronchodilatory activity in the dose range of 0.001-0.1mg/kgi.v. or 0.1-5.0 mg/kgi.d.

Asthma rat testThis test is used to evaluate the therapeutic effect of the compound of formula (1.0.0) on dyspnea symptoms, i.e. dyspnea or laboriousness, using rats syngeneically bred from asthmatic rats. Both female (190-250g) and male (260-400g) rats were used.

Ovalbumin (EA) (grade V, crystallized and lyophilized), aluminum hydroxide and mexican ergot hydrogen maleate were all commercially available. The excitation and subsequent breath recordings were made in a clear plastic box with an internal size of 10 x 6 x 4 inches. The top of the box is removed. In use, the top is held tightly in place by four clips and a soft rubber gasket is used to maintain the air tight seal. The atomizer was inserted in a gas-tight manner through the centre of each end face of the cell, and the box also had an outlet on each end face. The pneumotachograph is inserted into one end face of the box, connected to a positive displacement pressure transducer and then connected to a dyne recorder (dynograph) by means of a suitable connector. In aerosol antigen, the outlet is opened and the pneumotachograph is isolated from the chamber. The exit port is then closed and the pneumotachograph is connected to the chamber during recording of the breathing pattern. For priming, 2ml of 3% antigen in saline was placed in each nebulizer and an aerosol was formed from a small diaphragm pump using air at 10psi and 8 liters/m flow rate.

Rats were sensitized by subcutaneous injection of 1ml of a suspension containing 1mgEA and 200mg of aluminum hydroxide in physiological saline. It can be used 12-24 days after sensitization. To remove the response of the 5-hydroxytryptamine component, rats were pretreated with 3.0mg/kg of mexican by intravenous injection 5 minutes prior to aerosol challenge. Rats then received 3% EA saline aerosol for 1 minute and a further 30 minute breath profile was recorded after one mole. The duration of continuous dyspnea was determined from the breath record.

The test compound of formula (1.0.0) is typically administered orally 1-4 hours prior to challenge, or by intravenous injection 2 minutes prior to challenge. The compound is dissolved in normal saline or 1% methylcellulose, or suspended in 1% methylcellulose. The test compounds were administered in a volume of 1mg/kg (intravenous) or 10mg/mg (oral). Rats were fasted overnight before oral treatment. The activity of the rats was determined on the basis of their ability to reduce the duration of action of dyspnea symptoms compared to vehicle-treated controls. The evaluation of the test compound of the formula (1.0.0) is carried out using a series of doses, and from this the ED is derived₅₀The value, i.e. defined as the dose which enables the duration of symptoms to be suppressed by 50%.

Trained conscious squirrel monkey Lung mechanics ofThis method is useful for evaluating the ability of a compound of formula (1.0.0) to inhibit roundworm antigen-induced breathing parameters of squirrel monkeys, such as airway resistance. The test method comprises fixing a trained squirrel monkey on a chair placed in an aerosol treatment chamber. For control purposes, mechanical measurements of pulmonary respiratory parameters were recorded for approximately 30 minutes to establish day-of-day monkey normal control values. For oral administration, the compound of formula (1.0.0) is dissolved or suspended in a 1% methylcellulose solution (methylcellulose, 65HG, 400cps) at an amount of 1ml/kg body weight. For aerosol administration of the compound of formula (1.0.0), an ultrasonic nebulizer is used. The period of pretreatment of monkeys before challenge with aerosol dose roundworm antigen varied from 5 minutes to 4 hours.

After stimulation, for all the parameters including airway resistance (R)_L) And dynamic compliance (C)_dyn) For each respiratory parameter included, the data per minute was converted to a% rate of change from the control. Results for each test compound were then obtained (60 min shortest time post challenge test) and then compared to previously obtained historical baseline control values relating to the particular monkey. In addition, all values at 60 minutes post challenge, i.e., the historical baseline value and the test value, were averaged independently for each monkey and used to calculate the total percent inhibition of the test compound response to roundworm antigen. For statistical analysis of the results, a paired t-test was used.

Prevention of induced bronchoconstriction in allergic sheepThe therapeutic activity of the compound of formula (1.0.0) in the prevention of bronchoconstriction is tested as follows. This is based on the discovery that certain breed allergic sheep with known sensitivity to the specific antigen Ascaris suum (Ascaris suum) are able to respond to an inhaled challenge in the form of an acute or delayed bronchial response. The progression of acute or delayed bronchial responses over time approximates the time course observed in asthmatic patients; in addition, pharmacological changes in acute or delayed bronchial responses are similar to those found in humans. The response of these sheep to antigen challenge is likely to be observed in their large airways, allowing monitoring of this effect in the form of changes in lung resistance, i.e. specific lung resistance.

Adult sheep with an average body weight of 35kg (range: 18-50kg) were used. All animals used met two criteria: 1) they have a natural skin response to a 1: 1000 or 1: 10000 dilution of ascaris suum extract; and 2) they have previously responded to an inhaled challenge by ascaris suum, with acute bronchoconstriction and delayed bronchial obstruction. See Abraham et al, am. Rev. Resp. Dis.128839-844, 1983.

The sedated sheep were confined in the car in a prone position with the head fixed. After local anesthesia of the nasal passages with a 2% lidocaine solution, the balloon catheter was pushed into the lower esophagus through one nostril. Then, a soft fiber optic bronchoscope is used as a guide to insert a rubber tube head (cuffed) endotracheal tube into the animal body through the other nostril. Intrathoracic pressure is measured using an oesophageal balloon catheter (filled with 1ml of air) positioned to produce a clearly identifiable cardiogenic oscillatory negative pressure fluctuation on inspiration. The tracheal side pressure was measured with a side hole catheter (inner diameter: 2.5mm) inserted distal to the end of the nasal tracheal cannula. Transpulmonary pressure, i.e., the difference between tracheal pressure and intrapleural pressure, was measured using a differential pressure transducer. The test pressure transducer conduit system showed no phase shift between pressure and flow up to a frequency of 9 Hz. To measure pulmonary resistance (R)_L) The largest end of the nasal trachea is connected to the pneumotachograph. Recording flow and transpulmonary pressure signals by using an oscilloscope connected with a computer, and calculating R on line according to transpulmonary pressure, respiratory volume obtained by integration and flow_L. Analyzing 10-15 breaths to determine R_L. Intrathoracic volume of gas (V)_tg) Measured with a positive displacement plethysmograph to obtain pulmonary resistance (SR) _L＝R_L·V_tg).

An aerosol of ascaris suum extract (1: 20) was provided using a disposable medical nebulizer to produce a large number of aerosols (measured by an electrokinetic particle size analyzer) with a mean aerodynamic diameter of 6.2 μ M (geometric standard deviation, 2.1). The output end of the nebulizer is directed at the T-shaped piece of plastic, one end of which is connected to the nasal airway and the other end of which is connected to the inspiratory portion of a conventional respirator. The aerosol was sprayed at a rate of 20 ml/min for a total volume of 500 ml. Thus each sheep received an equivalent dose of antigen in both placebo and drug trials.

Obtaining SR before antigen challenge_LStarting the infusion of test compound 1 hour before the challenge and repeating the determination of SR_LThen, the pig roundworm antigen is inhaled to excite the sheep. Measurement of SR immediately after antigen challenge_LSR was then measured 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5 and 8 hours after antigen challenge_L. Placebo and drug trials were at least 14 days apart. In a further study, the sheep were administered a bolus dose of the test compound followed by a 0.5-1 hour infusion of the test compound prior to the ascaris suum challenge and 8 hours post ascaris suum challenge as described above. The acute immediate response and the maximum delayed response to antigen in the control animals and the drug-treated animals were compared using the Kruskal-Wallis one-way ANOVA test (Kruskal-Wallis one-way ANOVAtest).

Anti-inflammatory ActivityThe anti-inflammatory activity of the compound of formula (1.0.0) is demonstrated by the inhibition of eosinophil activation. In this test, a blood sample (50ml) was taken from a non-atopic volunteer, in which the eosinophil count was between 0.06 and 0.47X 10⁹L^-1In the meantime. Venous blood was collected into a centrifuge tube containing 5ml trisodium citrate (3.8%, pH 7.4).

Anticoagulated blood was diluted with phosphate buffered saline (PBS, i.e., neither calcium nor magnesium) (1: 1, v: v) and layered onto 15ml of isotonic Percoll (density 1.082-1.085g/ml, pH7.4) in a 50ml centrifuge tube. After centrifugation (30 min, 1000Xg, 20 ℃), the monocytes at the plasma/Percoll interface were carefully aspirated and discarded.

The neutrophil/eosinophil/erythrocyte pellet (about 5ml by volume) was slowly suspended in 35ml of an isotonic ammonium chloride solution (NH)₄Cl，155mM；KHCO₃10 mM; EDTA, 0.1 mM; 0 to 4 ℃ below zero. After 15 min, cells were washed twice (10 min, 400Xg, 4 ℃) in PBS containing fetal calf serum (2%, FCS).

Eosinophils and neutrophils were separated using a magnetic cell separation system. The system is capable of separating cells in suspension based on surface markers and comprises permanent magnets (placed in a column comprising a magnetizable steel matrix). Before use, the column was equilibrated with PBS/FCS for 1 hour and then flushed with ice-cold PBS/FCS through a 20ml syringe according to the retrograde basic principle. A21G hypodermic needle was attached to the bottom of the column and 1-2ml of ice cold buffer was passed through the needle.

After centrifugation of the granulocytes, the supernatant was aspirated and the cells were slowly resuspended with 100. mu.l of magnetic particles (anti-CD 16 monoclonal antibody, conjugated with super-magnetic particles). The eosinophil/neutrophil/anti-CD 16 magnetic particle mixture was incubated on ice for 40 minutes and then diluted to 5ml with ice-cold PBS/FCS. The cell suspension was slowly added to the top of the column and the linker was opened to allow the cells to move slowly into the steel matrix. The column was then washed with PBS/FCS (35ml), taking care to apply to the top of the column not to disturb the magnetically labelled neutrophils that had been trapped in the steel matrix. Unlabeled eosinophils were collected in 50ml centrifuge tubes and washed (10 min, 400Xg, 4 ℃). The resulting pellet was resuspended in 5ml Hank's Balanced Salt Solution (HBSS) so that cell number and purity could be determined prior to use. Separating the column from the magnet and eluting the neutrophil fraction. The column was then washed with PBS (50ml) and ethanol (anhydrous) and stored at 4 ℃.

Total cells were counted using a micro-cytometer. A drop of lysogenic solution was added to the sample and counted after 30 seconds to assess contamination with red blood cells. Cell spin spreads (Cytospinsmears) were prepared on a Shandon Cytosin2 cell spin machine (cytospinner) (100. mu.l sample, 3 min, 500 rpm). The preparations were stained and differential cell counts were determined by light microscopy to detect at least 500 cells. Cell viability was determined according to the trypan blue exclusion assay.

Eosinophils were diluted in HBSS and pipetted into a 96-well microtiter plate (MTP) at 1-10X 10 per well³And (4) cells. Each well contained 200 μ l of sample consisting of: 100 μ l eosinophil suspension; 50 μ l HBSS; 10 μ l lucigenin; 20 μ l of activating stimulin; and 20. mu.l of test compound.

The samples were incubated with the test compound before addition of the activated stimulator fMLP (10 μ M) in dimethyl sulfoxide and then diluted with buffer to give a maximum solvent concentration of 1% (in the case of a 100 μ M test compound concentration). The MTPs were agitated to facilitate mixing of the cells with the medium, and then the MTP was placed in the spectrometer. The total chemiluminescence and time profile of each well was measured simultaneously for a total of 20 minutes and the results were expressed in arbitrary units or as percentage of fMLP-induced chemiluminescence in the absence of test compound. According to the fitting result of the Hill equation, automatically calculating IC₅₀。

In the above assay methods, the compound of formula (1.0.0) is active at a concentration of 0.0001. mu.M-20.0. mu.M, and in a preferred embodiment, the compound of formula (1.0.0) is active at a concentration of 0.5nM-1000 nM.

In view of the foregoing, it can be seen that the compounds of formula (1.0.0) are useful in the treatment of inflammatory or obstructive airways diseases or other conditions associated with airway obstruction. They are particularly suitable for the treatment of bronchial asthma.

In view of their anti-inflammatory activity, their effect on airway hyperreactivity and their profile relative to PDE isoenzyme inhibition, in particular as selective PDE4 inhibitors, the compounds of formula (1.0.0) are suitable for the treatment, in particular prophylactic treatment, of obstructive or inflammatory airway diseases. For example, by continuous and chronic regular administration, the compounds of formula (1.0.0) may be used to provide superior protection against the recurrence of bronchoconstriction or the onset of other symptoms that occur in response to obstructive or inflammatory airway disease. The compounds of formula (1.0.0) are also useful in controlling, ameliorating or reversing the underlying state of this disease.

In view of their bronchodilator activity, the compounds of formula (1.0.0) are useful as bronchodilators, e.g. for the treatment of chronic or acute bronchoconstriction, and for the symptomatic treatment of obstructive or inflammatory diseases.

Thus, the words "treatment" and "treating" as used in the specification and claims of the present invention in connection with an obstructive or inflammatory airways disease shall be understood to encompass both prophylactic and symptomatic treatment.

From the foregoing, it will be appreciated that the invention also relates to a method of treating airway hyperresponsiveness in a mammal; a method of causing bronchodilation in a mammal; in particular, a method of treating an obstructive or inflammatory airway disease, especially asthma, in a mammalian subject in need thereof which comprises administering to the mammal being treated an effective amount of a compound of formula (1.0.0).

Obstructive or inflammatory airway diseases to which the present invention is applicable include asthma; pneumoconiosis; chronic eosinophilic pneumonia; chronic obstructive airways or lung disease (COAD or COPD); and Adult Respiratory Distress Syndrome (ARDS), as well as exacerbation of airway hyperreactivity following other drug therapies such as aspirin or beta-agonist therapy.

The compounds of formula (1.0.0) are useful in the treatment of asthma of any kind, etiology or pathogenesis; including intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by factors in the surrounding environment, and idiopathic asthma of unknown or unknown origin. The compounds of formula (1.0.0) are useful in the treatment of allergic (allergic/bronchial/IgE-mediated) asthma; they may also be used in the treatment of non-allergic asthma, including, for example, bronchitic asthma, emphysema asthma, exercise-induced asthma, and occupational asthma; infectious asthma, i.e. sequelae of microbial, especially bacterial, fungal, protozoal or viral infection; and other non-allergic asthma, such as incipient asthma (infantile asthma syndrome).

The compounds of formula (1.0.0) are further useful in the treatment of pneumoconiosis of any kind, etiology or pathogenesis; including, for example, alumina lung (bauxite worker disease); silicosis (miner asthma); asbestosis (central heating assembler asthma); pulmonitis chalicosa (flint disease); sucking ostrich hair dust to cause ostrich pneumoconiosis; iron pneumoconiosis caused by inhalation of iron particles; silicosis (abrasions); cotton scurf (cotton dust asthma); and pulmonary talc deposition disease.

8.2 Chronic Obstructive Pulmonary Disease (COPD)

The compounds of formula (1.0.0) are still further useful in the treatment of COPD or COAD, including chronic bronchitis, emphysema or dyspnea associated therewith. COPD is characterized by irreversible progressive airway obstruction. Chronic bronchitis is associated with hyperplasia and hypertrophy of submucosal mucous secretory glands in the airways of large cartilage. Goblet cell proliferation, infiltration of mucosal and submucosal inflammatory cells, edema, fibrosis, mucus plugs and smooth muscle proliferation are all seen in the terminal and respiratory bronchioles. Small airways are known to be the primary site of airway obstruction. Emphysema is characterized by destruction of the alveolar walls and loss of lung elasticity. A number of risk factors have been identified in connection with the occurrence of COPD. The link between smoking and COPD is well established. Other risk factors include exposure to coal dust and various genetic factors. See Sandford et al, "genetic factors at risk for chronic obstructive pulmonary disease", eur. respir. j.101380-1391, 1997. the incidence of COPD is increasing, representing a heavy economic burden for the population of industrialized countries. COPD also presents a variety of clinical deviations from simple chronic bronchitis without the disability of severely disabled patients with chronic respiratory failure.

COPD is characterized by airway inflammation as in the case of asthma, but the inflammatory cells found in bronchoalveolar lavage fluid and patient saliva are neutrophils rather than eosinophils. Inclusion of IL-8, LTB has also been found in COPD patients₄And TNF-alpha, and it has been found that the superficial epithelial and subepithelial membranes of these patient bronchi are infiltrated by T-lymphocytes and macrophages. For COPD patients, the use of β -agonists and anticholinergic bronchodilators can alleviate symptoms, but the disease course remains unchanged. COPD has been treated with theophylline, which, although it reduces the number of neutrophils in the saliva of COPD patients, is highly unsuccessful. Steroids also fail to bring high expectations as satisfactory therapeutic agents for COPD.

Thus, the use of compounds of formula (1.0.0) for the treatment of COPD and its associated diseases, including airway obstructive diseases, represents a great advance in the art. The present invention is not limited to any particular mode of action and hypothesis as to the manner of using the compound of formula (1.0.0) to achieve the desired therapeutic goal. It is generally accepted in the art that PDE4 is the predominant PDE in neutrophils and macrophages; cheng et al, "Synthesis and in vivo distribution of novel compounds of the series of catechol benzimidazoles. The discovery of potent, selective type IV phosphodiesterase inhibitors with greatly reduced affinity for the [3H ] rolipram binding site, bioorg.med.chem.lett.5, 1969-; wright et al, "differential inhibition of human neutrophil function: cyclic AMP-specific, cyclic GMP-insensitive phosphodiesterase action ", biochem. pharmacol.40699-707, 1990; schudt et al, "effects of selective phosphodiesterase inhibitors on human neutrophil function and cAMP and Cai levels", nauyn schmiedeebergs arch, pharmacol.344682-690, 1991; and Tenor et al, "cyclic nucleotide phosphodiesterase isozyme activity in human alveolar macrophages," Clin. exp. allergy 25625. 633, 1995.

For a better understanding of the invention, it may be pointed out here that the compounds of formula (1.0.0) are capable of inhibiting PDE4 in neutrophils, leading to reduced chemotaxis, activation, adhesion and degranulation; schudtdeng, supra; nelson et al, "effects of selective phosphodiesterase inhibitors on polymorphonuclear leukocyte respiratory burst" j.allergy clin.immunol.86801-808, 1990; and Blueman et al, "elevated cAMP levels in stimulated neutrophils inhibits adhesion to human bronchial epithelial cells" am.J. physiol.272L580-587, 1997.

It has also been shown that the compounds of formula (1.0.0) reduce PDE4s mediated production of superoxide anions in peripheral blood neutrophils and modulate PDE4s mediated synthesis of leukotrienes; wrigh et al, in the form of a,go out and go up(ii) a The process of Schudt et al,go out and go up(ii) a A Bloeman, etc. and the like,go out and go out simultaneously On the upper part(ii) a Alessas et al, "heterogeneity of circulating and exuding polymorphonuclear leukocytes in response to superoxide production by cyclic AMP and cyclic AMP enhancers: investigation of the basic mechanism, "biochem. Pharmacol.49315-322, 1995; ottonello et al, "Cyclic AMP enhancers negatively regulate the oxidative burst that granulocyte-macrophage colony-stimulating factor (GM-CSF) induces in adherent neutrophils," Clin. Exp. Immunol.101502-506, 1995; and Ottonello et al, "alpha tumor necrosis factor-induced oxidative burst in neutrophils attached fibronectin: cyclic AMP-enhancer utility, "br.j. haematol.91566-570, 1995.

One further indicates that the compound of formula (1.0.0) is capable of inhibiting the expression of CD11b/CD 18; berends et al, "inhibition of PAF-induced CD11b expression and L-selectin shedding on human neutrophils and eosinophils by the type IV selective PDE inhibitor rolipram", eur.respir.j.101000-1007, 1997; and Derian et al, "inhibition of chemotactic peptide-induced adhesion of neutrophils to vascular endothelial cells by cAMP modulators," J.Immunol.154308-317, 1995.

It is further noted that the compounds of formula (1.0.0) inhibit alveolar macrophage PDE4s, thereby reducing the release of chemotactic factor and TNF- α; moreover, the compound of formula (I) can synthesize inflammatory cytokine IL-10, promote the release of inflammatory cytokine IL-10 from monocytes, and the cytokine can reduce the production of TNF-alpha, IL-1 beta and GM-CSF by synovial monocytes, thereby increasing the total anti-inflammatory profile of the PDE4 inhibitor of formula (1.0.0); schudt et al, "PDE isozymes as targets for anti-asthma drugs," eur.respir.j.81179-1183, 1995; and Kambayashi et al, "type IV nucleotide phosphodiesterases are involved in the regulation of IL-10, which in turn inhibits the release of TNF- α and IL-16 from endotoxin-stimulated macrophages," J.Immunol.1554909-4916, 1995.

The use of PDE4 inhibitors for treating COPD patients has been demonstrated in clinical trials. Six consecutive weeks of treatment with SB-207,499 (also known as ariflo) as indicated above and below in formula (0.1.9) at a dose of 15mg twice daily has been shown to result in FEV₁And an increase in Forced Vital Capacity (FVC); brown, W.M. "SB-207499," Anti-inflam. Immunomodulatoryinvest. drugs 139-47, 1999. The clinical efficacy of SB-207,499 has also been demonstrated by the four week trial described below, which providesImprove FEV₁And also provides an improvement in FEV in a six week trial of COPD patients receiving 15mg twice daily₁(ii) evidence of (a); the content of Brown is as follows,go out Is treated as above. SB-207,499, or ariflo, as described earlier herein and can be represented by formula (0.1.9):

8.3 bronchitis and bronchiectasis

According to the specific and various inhibitory activities possessed by the compounds of formula (1.0.0) described hereinabove, they are useful in the treatment of bronchitis of any kind, etiology or pathogenesis, including acute bronchitis, which has a short-term and severe course of attack, whether due to coldness, inhalation of irritants or acute infections; acute laryngotracheobronchitis with formation of non-diphtheria croup; peanut kernel-induced inhaled bronchitis caused by peanut kernels present in the bronchi; catarrhal bronchitis, a form of acute bronchitis with profuse mucopurulent discharge; chronic bronchitis, a form of chronic bronchitis, has a tendency to recur to varying degrees after the quiescent period, resulting from recurrent episodes of acute bronchitis or chronic systemic disease, and is characterized by episodes of cough, little or more sputum, and secondary changes in the lung tissue; grubby bronchitis, characterized by severe cough and paroxysmal dyspnea; dry bronchitis, characterized by the discharge of small amounts of sticky sputum; infectious asthmatic bronchitis, a syndrome characterized by bronchospasm symptoms that occurs after respiratory infection in asthmatic patients; proliferative bronchitis, i.e. bronchitis associated with productive cough; staphylococcal or streptococcal bronchitis, i.e. caused by staphylococci or streptococci; and alveolar bronchitis, in which inflammation extends into the alveoli and millet-like white-yellow granulation is sometimes seen under the pleura.

Bronchiectasis is chronic bronchiectasis marked by bad breath and paroxysmal cough with mucopurulent sputum. It affects the tubular uniformly, in which case it is called cylindrical bronchiectasis, or it may occur in irregular pockets, in which case it is called saccular bronchiectasis. The term fusiform bronchiectasis is used when the dilated bronchi have a terminal bulb-like enlargement. In cases where the dilated condition involves bronchioles, it is referred to as bronchiectasis. If the shape of the bronchiectasis is spherical, the condition is called saccular bronchiectasis. When the infection is intermittent, dry bronchiectasis occurs, which may be accompanied by hemoptysis, blood sputum or sputum containing blood stain. During the resting period of dry bronchiectasis, sputum-free cough occurs. Follicular bronchiectasis is a type of bronchiectasis in which the lymphatic tissue of the lesion increases in height, protrudes into the lumen of the bronchi, can severely contort and partially occlude the bronchi. Thus, as a direct result of its inhibition of the PDE4 isoenzyme, the compound of formula (1.0.0) may be useful in the beneficial treatment of the various types of bronchodilation described above.

The efficacy of the compounds of formula (1.0.0) as bronchodilators or bronchospasmolytics in the treatment of bronchial asthma, chronic bronchitis, and related diseases and disorders described herein can be demonstrated using a variety of different in vivo animal models known in the art, including the models described in the next paragraph.

Activity of in vitro bronchospasmThe ability of the compound of formula (1.0.0) to cause relaxation of tracheal smooth muscle in guinea pigs was confirmed by the following test method. Guinea pigs (350-500g) were killed with sodium pentothiobarbital (100 mg/kgi.p.). The trachea is cut off and then cut into segments of 2-3cm in length. The trachea is transected at the transverse plane of the alternating cartilage annulus in order to obtain a tissue ring of 3-5mm depth. The proximal and distal loops are discarded. Each ring was mounted vertically on a stainless steel support, one end of which was fixed to the bottom of the organ bath and the other end was connected to an isometric transducer. Placing the ring at 37 deg.C, and charging with O₂/CO₂(95: 5, v/v) in Kjeldahl solution (composition. mu.M NaHCO: NaHCO)₃ 25；NaCl 113；KCl4.7；MgSO₄·7H₂O 1.2；KH₂PO₄ 1.2；CaCl₂2.5; glucose 11.7). The ring prepared in this way was preloaded to 1g, giving rise to self-contraction, after an equilibration period (45-60 minutes),can be continuously relaxed by adding spasmolytic. To determine spasmolytic activity, the compound of formula (1.0.0) was dissolved in physiological saline and added to the organ bath in increasing concentrations, with 5 min intervals between each dosing, to obtain a cumulative concentration-effect curve.

In the above test model, the compound of formula (1.0.0) produces concentration-dependent relaxation of the guinea pig airway ring in the concentration range of 0.001-1.0. mu.M.

Inhibition of airway hyperreactivity in PAF-treated animalsAnesthetizing guinea pigs as described above under "bombesin-induced bronchoconstriction inhibition" and prepared for recording lung function. Intravenous occlusion of small doses of histamine (1.0-1.8 μ g/kg) established airway sensitivity to spasmodics. After 1 hour post-PAF (platelet activating factor) infusion (total dose 600ng/kg), small doses of bombesin were injected and 20 minutes after infusion stopped showed the appearance of airway hyperreactivity, which can be expressed as the pairwise difference between the maximal response amplitudes before and after PAF treatment. Inhibition of PAF-and bombesin-induced airway hyperreactivity can be achieved by administration of the compound of formula (1.0.0) by infusion (at doses of 0.01-0.1mg/kg) during PAF treatment.

8.4 allergic and other types of rhinitis; sinusitis

Allergic rhinitis is characterized by nasal obstruction, itching, watery nasal discharge, sneezing and occasional loss of olfaction. Allergic rhinitis is divided into two disease types, seasonal and perennial, the former being caused by pollen or outdoor mould spores, and the latter by common allergens such as house dust mites, animal dander and mould spores. Allergic rhinitis generally manifests itself as a periodic and late phase reaction. The periodic response is associated with mast cell degranulation, while the late phase response is characterized by infiltration of eosinophils, basophils, monocytes and T-lymphocytes. These cells also release a variety of different mediators of inflammation, all of which may have an effect on the inflammation exhibited by the late phase response.

A particularly prevalent form of seasonal allergic rhinitis is hay fever, characterized by acute conjunctivitis with tearing and itching, swelling of the nasal mucosa, nasal catarrh, sudden sneezing, and often asthmatic symptoms. The compounds of formula (1.0.0) are particularly suitable for the treatment of hay fever.

Other types of rhinitis for which the compounds of formula (1.0.0) may be used as therapeutic agents include acute catarrhal rhinitis, i.e., acute congestive head cold of the nasal mucosa characterized by dryness followed by increased mucus secretions of the nasal mucosa, impeded nasal breathing, slight pain;

atrophic rhinitis, i.e. chronic rhinitis characterized by atrophy of mucous membranes and glands; rhinitis profunda, a chronic rhinitis with pus formation; and vasomotor rhinitis, a non-allergic rhinitis caused by stimuli such as mild cold, fatigue, anger, and anxiety, in which the vascular tone and permeability are transiently altered, as is the case with allergic rhinitis.

There is a well-established correlation between allergic rhinitis and asthma. Allergic rhinitis is often accompanied by asthma, and treatment of allergic rhinitis has also been shown to improve asthma. Epidemiological data can also be used to demonstrate the link between severe rhinitis and more severe asthma. For example, compound D-22888, which is being developed clinically for the treatment of allergic rhinitis, has shown strong antiallergic action against antigen-challenged pigs and inhibited runny nose. See, Marx et al 30: "D-22888-a novel PDE4 inhibitor for the treatment of allergic rhinitis and other allergic diseases," J.allergy Clin.Immunol 99S 444, 1997 Another test compound, AWD12-281, has been shown to be active in a rat model of allergic rhinitis. See the effects of Poppee et al "AWD 12-281 (a novel selective PDE-4 inhibitor), clorprenavir and beclomethasone in allergic rhinitis and severe models of airways in brown Norway mice," am.J.Respir.crit.Care Med.a95, 1999 Compounds D-22888 and AWD-12,281 are described earlier above and can be represented by formulas (0.0.28) and (0.0.34), respectively:

Sinusitis is associated with rhinitis in terms of anatomical proximity and, in some cases, the etiology and pathogenesis involved. Sinusitis is an inflammation of the sinuses, and the symptoms can be suppurative or non-suppurative, as well as acute or chronic. According to the location of the inflammation in the sinuses, it is called ethmoid sinusitis, frontal sinusitis, maxillary sinusitis or sphenoid sinusitis, respectively. The ethmoid sinus is a type of paranasal sinus that is located on the ethmoid. The frontal sinus is one of the paired paranasal sinuses located on the frontal bone. The maxillary sinus is one of a pair of paranasal sinuses located on the maxillary body. Accordingly, the compound of formula (1.0.0) is useful for treating acute or chronic sinusitis, especially chronic sinusitis.

8.5 rheumatoid arthritis, osteoarthritis, pain, fever and gout

Arthritis is defined as inflammation of the joints, and rheumatoid arthritis is a chronic systemic disease mainly involving the joints, often with multiple joints, characterized by inflammatory changes in the synovial membrane and joint structure, bone atrophy and osteoporosis. The advanced stages of rheumatoid arthritis manifest as ankylosis and deformity. Rheumatoid arthritis is a disabling autoimmune disease of unknown etiology, affecting more than 1% of the population.

The term "rheumatoid arthritis" as used herein includes within its scope related and related appropriate forms of arthritis well known in the art, as such arthritis may also be treated with the compounds of formula (1.0.0) of the present invention. Thus, the term "rheumatoid arthritis" includes acute arthritis, i.e., arthritis characterized by pain, heat, redness and swelling due to inflammation, infection or trauma; acute gouty arthritis, i.e., acute arthritis associated with gout; chronic inflammatory arthritis, i.e., arthritis in chronic diseases such as rheumatoid arthritis; degenerative arthritis, i.e., osteoarthritis; infectious arthritis, i.e., arthritis caused by bacteria, rickettsia, viruses, fungi, or parasites; lyme arthritis, i.e., the large arthritis associated with the Lyme20 disease; proliferative arthritis, i.e., inflammation of the joints with synovial hyperplasia, see rheumatoid arthritis; psoriatic arthritis, a syndrome in which psoriasis is complicated by inflammatory arthritis; and spondyloarthritis, an inflammation of the intervertebral disc involved.

Three of the major pathological features of rheumatoid arthritis that cause progressive destruction of joints are inflammation, abnormal responses of cells and body fluids, and synovial fluid proliferation. The characteristic cytopathology of rheumatoid arthritis includes the presence of T-cells and monocytes. The composition of T-cells (mainly memory T-cells) is up to 50% of the cells recovered from synovial tissue of patients with rheumatoid arthritis; moreover, of the monocytes found in the same tissue, 30-50% are antigen presenting cells, which are indicative of the autoimmune nature of the disease. Proinflammatory cytokines, such as IL-1, IL-4, IL-5, IL-6, IL-9, IL-13, and TNF- α, are major contributors to joint tissue damage, inflammation, hyperplasia, pannus formation, and bone resorption. See firstein, g.s. and Zvaifier, w.j., "how important T-cells are in chronic rheumatoid synovial fluid? "Arth. Rheum.33768-773, 1990. this importance has been demonstrated by the fact that monoclonal antibodies (Mabs) such as TNF- α have been promising for clinical trials in RA; maini et al, "blocking of the beneficial effects of alpha-tumor necrosis factor (TNF-alpha) on Rheumatoid Arthritis (RA)," Clin. Exp. Immunol.101207-212, 1995.

PDE4 inhibitors of formula (1.0.0) are useful for the treatment of rheumatoid arthritis due to their ability to inhibit the activity of various inflammatory cells including basophils, eosinophils and mast cells. These inhibitory activities of the compounds of formula (1.0.0) are also described earlier above, as they have various in vitro anti-inflammatory effects through the release of reactive oxygen species, prostaglandins and the inflammatory cytokines IL-5, IFN-gamma and TNF-alpha. See further Cohan et al, "novel phosphodiesterase type IV inhibitors, in vitro pharmacology of CP-80,633," j.pharm.exp.ther.2781356-1361, 1996; and Barnette et al, "SB 207499(ARIFLO), a second generation selective potent phosphodiesterase 4 inhibitor: anti-inflammatory effects in vitro, "J.pharm.Exp.Ther.284420-426, 1998. PDE4 inhibitors of formula (1.0.0) are also useful in the treatment of rheumatoid arthritis due to their potency to inhibit T-cell proliferation mediated by a variety of different factors including antigens such as house dust mite, as has been demonstrated by those skilled in the artPerforming; barnette and the like,go out and go up. The ability of the compound of formula (1.0.0) to promote the release of cytokine IL-10 by monocytes further increases the overall anti-inflammatory profile of the PDE4 inhibitor of formula (1.0.0), wherein the release of cytokine IL-10 further reduces the production of TNF- α, IL-1, IL-4, IL-5, IL-6, IL-9, IL-13, and GM-CSF by synovial monocytes; kambayashi et al, Go out and go up. In addition, the ability of the compounds of formula (1.0.0) to inhibit the release of TNF- α by stimulated monocytes may be associated with animal models of inflammation where the anti-inflammatory effect is consistent with inhibition of TNF- α aggregation. One such animal model involves orally administering a PDE4 inhibitor to the mice to inhibit LPS-induced TNF- α release; cheng et al, "phosphodiesterase type IV (PDE4) inhibitor CP-80,633 increased cyclic AMP levels and decreased TNF- α production in mice: adrenal resection effect, "j.pharm.exp.ther.280621-626, 1997. another such animal model involves oral administration of rolipram to inhibit paw edema in rats; singh et al, "synovial fluid levels of tumor necrosis factor in rat inflamed knees: regulation by dexamethasone and matrix metalloproteinases with inhibitors of phosphodiesterase, "Inflamm. Res.46(suppl.2) S153-S154, 1997.

Rheumatoid arthritis models have also been used in the art for the purpose of demonstrating the relationship between in vivo modulation of TNF- α by PDE4 inhibitors and their utility in treating rheumatoid arthritis. The activity of rolipram in animal models of acute inflammation, such as the mouse adjuvant arthritis model, has been demonstrated in the art; sekut et al, "anti-inflammatory activity of phosphodiesterase type IV (PDE) inhibitors in models of acute and chronic inflammation," olin. exp. Immunol.100(1)126-132, 1995. The ability to reduce the severity of collagen II-induced arthritis (CIA) model disease following subcutaneous (sc) or intraperitoneal (ip) injection of rolipram has been demonstrated in the art; nyman et al, "alleviation of collagen II-induced arthritis in rats by the phosphodiesterase type IV inhibitor rolipram,' olin. exp. Immunol 108415-419, 1997. In this study, the dosing regimen of rolipram was 2mg/kg twice daily for 5 consecutive days prior to the onset of arthritis, which significantly delayed the appearance of arthritic symptoms. After discontinuation of treatment, the test animals developed arthritis and reached and matched The same arthritis was highest grade as the group. Rolipram was also administered twice daily at a dose of 3mg/kg at the time of the appearance of arthritis in the same study. This treatment drastically alters the progression of the disease, and thus can arrest the progression of the disease, even after discontinuation of treatment, with levels of arthritis that are not observed in untreated animals. Researchers have also finally demonstrated a strong down-regulation of TNF-alpha and IFN7 mRNA expression in local lymph nodes, suggesting that rolipram mainly contributes to the effector phase of the inflammatory process. Nyman, etc., in a single crystal,go out and go up。

The inhibitory effect on the in vitro production of TNF- α by human monocytes of the compound of formula (1.0.0) can be demonstrated by the methods described in EP 411754(Badger et al) and WO90/15534 (Hanna). The above references also describe two models of endotoxic shock which can be used to determine the inhibitory activity of the compound of formula (1.0.0) in vivo. The methods used in these models are detailed therein, and the test compounds show positive results by reducing serum levels of TNF- α induced by endotoxin injection.

Selective PDE4 inhibitors such as RP73401 have been shown to show significant disease-modifying effects in animal models involving Streptococcal Cell Wall (SCW) induced arthritis, particularly in the improvement of joint destruction, synovitis and fibrosis; souness et al, "phosphodiesterase type IV inhibitors for the treatment of rheumatoid arthritis," Drugs 1541-.

Of particular value for the treatment of rheumatoid arthritis is the observation that PDE4 inhibitors have a positive effect at the site of action of the disease. For example, RP73401 has been shown to reduce TNF- α mRNA expression at the pannus/cartilage interface of collagen II-treated mouse paw joints. Sounness, etc. in a computer system,go out and go up. In a phase II placebo-controlled, double-blind study of 35 patients with rheumatoid arthritis (given 400pg compound three times a day), RP73401 has been used in a clinical study of patients with rheumatoid arthritis. The compounds of the invention are capable of inducing a positive trend towards clinical improvement in lowering serum levels of C-reactive protein and IL-6. Chikanza et al,"clinical effect of phosphodiesterase type IV inhibitor RP73401 on rheumatoid arthritis patients," br.j. rheumatol 36: abstr. suppl.1, 186, 1997.

Another assay using U-937 cells to determine the increase in cAMP accumulation in intact tissue-applicable to demonstrate the PDE4 inhibitory activity of the compound of formula (1.0.0) uses the human monocytic cell line U-937 cells containing large amounts of PDE 4. To evaluate the inhibition of PDE4 activity in intact cells, undifferentiated U-937 cells were plated at approximately 10%⁵The density of the cells/reaction tubes was incubated with test compound at a concentration of 0.01-1000pM for 1 minute and 1. mu.M prostaglandin E2 for 4 minutes. 5 minutes after the start of the reaction, 17.5% perchloric acid was added to lyse the cells, and 1M potassium carbonate was added to adjust the pH to neutrality. The amount of cAMP in the reaction tube was determined using the RIA method. A detailed protocol for this assay is described in Brooker et al, "radioimmunoassays of cyclic AMP and cyclic GMP," adv. cyclic Nucleotide Res.101-33, 1979.

Gout refers to a class of purine metabolic disorders, and the well-developed gout manifests as different combinations of the following conditions: hyperuricemia, recurrent classic acute arthritis caused by crystallization of monosodium urate monohydrate, arthritis of the four limbs and the presence of said crystalline grit-like deposits around them, leading to joint destruction and severe disability, and uric acid urolithiasis. Rheumatic gout is another name for rheumatoid arthritis. Tophaceous gout is gout with sodium urate tophus or chalk deposits. Some therapeutic agents are useful in the treatment of gout and its attendant inflammation, such as phenylbutazone and colchicine; while other therapeutic agents have only uricosuric properties, such as sulpirenone and benzbromarone.

Fever or fever may be the result of any of a number of different factors, but for the purposes of the present invention, fever is manifested as a pharyngoconjunctival or rheumatic fever, or as fever manifested during inflammation. The accompanying symptoms of inflammation are pain, especially pain experienced by joints and connective tissue of patients with rheumatoid arthritis and gout.

Thus, PDE4 inhibitor compounds of formula (1.0.0) are effective in treating gout and inflammation-associated fever and pain.

8.6 eosinophil-related diseases

The ability of the PDE4 inhibitor compounds of formula (1.0.0) of the present invention to inhibit eosinophil activation has been described above as part of their overall anti-inflammatory activity. Therefore, the compound of formula (1.0.0) is useful for the treatment of eosinophil-related diseases. Such diseases include eosinophilia, a massive abnormal formation and accumulation of eosinophils in the blood. The disease name is derived from "eosin", a rose dye or stain containing a bromine derivative of fluorescein, which readily stains "eosinophils" in the blood of a patient, thereby making them readily identifiable. A particular eosinophilic disorder that can be treated according to the present invention is a pulmonary eosinophilic infiltration characterized by infiltration of the lung parenchyma by eosinophils. This disease includes in particular Loffler syndrome, a condition characterised by temporary lung infiltration, a combination of cough, fever, dyspnea and eosinophilia.

Other eosinophilic diseases include chronic eosinophilic pneumonia, a chronic interstitial lung disease characterized by cough, dyspnea, malaise, fever, night sweats, weight loss, eosinophilia, and chest radiographs showing non-peripheral non-segmental, non-migratory infiltration; tropical pulmonary eosinophilia, a subacute or chronic recessive filariasis (typically filarial Malaria or filarial Myxoplasma) occurring in tropical, infected animals, characterized by episodic nocturnal wheezing and coughing, high eosinophilia, diffuse, nodular infiltrates in the lung field; one disease that results from infection of the bronchi and lungs with aspergillus (aspergillus funga) is caused by bronchopneumonia aspergillosis, which is manifested by inflammatory granulomatous lesions in the sinuses, as well as in the skin, ears, eye sockets, sometimes in the bones and meninges, leading to aspergillosis, the most common type of mycosis being formed by colonization of the bronchi or lung cavities by aspergillus.

The term "granulomatous" is meant to encompass rheumatoid granulomas, and the term "granulomatous" refers to any nodular, bounded collection of inflammatory monocytes, or such collection of deformed macrophages like epithelial-like cells, usually surrounded by a ring of lymphocytes, and fibrosis is often seen around lesions. Some granulomas contain eosinophils. Granuloma formation is a chronic inflammatory response caused by a variety of infectious or non-infectious agents. A number of such granulomatous disorders can be treated with compounds of formula (1.0.0), for example, allergic granulomatous vasculitis, also known as Churg-Strauss syndrome, a form of systemic necrotizing vasculitis, with prominent pulmonary disease, often manifested by eosinophilia, granulomatous-like reactions and often severe asthma; the associated condition is polyarthritis nodules (PAN), characterized by multiple inflammatory and arterial destructive lesions, a form of systemic necrotizing vasculitis that accumulates in small and medium-sized joints, with signs and symptoms resulting from infarction and scarring of the diseased organ system, particularly the lungs. Other eosinophil-related diseases that can be treated according to the present invention are those disorders affecting the airways induced or caused by a response to unrelated therapeutic agents to the compound of formula (1.0.0).

8.7 atopic dermatitis, urticaria, conjunctivitis and uveitis

Atopic dermatitis is a chronic inflammatory skin disease, seen in people with genetic factors that reduce the threshold of skin itching, often accompanied by allergic rhinitis, hay fever and asthma, and is characterized primarily by extreme itching. Atopic dermatitis is also known as allergic dermatitis, allergy or atopic eczema.

Atopic Dermatitis (AD) is the most common chronic inflammatory skin disease in infants, affecting 10% -15% of the child population. Atopic dermatitis is often complicated by asthma and allergic diseases and is therefore referred to as a component of the so-called "atopic triad" since it often occurs in the asthmatic and/or allergic rhinitis population. See Leung Dym, Atomic Dermatitis: from Pathologenesis Totreatment, R.G.Landes Co., Austin, Texas, 1-226, 1996. Thus, immune dysfunction associated with atopic dermatitis may be treated with a therapeutic agent that is a PDE4 inhibitor. For example, rolipram, Ro-201724 and denbufylline have been reported to produce concentration-related inhibition of proliferation of human peripheral blood mononuclear cells (HPBM) in normal patients and subjects with atopic dermatitis. See Torphy et al, Drugs and the Lung, eds. Page and Metzger, Rayen Press, New York, 1994, respectively; and O' Brien, mol. medicinetoday, 369, 1997 these studies also determined that HPBM proliferative responses in atopic dermatitis patients are more sensitive to PDE4 inhibitors than the proliferative responses observed in HPBM of normal subjects.

Th 2-like cytokine-secreting T-cells expressing antigen-associated skin lymphocytes play an important role in inducing local IgE responses and the recovery of eosinophils in this disease. Chronic inflammation seen in atopic dermatitis is thought to be the result of several interdependent factor actions, such as repeated or permanent exposure to allergens, which can lead to expansion of Th2 cells. It has been demonstrated that the frequency of allergen exposure is increased and that the levels of IL-4, IL-5 and IL-3 produced by specific T-cells are also increased in the blood of atopic dermatitis patients. See Leung Dym et al, "allergic and immunological skin diseases," JAMA278(22)1914-1923, 1997. This is important because IL-4 and IL-3 induce the expression of vascular adhesion molecule-1 (VCAM-1), which is involved in the migration of monocytes and eosinophils into inflammatory tissues. In addition, IL-5 is a key mediator of eosinophil activation and is a common feature of atopic diseases.

It has long been known that increased levels of cAMP in lymphocytes and basophils are associated with decreased mediator release from these cells, but more recently histamine, known as the H2 receptor, has been reported to lower cAMP levels and inhibit IL-4 production in mouse Th2 cells. It is said that there is a decrease in the beta-adrenergic response or an increase in PDE4 activity in the presence of a leukocyte inflammatory response in atopic diseases such as atopic dermatitis. The reduced cAMP response may be due to increased PDE4 activity on a genetic basis or in an acquired setting.

Studies comparing different cell types of atopic patients with healthy volunteers have been conducted and the results show thatThe increase of cAMP-PDE activity in atopic cells is associated with inflammatory and immune cell dysfunction in atopic dermatitis. In addition, the PDE4 enzyme of atopic leukocytes is more sensitive to PDE4 inhibitors than the PDE4 enzyme of normal leukocytes, and has been shown to be up to a 14-fold difference. See Chan and Hanifin, "difference in inhibitory effects of cAMP phosphodiesterase isoforms in atopic and normal leukocytes," j.lab.clin.med., 121(1)44-51, 1993. increased sensitivity can also be seen in the inhibition of peripheral blood mononuclear cell proliferation of atopic donors by treatment with PDE4 inhibitors. For example, rolipram has been found to be more effective in inhibiting PHA-stimulated proliferation of PBMC in atopic dermatitis than in normal PHA-stimulated PBMC, the IC of which₅₀Values were 280nM and 2600nM, respectively.

In addition, it has been demonstrated that various selective PDE4 inhibitors with different structures are effective in reducing cutaneous eosinophilia in guinea pigs mediated by various factors such as PAF, arachidonic acid, zymosan-activated plasma, and skin allergy proteins. See Beasley et al, "synthesis and evaluation of novel series of phosphodiesterase 4 inhibitors," bioorg. med. chem. letters.82629-2634, 1998. These data illustrate the utility of PDE4 inhibitors in the treatment of eosinophil-induced skin disorders. This therapy, using topical administration, for example, in clinical trials of 20 patients with bilateral topical administration of atizoram over 8 days, was found to effectively suppress all inflammatory parameters tested, showing qualitative and quantitative improvement, without side effects. See Hanifin et al, "phosphodiesterase type IV has clinical and in vitro antigenic effects on atopic dermatitis," J.invest.Dermatol.10751-56, 1996.

Therefore, as described above, the PDE4 inhibitor of formula (1.0.0) is useful for the treatment of atopic dermatitis. Another therapeutic application where compounds of formula (1.0.0) may also produce beneficial effects is the treatment of urticaria. Urticaria is a vascular response, usually transient, invading the upper dermis, resulting in localized edema, dilation of capillaries and increased permeability, characterized by the development of wheal or wheal masses. Many different stimuli can induce urticaria, which can be classified according to the cause: immune-mediated, complement-mediated (which may include immune or non-immune mechanisms), urticaria-causing substance-induced, physical factor-induced, stress-induced or idiopathic urticaria. They can be classified as acute or chronic depending on the duration of their onset. Angioneurotic edema is the same reaction that occurs in the deep dermis or in subcutaneous or submucosal tissues.

The most common type of urticaria that can be treated with compounds of formula (1.0.0) is cholinergic urticaria, characterized by the presence of a distinct punctate wheal surrounded by the erythematous region, which is believed to be a non-immunological anaphylactic reaction, induced by acetylcholine released at the end of the parasympathetic or motor nerves, to release mediators from mast cells, and caused by conditions of exertion, stress or elevated ambient temperature; cold urticaria, urticaria induced by cold air, cold water, or cold objects, exists in two forms: one is autosomal dominant with fever, joint pain and leukocytosis, lesions presenting as erythematous and febrile papules and maculas, and the other is more commonly acquired, usually idiopathic and self-limited; contact urticaria, a local or systemic transient wheal with flushing, caused by contact with rapidly absorbable urticaria-causing factors; giant urticaria, i.e. angioedema; and papular urticaria, a persistent rash that represents an allergic reaction to insect bites.

Therefore, PDE4 inhibitors of formula (1.0.0) may be useful in the effective treatment of the various types of urticaria described above. Other therapeutic applications in which the compounds of formula (1.0.0) may also produce beneficial effects are various ophthalmic applications, in particular for the treatment of conjunctivitis and uveitis.

The conjunctiva is a thin film that lines the eyelids and covers the exposed surface of the sclera. Conjunctivitis is a severe conjunctiva, which is generally accompanied by conjunctival congestion and secretions. The most common type of conjunctivitis treatable with the compound of formula (1.0.0) is actinic conjunctivitis caused by uv light; acute catarrhal conjunctivitis, an acute, infectious conjunctivitis, with a common cold or catarrhal characterized by significant hyperemia, edema, loss of translucency, and mucous or mucopurulent secretions; acute contagious conjunctivitis, a mucopurulent epidemic conjunctivitis, caused by haemophilus aegypti (haempophilus), with symptoms similar to acute catarrhal conjunctivitis, also known as "pinkeye"; allergic conjunctivitis, a form of hay fever; atopic conjunctivitis, an immediate allergic conjunctivitis caused by airborne allergens such as pollen, dust, spores and animal hair; chronic catarrhal conjunctivitis, chronic conjunctivitis with mild inflammation, only mild conjunctival congestion and mucous secretions; pyogenic conjunctivitis, an acute conjunctivitis caused by bacteria or viruses, particularly gonococci, meningococci, pneumococci, and streptococci, characterized by severe conjunctivitis and a large number of thick secretions; and vernal conjunctivitis, a seasonal bilateral conjunctivitis of unknown etiology in children, particularly boys, characterized by flattened papules and thick, gelatinous exudates. Therefore, PDE4 inhibitors of formula (1.0.0) are useful in the treatment of the various types of conjunctivitis noted above. Other relevant therapeutic applications where compounds of formula (1.0.0) may also produce beneficial effects are the treatment of uveitis.

The uveal layer is the vascular intermediate layer or membrane of the eye, including the iris, ciliary body, and choroid. Uveitis is an inflammation of all or part of the uvea of the eye, often invading other membranes of the eye, i.e., the sclera and cornea, and the retina. The most common type of uveitis treatable with a compound of formula (1.0.0) is anterior uveitis, a form of uveitis that attacks the iris and/or ciliary body structure, including iritis, cyclitis, and iridocyclitis; granulomatous uveitis, i.e., uveitis of any part of the uvea, especially the posterior part, characterized by accumulation of epithelioid cells and giant cells into nodules surrounded by lymphocytes; non-granulomatous uveitis, an inflammation of the anterior portion of the uvea (i.e., the iris and ciliary body); phakic antigenic uveitis, one of the lens-induced uveitis, is a severe uveitis, similar to that observed weeks or even months after extra-capsular lens surgery or other damage to the lens capsule; and posterior uveitis, i.e., uveitis affecting the back of the eye, including choroidal and chorioretinitis. Therefore, PDE4 inhibitors of formula (1.0.0) are useful for treating the various types of uveitis described above.

8.8 psoriasis

Psoriasis is a common recurrent, squamous, chronic, polygenic, inherited skin disorder characterized by microscopic, spongiform pustules, as well as erythema of various sizes, and dry desquamated plaques. Psoriasis is a common skin disease that affects approximately 2% of the population and is treated by more than 1.vz million patient consultation physicians each year in the united states. Psoriasis often recurs and in some cases can be extremely debilitating. The cause of psoriasis is unknown, but can be an autoimmune disease with a genetic predisposition.

Psoriasis involves large T-cell infiltrates in the damaged area of the skin, with CD4+ lymphocytes in the dermis and CD8+ lymphocytes in the epidermis. These lymphocytes secrete IL-2, IFN-gamma and TNF-alpha, which alter keratinocyte proliferation and differentiation. In addition, about 5% -10% of psoriasis patients develop psoriatic arthritis, and the symptoms thereof are like rheumatoid arthritis. As noted above, the broad spectrum of anti-inflammatory activity exhibited by PDE4 inhibitors enables these inhibitors to be effective in the treatment of psoriasis.

Treatment of epidermal basal cells with the PDE4 inhibitor Ro20-1724 in primary cultures has been shown to cause a three-fold increase in cAMP concentration. It has also been shown that treatment of psoriatic epidermal thin sections and keratotomy psoriatic epidermal sections with Ro20-1724 results in a very significant increase in cAMP concentration (compared to control). Specifically, a 1395% increase in cAMP concentration was observed in keratotomy psoriatic epidermis. It has also been shown that PDE4 inhibitors are also able to inhibit inflammatory responses of various mediators by local or systemic administration. For example, rolipram inhibits croton oil-induced ear inflammation in mice at topical doses as low as 0.03 mg/ear. Also, two double-blind trials comparing their efficacy with vehicle have been conducted on the selective PDE4 inhibitor Ro20-1724 and have been shown to ameliorate psoriatic lesions without systemic or cutaneous side effects.

8.9 multiple sclerosis and other inflammatory autoimmune diseases

Sclerosis is a induration or sclerosis, particularly a partial sclerosis caused by inflammation and interstitial diseases and increased formation of connective tissue. The term "sclerosis" is used primarily for the hardening of the nervous system due to the deposition of connective tissue, or to vascular sclerosis. Multiple Sclerosis (MS) is a disease of demyelination of the white matter of the central nervous system in the form of plaques with various sizes, sometimes spreading to gray matter,

the result is weakness, movement disorders, paresthesia, speech disorders and vision disorders. The etiology of multiple sclerosis is unknown and the course of the disease is long, with multiple remissions and relapses involved.

Multiple sclerosis is an autoimmune disease that, in addition to causing inflammation and demyelination, causes gliosis in the central nervous system. There are several disease subtypes, including primary progressive multiple sclerosis and relapsing-remitting multiple sclerosis. These disease subtypes differ from each other according to the course of the disease, the type of inflammation involved, and the use of Magnetic Resonance Imaging (MRI). The basic mechanisms of the disease may also be altered during multiple sclerosis, and the basic inflammatory process is subsequently replaced by processes that include demyelination and axonal injury. See Weilbach and Gold, "a disease modifying therapy for multiple sclerosis, how promising? "CNS Drugs 11133-157, 1999.

In the case of multiple sclerosis, although a hardened plaque characterized by demyelination is indicative thereof, inflammatory lesions are localized in, and generally spread throughout, the white matter of the central nervous system. Demyelination is itself caused by oligodendrocyte necrosis, and demyelination is associated with a permeate composed primarily of T-cells and macrophages, which together with local cells such as astrocytes, microglia, and microvascular brain endothelial cells express the class II major histocompatibility complex. These cells are therefore involved in antigen presentation and inflammatory responses, and a number of proinflammatory cytokines have been identified in brain tissue of patients with multiple sclerosis (including TNF-. alpha., TNF-. beta., IL-1, IL-6 and IFN-. gamma.), the presence of which is often associated with impaired activity. In particular, TNF- α has been the focus of attention because it mediates myelin and oligodendrocyte injury in vitro, induces astrocyte expression of surface adhesion molecules, and involves blood brain barrier lysis.

Animal models have been used to illustrate the role of TNF- α in multiple sclerosis, for example in Experimental Allergic Encephalomyelitis (EAE), administration of anti-TNF antibodies or soluble TNF receptors have been shown to provide a protective effect. See Selmaj et al, "prevention of chronic relapsing experimental autoimmune encephalomyelitis by soluble tumor necrosis factor," J.Neurohimunol.56135-141, 1995. A direct correlation between TNF-. alpha.mRNA levels and EAE progression has also been reported. See Reeno et al, "TNF- α expression by resident microglia and infiltrating leukocytes in the central nervous system of experimental allergic encephalomyelitis mice: regulation of Th1 cytokine, "J.Immunol.154944-953, 1995. Further evidence that TBF- α is a multiple sclerosis mediator is the increased concentration of TNF- α in the cerebrospinal fluid of patients with multiple sclerosis during the course of the disease. In addition, transgenic mice overexpress TNF- α in the central nervous system and exhibit idiopathic demyelination, while transgenic TNF- α knockout mice exhibit protective effects. See Probert et al, "transgenic mice idiopathic inflammatory demyelinating diseases exhibit central nervous system-specific expression of α -TNF," Proc. Natl. Acad. Sci. USA 9211294-11298, 1995; and Liu et al, "TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination," Nature Med.478-83, 1998.

Since PDE4 inhibitors are also able to reduce TNF-. alpha.they are beneficial for the treatment of multiple sclerosis, since TNF-. alpha.plays an important role in mediating multiple sclerosis (see above). For example, rolipram has been found to inhibit the appearance of clinical signs and to eliminate abnormalities in MRI imaging in a marmoset model of experimental allergic encephalomyelitis. In another study on the effect of rolipram on chronic relapsing experimental allergic encephalomyelitis in SJL mice, rolipram has been shown to alleviate clinical signs and pathological changes in this model. See Genain et al, "prevention of autoimmune demyelination in non-human primates by cAMP-specific phosphodiesterase," Proc.Natl.Acad.Sci.USA.923601-3605, 1995; and Sommer et al, "inhibition of type IV phosphodiesterase for the therapeutic potential of chronic autoimmune demyelinating diseases," J.Neurohimunol.7954-61, 1997.

In addition to inhibiting PDE4 activity and TNF- α production, the compounds of formula (1.0.0) are also active as immunosuppressive agents, and are particularly useful in the treatment of autoimmune diseases, where inflammation is a component of such autoimmune diseases, or is a partial cause of autoimmune diseases, or is involved in autoimmune diseases. On the other hand, the compounds of formula (1.0.0) are also anti-inflammatory agents for the treatment of inflammatory diseases, wherein the autoimmune response is a component of the inflammatory disease, or the autoimmune response is a partial cause of the inflammatory disease, or the autoimmune response is involved in the inflammatory disease. Thus, as detailed above, the compounds of formula (1.0.0) are suitable for the treatment of multiple sclerosis.

Other autoimmune/inflammatory diseases that can be treated with therapeutic agents including compounds of formula (1.0.0) include, but are not limited to, autoimmune hematological disorders such as hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura; systemic lupus erythematosus; polychondritis; scleroderma; wegner granulomatosis; dermatomyositis; chronic active hepatitis; muscle weakness; Stevens-Johnson syndrome; idiopathic slogan; autoimmune inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease; endocrine eye diseases; grave's disease; sarcoidosis; alveolitis; chronic allergic pneumonia; primary biliary cirrhosis; juvenile diabetes (type I diabetes); anterior uveitis and granulomatous (posterior) uveitis; keratoconjunctivitis sicca and epidemic keratoconjunctivitis; diffuse interstitial pulmonary fibrosis (interstitial pulmonary fibrosis); idiopathic pulmonary fibrosis; cystic fibrosis; psoriatic arthritis; glomerulonephritis with and without nephrotic syndrome, including acute glomerulonephritis, idiopathic nephrotic syndrome, and minimal change nephropathy; inflammatory/hyperproliferative skin diseases, including psoriasis and atopic dermatitis, contact dermatitis, allergic contact dermatitis, benign familial pemphigus, pemphigus erythematodes, pemphigus foliaceus and pemphigus vulgaris as described in detail above.

Further, the compounds of formula (1.0.0) are useful as immunosuppressive agents for the prevention of allograft rejection after organ transplantation, which typically includes bone marrow, intestinal, heart, kidney, liver, pancreas, skin and corneal tissue.

8.10 inflammatory bowel disease

Ulcerative Colitis (UC) is a chronic recurrent ulcer of unknown origin, mainly involving the colonic mucosa and submucosa, and is clinically manifested by spastic abdominal pain, rectal bleeding, and a decrease in blood, pus, and mucous secretions with little fecal mass. Related bowel diseases include collagenous colitis, a colitis with unknown etiology. It is characterized in that collagen substances are deposited on the upper and lower skin of colon and are manifested as spastic abdominal pain, the absorption of liquid and electrolyte is obviously reduced, and watery diarrhea is generated; polypoid colitis, an ulcerative colitis with the formation of pseudopolyps (i.e. the edema inflammatory mucosal islands between the ulcerated regions); and transmural colitis, an inflammation that affects the thickness of the entire intestinal wall, rather than mucosal and submucosal lesions, usually with the formation of non-caseous granulomas, clinically similar to ulcerative colitis, but ulcers tend to be longitudinal or deeper, lesions are often segmental, usually stenotic, and fistulas (particularly the perineum) are a common complication.

Crohn's Disease (CD) is a chronic granulomatous inflammatory disease of unknown etiology that can invade any part of the gastrointestinal tract, but usually involves the terminal ileum, scarring and thickening of the intestinal wall, often resulting in intestinal obstruction, fistula and abscess formation, with high recurrence rates after treatment. Ulcerative colitis, Crohn's disease, and related diseases discussed above are collectively referred to as Inflammatory Bowel Disease (IBD). These diseases are chronic, idiopathic recurrent conditions of unknown cause, immunologically mediated, the pathogenesis of which has been determined using animal chronic and advanced immunological techniques. See Bickston and camminelli, "recent advances in IBD medical treatment," curr. opin. gastroenterol.146-10, 1998; and Murthy et al, "inflammatory bowel disease: a new class of therapeutic waves, "exp. opin. the. patent 8(7) 785-. While the incidence of ulcerative colitis remains relatively stable, the incidence of Crohn's disease is increasing dramatically.

Current treatments for inflammatory bowel disease include 5-aminosalicylic acid, corticosteroids, and immunomodulators such as azathioprine, 6-mercaptopurine, and methotrexate. These agents have various side effects and do not alleviate the disease itself, and thus there is still a need for more effective therapeutic agents. The compounds of formula (1.0.0) are effective in treating inflammatory bowel disease by inhibiting the production of TNF- α, which causes immune cell activation, proliferation and release of mediators of inflammatory bowel disease. See Radford-Smith and Jewell, "cytokine and inflammatory bowel disease," baillieselcin. gasteroentol.10151-164, 1996 TNF- α has also been detected in the stool and intestinal mucosa of patients with inflammatory bowel disease. In addition, early clinical studies of Crohn's disease using TNF monoclonal antibodies have shown great promise.

As described in detail above, selective PDE4 inhibitors have significant in vitro or in vivo inhibitory effects on the release of TNF- α by peripheral blood mononuclear cells following stimulation with various mediator mediators. The selective PDE4 inhibitor arofylline showed beneficial effects when tested in the rat colitis model. In addition, rolipram and the selective PDE4 inhibitor LAS31025 showed a beneficial effect comparable to prednisone in the dextran sulfate induced rat colitis model. Both experimental compounds were shown to alleviate bleeding and inflammatory markers. See Puig et al, "phosphodiesterase type IV inhibitors for treatment of sodium dextran sulfate induced colitis in rats," Gastroenterology114(4) a1064, 1998. Other investigators have used other models to demonstrate the ability of selective PDE4 inhibitors to produce gastrointestinal protection. For example, lipopolysaccharide-induced extravasation of rat erythrocytes and hypoperfusion of porcine intestinal blood flow have been shown to be alleviated with the selective PDE4 inhibitors rolipram and denbufylline. See, Cardelus et al, "inhibition of LPS-induced intestinal extravasation of rat intestinal erythrocytes and hypoperfusion of porcine mesenteric blood flow with phosphodiesterase inhibitors," Eur.J. Pharmacol.299153-159, 1996; and Cardlous et al, "protective effects of denbufylline on endotoxin-induced intestinal proliferation," Met. Find. Exp. Clin. Pharmacol.17(suppl. A)142, 1995.

8.11 septic shock, renal failure, cachexia, and infection

Septic shock is a shock associated with severe infections (most commonly seen with gram-negative bacterial infections), but it can also be caused by other bacteria, viruses, fungi and protozoa. Septic shock is thought to be the result of endotoxin or other products of the infectious agent acting on the vascular system, causing large amounts of blood to pool in capillaries and veins. It may also be associated with the activation of complement and kinin systems, as well as the release of histamine, cytokines, prostaglandins and other mediators.

It has been demonstrated that administration of a selective PDE4 inhibitor at a post-treatment of 10 μ g/kg/min in an endotoxin-induced rat acute renal failure model highly increases urinary cAMP secretion, significantly reduces endotoxin-induced renovascular resistance, and reduces renal blood flow and glomerular filtration rate. Ro-201742 was also shown to improve endotoxin-induced rat survival. See Carcillo et al, Pharmacol. exp. Ther.2791197, 1996. Pentoxifylline has also been studied in patients with septic shock. 24 persons meeting septic shock criteria were selected in this study, 12 of which received 1mg/kg/hr pentoxifylline over a 24 hour period, while the other 12 were used as controls. After 24 hours, a significant decrease in TNF- α levels, and a significant increase in IL-6 levels, was observed in the treated group.

In another study, it has been demonstrated that pretreatment with pentoxifylline at 5-50mg/kg i.p.3 x, or with the selective PDE4 inhibitor rolipram at 10-30mg/kg i.p.3 x, and with denbufylline at 0.1-3mg/kg i.p.3 x, reduces lipopolysaccharide-induced intestinal erythrocyte extravasation in rats, and that denbufylline is 100-fold stronger than pentoxifylline in inhibiting lipopolysaccharide-induced decrease in mesenteric blood flow, and does not affect renal blood flow or cardiac index. See, Cardelus et al, supra, eur.j.

Renal failure is the inability of the kidney to excrete metabolites to normal plasma levels under normal stress. In the acute form, the hallmark is uremia, often oliguria or anuresis, with hyperkalemia and pulmonary edema. Based on the activity of the selective PDE4 inhibitors described above, selective PDE4 inhibitors have been shown to be useful in the treatment of renal failure, particularly acute renal failure. See Begany et al, "inhibition of phosphodiesterase type IV by Ro-20-1724 slows down endotoxin-induced acute renal failure," J.Pharmacol. Exp.Thera.27837-41, 1996. See also WO98/00135, assigned to University of Pittsburgh. Accordingly, the compounds of formula (1.0.0) are useful for the treatment of renal failure, particularly acute renal failure.

Cachexia is a heavy, prominent constitutional disease state characterized by general health and malnutrition. Cachexia may be the end result of various causes, for example it may be the result of infection by any of a variety of different unicellular organisms or microorganisms, including bacterial, viral, fungal and protozoal infections. Malaria cachexia is typical and includes a series of chronic qualitative signs from the first episode of severe malaria, the main signs being anemia, sallowness of the skin, yellow sclera, splenomegaly, and hepatomegaly. Another cause of cachexia is the loss or deterioration of bodily fluids or other organic functions, for example, pituitary cachexia includes a series of syndromes resulting from the complete loss of pituitary gland function, including tuberculosis, loss of sexual function, atrophy of pituitary target glands, bradycardia, hypothermia, apathy, and coma. Uremic cachexia is cachexia associated with other systemic symptoms of severe renal failure. Cardiac cachexia includes wasting due to heart disease. Adrenal cachexia, or Addison's disease, is a condition characterized by hypotension, weight loss, anorexia, and weakness, caused by adrenocortical hormone deficiency. This is due to abortive tuberculosis of the adrenal cortex-or autoimmune-induced destruction leading to aldosterone and cortisol deficiency.

Cachexia may also be the result of various types of morbidity. Cancer cachexia includes the debilitating, debilitating state found in patients with malignant tumors. Cachexia can also be the result of Human Immunodeficiency Virus (HIV) infection, including the symptoms commonly referred to as acquired immunodeficiency syndrome (AIDS). The compounds of formula (1.0.0) are useful in the treatment of various types of cachexia as described above because they are capable of down-regulating or inhibiting TNF- α release. The selective PDE4 inhibitor has obvious inhibiting effect on the release of TNF-alpha of peripheral blood mononuclear cells after being stimulated by various mediator. TNF- α release is involved in or mediates in diseases or conditions whose etiology involves or includes pathological, i.e., unhealthy, excessive or unregulated, TNF- α release.

The PDE4 inhibitor compounds of the compounds of formula (1.0.0) are further useful in the treatment of infections, particularly viral infections, where these viruses increase the production of TNF- α in their host, or where these viruses are susceptible to upregulation of TNF- α in their host, thereby adversely affecting their replication or other important activities. These viruses include, for example, HIV-1, HIV-2 and HIV-3; cytomegalovirus; a CMV; an influenza virus; an adenovirus; and herpes viruses, particularly shingles and herpes simplex.

The PDE4 inhibitor compounds of formula (1.0.0) are further useful in treating infections with yeasts and fungi that are sensitive to the upregulation of TNF- α or that cause the production of TNF- α in their hosts. A particular disease treatable in this way is fungal meningitis. The compounds of formula (1.0.0) also provide beneficial effects when administered in combination, i.e., in conjunction, with other agents selected for the treatment of systemic yeast and fungal infections. Such agents of choice include, but are not limited to, polymyxins, such as polymyxin B; imidazole compounds such as clotrimazole, econazole, miconazole, and ketoconazole; triazole compounds such as fluconazole and itraconazole; and amphotericins, such as amphotericin B and lipidic amphotericin B. As used herein, the term "co-administration" with respect to a compound of formula (1.0.0) and a selected drug for the treatment of systemic yeast and fungal infections refers to and includes (a) administering such compound and drug simultaneously to a subject when formulated together in a single dosage form; (b) when formulated in separate dosage forms with one another, administering the compound and the drug to the subject substantially simultaneously; and (c) when they are formulated independently of each other and administered sequentially at certain time intervals, sequentially administering the compound and the drug to the subject.

8.12 liver injury

In addition to the above-mentioned side effects of TNF- α, it also causes liver failure, a phenomenon that has been demonstrated in various animal models. For example, i.p. administration of rolipram at a dose of 0.1-10mg/kg 30 minutes prior to challenge with concanavalin a or staphylococcal enterotoxin B in an acute model of T-cell mediated liver failure has been shown to significantly reduce plasma TNF- α and INF- γ concentrations but also to significantly increase IL-10 levels. See Gantner et al, J.Pharmacol.Exp.Ther.28053, 1997. In the same study, rolipram was also shown to inhibit concanavalin a-induced IL-4 release. Liver-specific enzymes ALT, AST and SDH were also evaluated in this study, as any increase in their levels showed substantial hepatocyte destruction. It has been found that rolipram is able to dose-dependently inhibit the above plasmatic enzyme activity in untreated (naive) mice receiving concanavalin a or galactosamine sensitized mice receiving galactosamine/staphylococcal enterotoxin B pretreated with 0.1-10mg/kg i.p. rolipram. Accordingly, the compounds of formula (1.0.0) are useful in the treatment of T-cell disorders, such as liver failure.

8.12 pulmonary hypertension

Phosphodiesterase activity, which hydrolyzes vasodilatory second messengers cAMP and cGMP, is known to be elevated by hypoxia-induced pulmonary arterial hypertension (HPH). Hypoxia means that although the tissue is well perfused with blood, the tissue's oxygen supply is below physiological levels. The pulmonary hypertension produced is characterized by elevated pressure, i.e., systolic pressure of the pulmonary arterial cycle above 30mmHg and diastolic pressure above 12 mmHg. Using a model of isolated pulmonary artery rings using normal rats and hypoxia-induced pulmonary hypertension rats, the selective PDE4 inhibitor rolipram has been shown to enhance the diastolic activity of isoproterenol and forskolin. The same effect was also observed with the selective PDE3 inhibitor milone, thus demonstrating that PDE3 and PDE4 can be inhibited in order to highly improve pulmonary artery vasodilation of hypoxia-induced pulmonary hypertension. See Wagner et al, j. Thus, the compounds of formula (1.0.0) are useful in the treatment of pulmonary hypertension, especially hypoxia-induced pulmonary hypertension.

8.14 bone loss disorders

Bone loss disease, more commonly referred to as osteoporosis, is a condition of osteopenia and microstructural destruction, resulting in fractures with minor trauma. Secondary osteoporosis is caused by systemic diseases or by pharmacological treatments such as glucocorticoids. Primary osteoporosis, which has been controversial, is considered to include two cases: type I osteoporosis, a trabecular bone loss during menopause due to estrogen deficiency, and type II osteoporosis, i.e. cortical and trabecular bone loss due to long-term ineffectiveness to remodelling, under-diet and age-related parathyroid activation. The major regulatory factors of adult bone mass include body movement, regenerative endocrine status and calcium intake, and the optimal way to maintain bone requires all three of these aspects to be very adequate.

Selective PDE4 inhibitors have been shown to be useful in the treatment of bone loss diseases, particularly osteoporosis. The effects of denbufylline on bone loss in Walker256/S bearing mice as well as mineral-rich bone morphogenesis and osteoclast-like cell formation have been studied in bone marrow culture systems. Continuous oral administration of denbufylline was found to inhibit the decrease in mineral density of the femoral bone in Walker256/S bearing mice, repair bone and a large number of osteoclasts and osteoblasts on the surface of each trabecular bone at the metaphysis of the femoral bone. Denbufylline administration has also been found to result in massive mineral enrichment of bone and a reduction of massive osteoclast-like cells in vitro bone marrow culture systems. These beneficial effects are characteristic of PDE4 inhibition and can be mimicked with dibutyryl cAMP, suggesting that PDE4 isoenzyme plays an important role in bone turnover via cAMP. See Miyamoto et al, biochem. pharmacol.54613, 1997; waki et al, "effect of phosphodiesterase 4 inhibitor XT-44 on osteoblast formation and osteoclast formation in culture medium, and its therapeutic effect in rat osteopenia model," Jpn.J. Pharmacol.79477-483, 1999; and JP 9169665(1997), assigned to Myyamoto, therefore selective PDE4 inhibitors of formula (1.0.0) are useful in the treatment of diseases which involve bone loss, especially osteoporosis.

8.15 CNS disorders

Rolipram, a selective inhibitor of PDE4, was originally developed as an antidepressant and continued to be studied in clinical trials for this indication. In addition, selective PDE4 inhibitors have been shown to have beneficial effects on other central nervous system disorders, including Parkinson's disease. Hulley et al, "phosphodiesterase type IV inhibitors reduce toxicity of MPTP in the substantia nigra axon," Eur.J.Neurosci.72431-2440, 1995; and cognitive and memory impairment, Egawa et al, "phosphodiesterase inhibitor rolipram and its optical isomers attenuate scopolamine induced cognitive and memory impairment in rats," jpn.j. pharmacol.75275-281, 1997; imanishi et al, "alleviation of experimentally induced rodent cognitive and memory impairment" eur.j. pharmacol.321273-278, 1997; and Barad et al, "type IV specific phosphodiesterase inhibitor rolipram promotes the establishment of long-term sustained action efficacy and improves memory," proc.natl.acad.sci.usa9515020-15025, 1998.

The use of PDE4 inhibitors for the treatment of tardive dyskinesia and drug dependence has been disclosed in the art, see WO95/28177 and JP92221423(1997), both assigned to MeijiSeika Kaisha Ltd. The PDE4 isozyme has been found to play an important role in controlling dopamine biosynthesis in neurons of the brain; PDE4 inhibitors are therefore useful for treating disorders and diseases associated with or mediated by dopamine in and around neurons of the midbrain. Yamashita et al, "selective phosphodiesterase type IV inhibitor rolipram significantly enhances forskolin-induced enhanced dopamine biosynthesis in the brains of primary cultured rats," jpn.j. pharmacol. 7591-95, 1997.

PDE4 inhibitor compounds of formula (1.0.0) are further useful in the treatment of arteriosclerotic dementia and subcortical dementia. Arteriosclerotic dementia, also known as vascular dementia and multi-infarct dementia, is a series of irregularly distributed neurological deficits resulting from seizures with a progressive degenerative process and cerebrovascular disease. Subcortical dementia results from damage affecting the subcortical structure of the brain and is characterized by impaired memory with concomitant information handling or mental retardation. Including dementia with Huntington's chorea, Wilson's disease, paralysis agitans, and thalamottle.

8.16 other therapeutic applications

PDE4 inhibitors have been shown to be useful in the treatment of ischemia-reperfusion injury, Block et al, "delayed treatment of rolipram to protect rats against neuronal injury following global ischemia," NeuroReport 83829-3832, 1997 and Belayev et al, "type IV phosphodiesterase inhibitor BBB022 for protection of blood brain barrier breakdown in focal cerebellar ischemia: quantitative Studies, "Brain Res.787277-285, 1998; for the treatment of autoimmune Diabetes, Liang et al, "phosphodiesterase inhibitors denbufylline and rolipram for the prevention of Diabetes in NOD mice," Diabetes 47570-575, 1998; for the treatment of retinal autoimmunity, Xu et al, "protection of rolipram, a phosphodiesterase type IV inhibitor, in EAU: protection was independent of IL-10 induction activity, "invest. ophthalmol. visual sci.40942-950, 1999; for the treatment of chronic lymphocytic leukemia, Kim and Lerner, "type IV adenosine monophosphate phosphodiesterase as a therapeutic agent for chronic lymphocytic leukemia," Blood 922484-; for the treatment of HIV infection, Angel et al, "specific phosphodiesterase type IV inhibitor rolipram is a potent inhibitor of HIV-1 replication," AIDS 91137-1144, 1995 and Navarro et al, "phosphodiesterase type IV inhibition inhibits the replication of human immunodeficiency virus type I and cytokine production in primary T cells: NF-KappaB and NFAT, "J.Virol.724712-4720, 1998; JP10067682(1998) assigned to Fujsawa pharm. co. ltd, for the treatment of lupus erythematosus; for the treatment of renal and urethral disorders, DE4230755(1994), assigned to Schering AG; for the treatment of urogenital and gastrointestinal disorders, WO94/06423 assigned to ScheringAG; and for the treatment of prostatosis, WO99/02161 assigned to Porssmann and WO99/02161 assigned to Stief.

From the above description, it will be appreciated that the compounds of formula (1.0.0) may be useful in the effective treatment of one or more conditions selected from the following diseases, disorders and conditions:

-asthma of any kind, etiology or pathogenesis; or asthma selected from the following categories: atopic asthma; non-atopic asthma; allergic asthma; atopic, bronchial, IgE-mediated asthma; bronchial asthma; idiopathic asthma; true asthma; intrinsic asthma caused by pathophysiological disorders; extrinsic asthma caused by environmental factors; idiopathic asthma of unknown or non-overt cause; non-atopic asthma; bronchial asthma; emphysema-associated asthma; exercise-induced asthma; occupational asthma; infectious asthma caused by bacterial, fungal, protozoal or viral infection; non-allergic asthma; incipient asthma; infant asthma syndrome;

-chronic or acute bronchoconstriction; chronic bronchitis; fine airway obstruction; and emphysema;

-obstructive or inflammatory airways diseases of any type, etiology or pathogenesis; or an airway obstructive or inflammatory disease selected from: asthma; pneumoconiosis; chronic eosinophilic pneumonia; non-chronic obstructive disease (COPD); COPD including chronic bronchitis, emphysema or dyspnea associated therewith; COPD, which is characterized by irreversible progressive airway obstruction; adult Respiratory Distress Syndrome (ARDS), and exacerbation of airway hyperresponsiveness by other drug therapies;

-a pneumoconiosis disease of any kind, etiology or pathogenesis, or a pneumoconiosis disease selected from: alumina lung or bauxite worker disease; silicosis or miner asthma; asbestosis or central heating assembler asthma; pulmonitis scleritis or flint disease; sucking ostrich hair dust to cause ostrich pneumoconiosis; iron pneumoconiosis caused by inhalation of iron particles; silicosis or abrasions; cotton scurf or cotton dust asthma; and talc pneumoconiosis;

-bronchitis of any kind, etiology or pathogenesis; or bronchitis selected from: acute bronchitis; laryngotracheobronchitis; peanut kernel inhalational bronchitis; catarrhal bronchitis; grubbs bronchitis; dry bronchitis; infectious asthmatic bronchitis; proliferative bronchitis; staphylococcal or streptococcal bronchitis; and alveolar bronchitis;

-any kind, etiology or pathogenesis of bronchiectasis, or bronchiectasis selected from: cylindrical bronchiectasis; saccular bronchiectasis; fusiform bronchiectasis; bronchiectasis; saccular bronchiectasis; dry bronchiectasis; and follicular bronchiectasis;

-seasonal allergic rhinitis of any kind, etiology or pathogenesis; or persistent allergic rhinitis; or sinusitis of any kind, etiology or pathogenesis; or sinusitis selected from: suppurative or non-suppurative sinusitis; acute or chronic sinusitis; and ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, or sphenoiditis;

-rheumatoid arthritis of any kind, etiology or pathogenesis; or rheumatoid arthritis selected from: acute arthritis; acute gouty arthritis; chronic inflammatory arthritis; degenerative arthritis; infectious arthritis; lyme arthritis; proliferative arthritis; psoriatic arthritis; and spondyloarthritis;

-gout, fever and pain associated with inflammation;

-any kind, etiology or pathogenesis of eosinophil-related diseases; or an eosinophil-associated disease selected from: eosinophilia; hypereosinophilic infiltration of the lung; loffler's syndrome; chronic eosinophilic pneumonia; tropical pulmonary eosinophilia; bronchopneumonia aspergillosis; swollen with aspergillus; eosinophil-containing rheumatic granulomas; allergic granulomatous vasculitis or Churg-Strauss syndrome; polyarthritis nodules (PAN); and systemic necrotizing nodular vasculitis;

-atopic dermatitis; or allergic contact dermatitis; or allergic or atopic eczema;

-urticaria of any kind, etiology or pathogenesis; or urticaria selected from: immune-mediated urticaria; complement-mediated urticaria; urticaria induced by urticaria-causing substances; urticaria induced by physical factors; stress-induced urticaria; idiopathic urticaria; acute urticaria; chronic urticaria; angioedema; cholinergic urticaria; cold urticaria exists in two forms: one is autosomal dominant and acquired; contact urticaria; giant urticaria; and papular urticaria;

-conjunctivitis of any kind, etiology or pathogenesis; or conjunctivitis selected from: actinic conjunctivitis; acute catarrhal conjunctivitis; acute contagious conjunctivitis; allergic conjunctivitis; atopic conjunctivitis; chronic catarrhal conjunctivitis; suppurative conjunctivitis; and vernal conjunctivitis;

-uveitis of any kind, etiology or pathogenesis; or uveitis selected from the group consisting of: inflammation of all or part of the uveal tract; uveitis of the anterior eye; iritis; ciliaris; iridocyclitis; granulomatous uveitis; non-granulomatous uveitis; lenticular antigenic uveitis; posterior uveitis; choroiditis; and chorioretinitis;

-psoriasis;

-multiple sclerosis of any kind, etiology or pathogenesis; or multiple sclerosis selected from the group consisting of primary progressive multiple sclerosis and relapsing-remitting multiple sclerosis species;

-autoimmune/inflammatory diseases of any kind, etiology or pathogenesis; or an autoimmune/inflammatory disease selected from the following classes: autoimmune hematological disorders; hemolytic anemia; aplastic anemia; pure red cell anemia; idiopathic thrombocytopenic purpura; systemic lupus erythematosus; polychondritis; scleroderma; wegner granulomatosis; dermatomyositis; chronic active hepatitis; muscle weakness; Stevens-Johnson syndrome; idiopathic slogan; autoimmune inflammatory bowel disease; ulcerative colitis; crohn's disease; endocrine eye diseases; grave's disease; sarcoidosis; alveolitis; chronic hypersensitivity pneumonitis; primary biliary cirrhosis; juvenile diabetes or type I diabetes; uveitis of the anterior eye; granulomatous or posterior uveitis; keratoconjunctivitis sicca; epidemic keratoconjunctivitis; diffuse interstitial pulmonary fibrosis or interstitial pulmonary fibrosis; idiopathic pulmonary fibrosis; cystic fibrosis; psoriatic arthritis; glomerulonephritis with and without nephrotic syndrome; acute glomerulonephritis; idiopathic nephrotic syndrome; minimal change renal disease; inflammatory/hyperproliferative skin disorders; psoriasis; atopic dermatitis; contact dermatitis; allergic contact dermatitis; benign familial pemphigus; pemphigus erythraea; pemphigus foliaceus and pemphigus vulgaris;

-prevention of allograft rejection after organ transplantation;

-Inflammatory Bowel Disease (IBD) of any kind, etiology or pathogenesis; or an inflammatory bowel disease selected from the following classes: ulcerative Colitis (UC); collagenous colitis; polypoid colitis; transmural colitis; and Crohn's Disease (CD);

-septic shock of any kind, etiology or pathogenesis; or septic shock selected from the following classes: renal failure; acute renal failure; cachexia; malaria cachexia; pituitary cachexia; uremic cachexia; cardiac cachexia; adrenal cachexia or Addison's disease; cancer cachexia; cachexia caused by Human Immunodeficiency Virus (HIV) infection;

-liver damage;

-pulmonary arterial hypertension; and hypoxia-induced pulmonary hypertension;

-bone loss diseases; primary osteoporosis; and secondary osteoporosis;

-central nervous system diseases of any kind, etiology or pathogenesis; or a central nervous system disorder selected from the following classes: depression; parkinson's disease; cognitive and memory impairment; tardive dyskinesia; drug dependence; dementia with arteriosclerotic disease; and dementia with Huntington's chorea, Wilson's disease, paralysis agitans, and thalamottle;

-infections, in particular viral infections, which increase the production of TNF- α in their host, or which are susceptible to the upregulation of TNF- α in their host, thereby adversely affecting their replication or other important activities, including viruses selected from: HIV-1, HIV-2 and HIV-3; cytomegalovirus; a CMV; an influenza virus; an adenovirus; and herpes viruses, including herpes zoster and herpes simplex;

-infections by yeasts and fungi that are sensitive to the up-regulation of TNF- α, or that cause the production of TNF- α by their host, such as fungal meningitis; particularly when combined with other agents selected for the treatment of systemic yeast and fungal infections, such agents include, but are not limited to, polymyxins, such as polymyxin B; imidazole compounds such as clotrimazole, econazole, miconazole, and ketoconazole; triazole compounds such as fluconazole and itraconazole; and amphotericins, such as amphotericin B and lipidic amphotericin B;

-ischemia-reperfusion injury; (ii) autoimmune diabetes; retinal autoimmunity; chronic lymphocytic leukemia; HIV infection; lupus erythematosus; kidney and urinary tract disorders; urogenital and gastrointestinal disorders; and prostate diseases.

Detailed Description

9.0 combination with other drugs and therapeutics

The present invention relates to embodiments wherein the compound of formula (1.0.0) is the sole therapeutic agent for use in the methods of treatment described herein, which compound may be used alone, but is more commonly found in a suitable dosage form for administration to a patient with a pharmaceutically acceptable carrier. Other embodiments of the invention relate to the combination of a compound of formula (1.0.0) with one or more other therapeutic agents administered to a patient to achieve certain specific desired end-use therapeutic results. The second isotherapeutic agent may also be one or more compounds of formula (1.0.0), or one or more PDE4 inhibitors known in the art and described in detail herein. More typically, the second such therapeutic agent is selected from a different class of therapeutic agents. These options are described in detail below.

The terms "co-administration", and "combination" as used herein with reference to a compound of formula (1.0.0) and one or more other therapeutic agents means, particularly refers to and includes the following: (a) simultaneously administering to a patient in need of treatment a combination of the compound and the therapeutic agent, i.e., in the case of a single dosage form wherein the components are formulated together to substantially simultaneously release the components to the patient; (b) administering to a patient in need of treatment such combination of compound and therapeutic agent substantially simultaneously, i.e., where the components are formulated independently of each other into separate dosage forms capable of being ingested by the patient substantially simultaneously, thereby enabling substantially simultaneous release to the patient; (c) sequentially administering to a patient in need of treatment such combination of compound and therapeutic agent in a situation where the components are formulated independently of each other into separate dosage forms for sequential ingestion by the patient, but with a relatively long time interval between each ingestion, thereby enabling release to the patient over substantially different times; (d) the combination of compound and therapeutic agent is administered sequentially to a patient in need of treatment, i.e., where the components are formulated together in a single dosage form that releases the components in a controlled manner such that they can be administered by the patient in parallel, sequentially and/or overlapping intakes at the same and/or different times.

9.1 in combination with leukotriene biosynthesis inhibitors: 5-lipoxygenase (5-LO) inhibitors and 5-lipoxygenase activating protein (FLAP) antagonists

One or more compounds of formula (1.0.0) may be used in combination with leukotriene biosynthesis inhibitors, i.e., 5-lipoxygenase inhibitors and/or 5-lipoxygenase activating protein antagonists, to constitute embodiments of the present invention. As already described above, 5-lipoxygenase (5-LO) is one of two groups of enzymes that metabolize arachidonic acid, the other being the cyclooxygenase enzymes, COX-1 and COX-2. The 5-lipoxygenase activating protein is an 18kDa membrane bound, arachidonic acid binding protein which stimulates the conversion of cellular arachidonic acid via the 5-lipoxygenase pathway. Arachidonic acid is converted to 5-hydroperoxy 20-arachidonic acid (5-HPETE), the pathway ultimately leading to inflammatory leukotriene production; thus, blocking 5-lipoxygenase activating protein or 5-lipoxygenase itself provides a desirable target for effective intervention in this pathway. One such 5-lipoxygenase inhibitor is zileuton of formula (0.1.14), as described hereinabove and hereinbelow. The class of leukotriene synthesis inhibitors which can form therapeutic cocktails with the compounds of formula (1.0.0) are as follows:

(a) redox active agents including N-hydroxyureas; n-alkyl hydroxamic acids; selenite; hydroxybenzofurans; hydroxylamines; and catechols; see Ford-Hutchinson et al, "5-lipoxygenase," Ann.Rev.biochem.63383-417, 1994; weitzel and Wendel, "selenylases regulate leukocyte 5-lipoxygenase activity via peroxide status," j.biol chem.2686288-92, 1993; bjornnstedt et al, "selenite production by incubation with NADPH and mammalian thioredoxin reductase, selenide inhibition, lipoxygenase inhibition, modification of the electron spin resonance spectrum of the active site iron," Biochemistry358511-6, 1996; and Stewart et al, "Structure-Activity relationship for N-hydroxyurea 5-lipoxygenase inhibitors," J.Med.chem.401955-68, 1997;

(b) Alkylating agents and compounds which have been found to be capable of inhibiting leukotriene synthesis in vitro and which react with SH groups; see Larsson et al, "1-chloro-2, 4, 6-trinitrobenzene effects on 5-lipoxygenase activity and cellular leukotriene synthesis," biochem. Pharmacol.55863-71, 1998; and

(c) 5-lipoxygenase competitive inhibitors based on thiopyranoindole and methoxyalkylthiazole structures, which are useful as 5-lipoxygenase inhibitors; see Ford-Hutchinson et al, supra; and Hamel et al, "synthesis, biological properties and pharmacokinetics of substituted (pyridylmethoxy) naphthalene-L-739, 010 as potent orally active inhibitors of 5-lipoxygenase," j.med.chem.402866-75, 1997.

The observation that arachidonoylhydroxyhydroxamic acid (arachidonoylhydroxyhydroxamate) inhibits 5-lipoxygenase led to the discovery of clinically effective selective 5-lipoxygenase inhibitors such as the N-hydroxyurea derivatives zileuton and ABT-761, represented by formulas (0.1.14) and (5.2.1), respectively:

another N-hydroxyurea compound is fenleuton (Abbott-76745), represented by formula (5.2.2):

zileuton is included in US4,873,259(Summers et al) assigned to Abott Laboratories, which discloses indole, benzofuran, and benzothiophene lipoxygenase inhibiting compounds that may be represented by formula (5.2.3): Wherein R is₁Is as follows; (C)₁-C₄) An alkyl group; (C)₂-C₄) An alkenyl group; or NR₂R³Wherein R is₂And R³Is H; (C)₁-C₄) An alkyl group; or OH; x is O; s; SO (SO)₂(ii) a Or NR₄Wherein R is₄Is H; (C)₁-C₆) An alkyl group; (C)₁-C₆) An alkanoyl group; aroyl; or an alkylsulfonyl group; a is (C)₁-C₆) An alkylene group; or (C)₂-C₆) An alkenylene group; n is 1 to 5; and Y is H; halogen; OH; CN; alkyl halidesA group; (C)₁-C₁₂) An alkyl group; (C)₂-C₁₂) An alkenyl group; (C)₁-C₁₂) An alkoxy group; (C)₃-C₈) A cycloalkyl group; (C)₁-C₈) An alkylthio group; an aryl group; an aryloxy group; an aromatic acid group; (C)₁-C₁₂) Aralkyl group; (C)₂-C₁₂) An aralkenyl group; (C)₁-C₁₂) An aralkyloxy group; (C)₁-C₁₂) An arylthioalkoxy group; or aryl, aryloxy, aroyl, (C)₁-C₁₂) Aralkyl, (C)₂-C₁₂) Aralkenyl, (C)₁-C₁₂) Aralkyloxy, (C)₁-C₁₂) Substituted derivatives of arylthioalkoxy; wherein the substituent is halogen; NO₂(ii) a CN; or (C)₁-C₁₂) -alkyl-alkoxy and-haloalkyl; z is O or S; and M is H; a pharmaceutically acceptable cation; aroyl; or (C)₁-C₁₂) An alkanoyl group.

Related compounds are disclosed in the following documents: US4,769,387(Summers et al); US4,822,811 (summmers); US4,822,809 (summmers and Stewart); US4,897,422 (summmers); US4,992,464(Summers et al); and US5,250,565(Brooks and Summers); each of these documents is incorporated by reference herein in its entirety, as if fully set forth herein.

Zileuton, or any of the above derivatives thereof, may be used in combination with a compound of formula (1.0.0) to form an embodiment of the invention.

Fenleuton is described in the following references: US5,432,194; US5,446,062; US5,484,786; US5,559,144; US5,616,596; US5,668,146; US5,668,150; US5,843,968; US5,407,959; US5,426,111; US5,446,055; US5,475,009; US5,512,581; US5,516,795; US5,476,873; US5,714,488; US5,783,586; US5,399,699; US5,420,282; US5,459,150; and US5,506,261; each of these documents is incorporated by reference herein in its entirety, as if fully set forth herein. A description of these N-hydroxyureas and related inhibitors of 5-lipoxygenase and inflammatory leukotriene synthesis is found in WO 95/30671; WO 96/02507; WO 97/12865; WO 97/12866; WO 97/12867; WO 98/04555; and WO 98/14429.

Tepoxalin is a dual COX/5-LO inhibitor with short in vivo activity survival time, resulting in the production of two series of mixed compounds, N-hydroxyureas and hydroxamates of the formulae (5.2.4) and (5.2.5), respectively:wherein R is¹-R⁴Is H; cl; CH (CH)₃(ii) a An ethyl group; isopropyl group; or n-propyl; or R³And R ⁴Together represent (CH)₂)₅Or (CH)₂)₂O(CH₂)₂(ii) a And R is⁵Is methyl; an ethyl group; isopropyl group; a methoxy group; a trifluoromethyl group; chloromethyl; ethyl propionate; a phenyl group; 2-furyl; a 3-pyridyl group; or a 4-pyridyl group. See Connolly et al, "inhibitors of N-hydroxyurea and hydroxamic acid of cyclooxygenase and 5-lipoxygenase," Bioorganic& Medicinal Chemistry Letters9979-984，1999。

Another N-hydroxyurea compound is Abbott-79175 shown in formula (5.2.6):

abbott-79175 has a longer duration than zileuton; brooks et al, J.pharm.exp.Therapeut.272724, 1995.

Yet another N-hydroxyurea compound is Abbott-85761 represented by formula (5.2.7):

abbott-85761 was delivered to the lungs in a uniform, physically stable and nearly monodisperse formulation via aerosol administration; gupta et al, "pulmonary administration of 5-lipoxygenase inhibitors in the form of beagledogs (beagledogos)," Abbott-85761, "International Journal of pharmaceuticals 147207-.

Fenleuton, Abbott-79175, Abbott-85761, or any of their aforementioned derivatives or tepoxalin may be used in combination with a compound of formula (1.0.0) to form embodiments of the present invention.

Since the elucidation of the 5-LO biosynthetic pathway, there has been ongoing debate as to whether it is more beneficial to inhibit 5-lipoxygenase or to antagonize peptidyl or non-peptidyl leukotriene receptors. It is believed that 5-lipoxygenase inhibitors are superior to LT-receptor antagonists because 5-lipoxygenase inhibitors block the full spectrum of action of the 5-LO product, while LT-antagonists produce limited effects. Nonetheless, embodiments of the invention include the combination of a compound of formula (1.0.0) with an LT-antagonist and an inhibitor of 5-LO, as described below. 5-lipoxygenase enzymes having chemical structures other than those of the N-hydroxyurea and hydroxamate classes described above may also be used in combination with the (1.0.0) compounds to form another embodiment of the present invention. Examples of such different classes of compounds are N- (5-substituted) -thiophen-2-alkylsulfonamides of the formula (5.2.8): Wherein X is O or S; r is methyl, isopropyl, n-butyl, n-octyl or phenyl; and R is n-pentyl, cyclohexyl, phenyl, tetrahydro-1-naphthyl, 1-or 2-naphthyl, or is substituted by Cl, F, Br, CH₃、OCH₃、SCH₃、SO₂CH₃、CF₃Or isopropyl mono-or di-substituted phenyl. Preferred compounds are represented by formula (5.2.9):

further description of these compounds can be found in Beers et al, "N- (5-substituted) thiophene-2-alkylsulfonamides as potent inhibitors of 5-lipoxygenase," Bioorganic & Medicinal Chemistry5(4)779-786, 1997.

Another different class of 5-lipoxygenase inhibitors are the 2, 6-di-tert-butylphenol hydrazone compounds described in Cuadro et al, "Synthesis and biological evaluation of 2, 6-di-tert-butylphenol hydrazone Compounds as 5-lipoxygenase inhibitors" Bioorganic&Medicinal Chemistry 6173-. Such compounds are represented by formula (5.2.10):wherein "Het" is benzoxazol-2-yl; benzothiazol-2-yl; pyridin-2-yl; pyrazin-2-yl; pyrimidin-2-yl; 4-phenylpyrimidin-2-yl; 4, 6-diphenylpyrimidin-2-yl; 4-methylpyrimidin-2-yl; 4, 6-dimethylpyrimidin-2-yl; 4-butylpyrimidin-2-yl; 4, 6-dibutylpyrimidin-2-yl and 4-methyl-6-phenylpyrimidin-2-yl.

N- (5-substituted) -thiophen-2-alkylsulfonamides of formula (5.2.8), or 2, 6-di-tert-butylphenol hydrazones of formula (5.2.10), or any of their above derivatives, may be used in combination with compounds of formula (1.0.0) to form embodiments of the invention.

Another class of different 5-lipoxygenase inhibitors are the methoxytetrahydropyran compounds to which Zeneca ZD-2138 belongs. ZD-2138 is represented by formula (5.2.11):

ZD-2138 has high selectivity and high oral activity among various substances, and has been evaluated for the treatment of asthma and rheumatoid arthritis by oral administration. Further details regarding ZD-2138 and derivatives thereof are described in Crawley et al, j.med.chem., 352600, 1992; and Crawley et al, J.Med.chem.36295, 1993.

Another different class of 5-lipoxygenase inhibitors is the compound SmithKline Beecham SB-210661 SB-210661 is represented by formula (5.2.12):

two other different and related classes of 5-lipoxygenase inhibitors include the pyridyl-substituted series of 2-cyanonaphthalene compounds and the series of 2-cyanoquinoline compounds found in merckfrost. These two classes of 5-lipoxygenase inhibitors are exemplified by L-739,010 and L-746,530, which are represented by formulas (5.2.13) and (5.2.14), respectively:

Details of L-739,010 and L-746,530 are found in Dube et al, "quinoline compounds as potent inhibitors of 5-lipoxygenase: synthesis and biological Properties of L-746,530, "Bioorganic & Medicinal Chemistry 81255-; and WO95/03309(Friesen et al).

The methoxytetrahydropyran compound comprises Zeneca ZD-2138 of formula (5.2.11); or a lead compound SB-210661 of formula (5.2.12) and the class to which it belongs; or the pyridyl-substituted 2-cyanonaphthalene compound series to which L-739,010 belongs, or the 2-cyanoquinoline compound series to which L-746,530 belongs; or any of the above derivatives of any of the above classes, may be used in combination with a compound of formula (1.0.0) to form an embodiment of the present invention.

In addition to 5-lipoxygenase, another endogenous factor that plays an important role in leukotriene biosynthesis is the 5-lipoxygenase activating protein (FLAP). Unlike the direct effect of 5-lipoxygenase, this effect is indirect. Although antagonists of 5-lipoxygenase activating protein may still be useful for inhibiting cellular synthesis of leukotrienes, they can also be used in combination with compounds of formula (1.0.0) to form embodiments of the invention.

Compounds capable of binding to the 5-lipoxygenase activating protein and thereby blocking the utilization of the original reserves present in arachidonic acid have been synthesized from indole and quinoline structures; see Ford-Hutchinson et al, supra; rouzer et al, "MK-886, a potent specific leukotriene biosynthesis inhibitor, blocks and reverses ionophore-stimulated 5-lipoxygenase associated membranes in leukocytes," j.biol.chem.2651436-42, 1990; and Gorenn et al, "{ (R) -2-quinolin-2-yl-methoxy } phenyl } -2-cyclopentylacetic acid } (BAYx1005), a potent inhibitor of leukotriene synthesis: effect on anti-IgE stimulation of human airways, "j. pharmacol. exp. ther.268868-72, 1994.

MK-591, referred to as quiflon sodium, is represented by formula (5.2.15):

the indole and quinoline compounds described above, as well as the specific compounds MK-591.MK-886 and BAYx1005, which they belong to, or any of the derivatives described above of any of the above classes, can be used in combination with a compound of formula (1.0.0) to form embodiments of the invention.

9.2 with leukotriene LTB ₄ ，LTC ₄ ，LTD ₄ And LTE ₄ Combination of receptor antagonistsOne or more compounds of formula (1.0.0) may be reacted with leukotriene LTB₄，LTC₄，LTD₄And LTE₄A combination of receptor antagonists. The most important of these leukotrienes is LTB in terms of mediating the inflammatory response₄And LTD₄. The classes of antagonists for these leukotriene receptors are described in the following paragraphs.

The 4-bromo-2, 7-diethoxy-3H-phenothiazin-3-one compound, including L-651,392, is LTB₄Are described in US4,939,145 (Guidon et al) and US4,845,083(Lau et al). L-651,392 is represented by formula (5.2.16) formula (5.2.16):

a class of amidino compounds, including CGS-25019c, is described in US5,451,700(Morrissey and Suh); US5,488,160 (Morrissey); and US5,639,768(Morrissey and Suh)₄The receptor antagonist is represented by CGS-25019c and is represented by formula (5.2.17):

ontazolast, benzoxazolamines LTB₄Members of the receptor antagonists described in EP535,521(Anderskewitz et al); represented by formula (5.2.18):

The same group of researchers also found a class as LTB₄Benzamidine compounds which are receptor antagonists are described in WO97/21670(Anderskewitz et al); and WO98/11119(Anderskewitz et al); representative is BIIL284/260, represented by formula (5.2.19):

zafirlukast is LTC₄，LTD₄And LTE₄Under the trade name Acclate . Belongs to US4,859,692(Bernstein et al); US5,319,097(Holohan and Edwards); US5,294,636(Edwards and Sherwood); US5,482,963; US5,583,152(Bernstein et al); and heterocyclic amide derivatives described in US5,612,367(Timko et al). Zafirlukast is represented by formula (5.2.20):

ablukast is LTD₄Is referred to as Ro23-3544/001 and is represented by formula (5.2.21):

montelukast is LTD₄The receptor antagonist of (1) is under the trade name Singulair  and is described in US5,565,473. Montelukast is represented by the formula (5.2.22):

other LTDs₄Receptor antagonists include pranlukast, vilanter (MK-679), RG-12525, Ro-245913, ilaster (CGP 45715A), and BAYx 7195.

Phenothiazin-3-ones as described above including L-651,392; amidino compounds including CGS-25019 c; benzoxazolamines, including Ontazolast; benzamidine compounds represented by BIIL-284/260; heterocyclic amide derivatives including Zafirlukast; the species of compounds to which these belong, the species of Montelukast and Montelukast; and any of the above derivatives of any of the above classes of compounds may be used in combination with a compound of formula (1.0.0) to form embodiments of the present invention.

9.3 combination with other therapeutic agents to form further combinations

One or more compounds of formula (1.0.0) are used with other therapeutic agents as well as non-therapeutic agents to form combinations that constitute further embodiments of the invention and are useful in the treatment of a variety of different diseases, disorders, and conditions described herein. Such embodiments include one or more compounds of formula (1.0.0) and one or more of the following:

PDE4 inhibitors, including isotype PDE4D inhibitors;

5-lipoxygenase (5-LO) inhibitors; or a 5-lipoxygenase activating protein (FLAP) antagonist;

a dual inhibitor of 5-lipoxygenase (5-LO) and a Platelet Activating Factor (PAF) antagonist;

leukotriene antagonists (LTRAs), including LTB₄、LTC₄、LTD₄And LTE₄An antagonist;

antihistaminic H₁Receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azo  statin, and chlorpheniramine;

stomach protective property H₂A receptor antagonist;

oral or topical administration of alpha for decongestion₁-and α₂-adrenergic receptor agonists, vasoconstrictors, sympathomimetics including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydronaphazoline hydrochloride, xylometazoline hydrochloride, and ethyl norepinephrine hydrochloride;

Alpha 1-and alpha 2-adrenoceptor agonists in combination with 5-lipoxygenase (5-LO);

anticholinergic agents include ipratropium bromide, tiotropium bromide, oxitropium bromide, perenzapine, and tiotropium;

β₁-to beta₄The adrenergic receptor agonist includes metaproterenol, isoproterenol, albuterol, salbutamol, formoterol, salmeterol, terbutaline, metaproterenol, bitolterol mesylateSalt and pirbuterol;

theophylline and aminophylline;

sodium cromoglycate;

muscarinic receptor (M1, M2 and M3) antagonists;

COX-1 inhibitors (NSAIDs); COX-2 selective inhibitors, including rofecoxib; and nitric oxide NSAIDs;

type I insulin-like growth factor (IGF-1) mimetics;

ciclesonide;

glucocorticoid inhalants with low systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate;

tryptase inhibitors;

platelet Activating Factor (PAF) antagonists;

monoclonal antibodies against endogenous inflammatory entities;

IPL576；

anti-tumor necrosis factor (TNF α) agents including Etanercept, Infliximab, and D2E 7;

DMARDs include leflunomide;

a TCR peptide;

interleukin Converting Enzyme (ICE) inhibitors;

an IMPDH inhibitor;

adhesion molecule inhibitors, including VLA-4 antagonists;

(ii) a cathepsin;

MAP kinase inhibitors:

glucose-6-phosphate dehydrogenase inhibitors;

kinin-B₁-and B₂-a receptor antagonist;

gold in the form of a aurothioylene group having various hydrophilic groups;

immunosuppressants such as cyclosporin, azathioprine and methotrexate;

anti-gout agents, such as colchicine;

xanthine oxidase inhibitors, such as allopurinol;

uricosuric agents, such as probenecid, sulindac, and benzbromarone;

antineoplastic agents, especially antimitotic agents, including vinca alkaloids such as vinblastine and vincristine;

growth hormone secretagogues;

inhibitors of Matrix Metalloproteinases (MMPs), i.e. stromelysin, collagenase and gelatinase, and aggrecanase (aggrecanase); especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11);

transforming growth factor (TGF β);

platelet Derived Growth Factor (PDGF);

fibroblast growth factors, such as basic fibroblast growth factor (bFGF);

Granulocyte macrophage colony stimulating factor (GM-CSF);

capsaicin cream;

tachykinin NK-1, NK-1/NK-2, NK-2, and NK-3 receptor antagonists including NKP-608C, SB-233412(talnetant), and D-4418;

elastase inhibitors, including UT-77, and ZD-0892; and

adenosine A2a receptor agonists.

Detailed Description

10.0 pharmaceutical compositions and formulations

The following description refers to the manner in which the compound of formula (1.0.0) and other therapeutic or non-therapeutic agents as desired are combined with a pharmaceutically acceptable carrier, which is usually conventional, to form a dosage form suitable for different routes of administration, which may be administered to any particular patient, and which is suitable for any disease, disorder or condition of the particular patient being treated.

The pharmaceutical compositions of the present invention comprise one or more of the inhibitor compounds of the present invention described above, or a pharmaceutically acceptable salt thereof as described above, and a pharmaceutically acceptable carrier as is well known in the relevant art as required by the nature and desired performance.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary with the host treated, the particular mode of administration. It will be understood, however, that the specific dose and therapeutic regimen appropriate for a particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the attending physician and the severity of the particular disease undergoing therapy. The amount of active ingredient, if present in the combination, will also depend on the therapeutic or prophylactic agent with which the active ingredient is being used.

The compounds of the invention described above may be used in the form of acids, esters or other chemical species falling within the scope of the compounds. These compounds may also be used within the scope of the present invention, i.e. in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases, according to the methods described in detail above and well known in the art. The active ingredients comprising the compounds of formula (1.0.0) are often used in the form of their salts, in particular these salt forms, i.e. they are capable of imparting improved pharmacokinetic properties to the active ingredient compared to the free form of the active ingredient or some other salt form of the active ingredient used previously. The pharmaceutically acceptable salt form of the active ingredient may also initially impart to the active ingredient beneficial pharmacokinetic properties that it did not previously possess, and which can positively influence the pharmacokinetics even for the in vivo therapeutic activity of the active ingredient.

The pharmacokinetic properties of the active ingredients that can be favorably influenced include, for example, the way in which the active ingredients are transported across the cell membrane, which in itself can directly and positively influence the absorption, distribution, biotransformation and excretion of the active ingredients. While the route of administration of the pharmaceutical composition is important, and various anatomical, physiological and pathological factors can have a significant impact on bioavailability, the solubility of the active ingredient generally depends on the nature of the particular salt form used. Furthermore, as is known to those skilled in the art, aqueous solutions of the active compounds will enable the active ingredient to be absorbed most rapidly into the body of the patient to be treated, whereas lipid solutions and suspensions, as well as solid dosage forms, do not enable the active ingredient to be absorbed rapidly. Oral ingestion of the active ingredient is the most preferred route of administration for reasons of safety, convenience and economy, but absorption of such oral dosage forms can be adversely affected by physical properties such as polarity, vomiting due to irritation of the gastrointestinal mucosa, destruction by digestive enzymes and low pH, irregular absorption or propulsion in the presence of food or other drugs, and enzymatic metabolism of the mucosa, intestinal flora or liver. Formulating the active ingredient into different pharmaceutically acceptable salt forms is effective in overcoming or alleviating one or more of the above-mentioned problems encountered with absorption of oral dosage forms.

Among the above pharmaceutically acceptable salts, preferred include, but are not limited to, acetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiolate, tosylate and trimethylamine.

When the compounds of the present invention contain more than one group capable of forming such pharmaceutically acceptable salts, double salt forms are also included within the scope of the present invention. Examples of typical double salt forms include, but are not limited to, ditartrate, diacetate, difumarate, diglucamine, diphosphate, disodium and trihydrochloride.

The pharmaceutical compositions of the present invention comprise one or more of the inhibitor compounds of the present invention described above, or a pharmaceutically acceptable salt thereof as described above, and a pharmaceutically acceptable carrier as is well known in the relevant art as required by the nature and desired performance.

The term "carrier" as used herein includes acceptable diluents, excipients, adjuvants, carriers, solubilizers, viscosity modifiers, preservatives and other materials known in the art for providing advantageous properties in the final pharmaceutical composition. To illustrate these carriers, the following brief summary of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention, and a detailed description of these various types of components follows. Typical carriers include, but are not limited to, ion exchange compositions; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; a phosphate salt; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; hydrogenated palm oil; water; salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; a cellulose-based substance; such as sodium carboxymethylcellulose; polyethylene glycol; polyacrylates, paraffins; polyethylene-polyoxypropylene block copolymers and lanolin.

More specifically, the carriers for use in the pharmaceutical compositions of the present invention include various types and kinds of modulators selected substantially independently from the substances listed in the following paragraphs.

Acidulants and alkalizers, including acidulants such as acetic, glacial, malic, and propionic acids, are added to achieve the desired or predetermined pH. Strong acids such as hydrochloric acid, nitric acid and sulfuric acid may also be used (but less preferred). The alkalizing agent includes, for example, edenol (edetol), potassium carbonate, potassium hydroxide, sodium borate, sodium carbonate and sodium hydroxide. Basifying agents containing active amine groups, such as diethanolamine and triethanolamine (trolamin), may also be used.

Aerosol propellants are required when pharmaceutical compositions are administered in aerosol form under sufficient pressure. Such propellants include, for example, acceptable chlorofluorocarbons such as dichlorodifluoromethane, dichlorotetrafluoroethane and trichloromonofluoromethane; nitrogen gas; or a volatile hydrocarbon such as butane, propane, isobutane or mixtures thereof.

Antimicrobial agents, including antibacterial, antifungal and antiprotozoal agents, are added in the case of topical administration of pharmaceutical compositions to an area of skin that may have had a deleterious condition or been continuously abraded or cut and whose skin is infected with bacteria, fungi or protozoa. Antimicrobial agents include compounds such as benzyl alcohol, chlorobutanol, phenylethyl alcohol, phenyl mercuric acetate, potassium sorbate, and sorbic acid. Antifungal agents include compounds such as benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, and sodium benzoate.

The addition of antimicrobial preservatives to the pharmaceutical compositions of the present invention serves to protect them from the growth of potentially harmful microorganisms which normally invade the aqueous phase of the composition but which may in some cases also grow in the oil phase. Thus, preservatives that are both water soluble and lipid soluble are needed. Suitable antimicrobial preservatives include, for example, alkyl esters of p-hydroxybenzoic acid, propionate salts, phenoxyethanol, sodium methylparaben, sodium propylparaben, sodium dehydroacetate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, acetolactam derivatives, quaternary ammonium compounds and cationic polymers, imidazolidinyl urea, diazolidinyl urea, and trisodium Ethylenediaminetetraacetate (EDTA). Preservatives are preferably used in amounts of about 0.01% to about 2.0% by weight of the total composition.

In order to protect the ingredients of the pharmaceutical composition from damage or degradation by oxidizing agents present in the composition itself or in the environment of use, antioxidants are added, such as anoxomer, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, potassium metabisulfite, propyl, octyl and dodecyl esters of gallic acid, sodium metabisulfite, sulfur dioxide and tocopherol;

The use of a buffer maintains the established pH of the composition, preventing the effects of foreign substances and the mobile equilibrium of the components of the composition. The buffer is selected from those well known to those skilled in the art of pharmaceutical composition preparation, such as calcium acetate, potassium metaphosphate, potassium dihydrogen phosphate and tartaric acid.

Chelating agents, including, for example, dipotassium edetate, disodium edetate, and edetic acid, are used to help maintain the ionic strength of the pharmaceutical composition and to bind and effectively remove harmful compounds and metals.

To the topically applied pharmaceutical compositions of the present invention are added dermatologically active substances including, for example, wound healing agents such as peptide derivatives, yeast, panthenol, hexylresorcinol, phenol, tetracycline hydrochloride, lamin, and kinetin, vitamins for the treatment of skin cancer, such as vitamin a, tretinoin, isotretinoin, etretinate, acitretin, and arotinoid; mild antibacterial agents for treating skin infections, such as resorcinol, salicylic acid, benzoyl peroxide, erythromycin-benzoyl peroxide, erythromycin and clindamycin; antifungal agents for the treatment of tinea corporis, tinea pedis, candidiasis and tinea versicolor, e.g. griseofulvin, azoles such as miconazole, econazole, itraconazole, fluconazole and ketoconazole, and allylamines such as naftifine and terfinafine; antiviral agents such as acyclovir, famciclovir and valacyclovir for the treatment of cutaneous herpes simplex, herpes zoster and varicella; antihistamines for the treatment of pruritis, atopic rashes, and contact rashes, such as diphenhydramine, terfenadine, astemizole, loratadine, cetirizine, atorvastatin, and temelastine; local anesthetics for pain, irritation and itching relief, such as benzocaine, lidocaine, dibucaine and pramoxine hydrochloride; topical analgesics for pain and inflammation, such as methyl salicylate, camphor, menthol and resorcinol; topical preservatives for the prevention of infection, such as benzalkonium chloride and povidone iodine; and vitamins and their derivatives, such as tocopherol, tocopheryl acetate, retinoic acid, and vitamin alcohol.

Dispersing agents and suspending agents are used as aids for preparing stable formulations and include, for example, poliglenen, polyvinylpyrrolidone and silica.

Emollients are substances used to soften and lubricate the skin, especially skin that has dried due to excessive water loss, and are preferably non-oily and water-soluble. These materials are used with the pharmaceutical compositions of the present invention for topical administration and include, for example, hydrocarbon oils and waxes, triglycerides, acetylated monoglycerides, C₁₀-C₂₀Methyl and other alkyl esters of fatty acids, C₁₀-C₂₀Fatty acid, C₁₀-C₂₀Fatty alcohols, lanolin and its derivatives, polyol esters such as polyethylene glycol (200-; emulsifiers for the preparation of oil-in-water emulsions; excipients, such as laurocapram and polyethylene glycol monomethyl ether; humectants, such as sorbitol, glycerol and hyaluronic acid; ointment bases such as petrolatum, polyethylene glycol, lanolin, and poloxamer (poloxamer); permeation enhancers such as dimethyl isosorbide, diethyl-ethylene glycol-monoethyl ether, 1-dodecylazacycloheptan-2-one, and Dimethylsulfoxide (DMSO); preservatives, such as benzalkonium chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, hydantoin derivatives, cetylpyridinium chloride, propyl p-hydroxybenzoate, quaternary ammonium compounds, such as potassium benzoate and thimerosal; chelating agents, including cyclodextrins; solvents such as acetone, alcohols, amylene hydrate, butanol, corn oil, cottonseed oil, ethyl acetate, glycerol, hexylene glycol, isopropanol, isostearyl alcohol, methanol, methylene chloride, mineral oil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether, propylene glycol diacetate, sesame oil and purified water; stabilizers, such as calcium saccharinate and thymol; surfactants, such as ropinirole; lauryl ether 4, i.e., α -dodecyl- ω -hydroxy-poly (oxy-1, 2-ethylene) or polyethylene glycol monododecyl ether.

Emulsifiers, including emulsifying and hardening agents and emulsion adjuvants, are useful in the preparation of oil-in-water emulsions when they form the primary component of the pharmaceutical compositions of the present invention. These emulsifiers include, for example, nonionic emulsifiers such as C₁₀-C₂₀Fatty alcohols and said fatty alcohols condensed with 2 to 20 moles of ethylene oxide or propylene oxide, condensed with 2 to 20 moles of ethylene oxide (C)₆-C₁₂) Mono-and di-C of alkylphenols, ethylene glycol₁₀-C₂₀Fatty acid esters, C₁₀-C₂₀Fatty acid monoglycerides, diethylene glycol, polyethylene glycols of MW200-6000, polypropylene glycols of MW200-3000, in particular sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan, hydrophilic wax esters, cetostearyl alcohol, oleyl alcohol, lanolin alcohol, cholesterol, mono-and diglycerides, glycerol monostearate, mixed mono-and distearate of ethylene glycol and polyoxyalkylene glycols, propylene glycol monostearate and hydroxypropylcellulose. Emulsifiers containing reactive amine groups, which are generally anionic emulsifiers such as fatty acid soaps, e.g. C, may also be used₁₀-C₂₀Sodium, potassium and triethanolamine soaps of fatty acids; (C)₁₀-C₃₀) Alkyl sulfuric acid, (C)₁₀-C₃₀) Alkyl sulfonic acids and (C) ₁₀-C₅₀) Alkali metal, ammonium or substituted ammonium salts of alkyl ethoxy ether sulfonic acids. Other suitable emulsifiers include castor oil and hydrogenated castor oil; polymers of lecithin and 2-acrylic acid and acrylic acid polymers, both crosslinked with allyl ethers of sucrose and/or pentaerythritol and having variable viscosity, identified by the product names acrylic acid polymers carbomer910, 934, 934P, 940, 941 and 1342. Cationic emulsifiers containing active amine groups can also be used, including those based on quaternary ammonium, morpholinium, and pyridinium compounds. Amphoteric emulsifiers containing active amine groups, such as cocobetaine, lauryl dimethyl amine oxide and cocoimidazoline, can likewise be used. Useful emulsifying and hardening agents also include cetyl alcohol and sodium stearate; and emulsion adjuvants such as oleic acid, stearic acid and stearyl alcohol.

Excipients include, for example, laurocapram and polyethylene glycol monomethyl ether.

In the case of topical administration of pharmaceutical compositions, penetration enhancers may be used, including, for example, dimethyl isosorbide, diethyl-ethylene glycol-monoethyl ether, 1-dodecylazacycloheptan-2-one, and dimethyl sulfoxide (DMSO). Such compositions also typically include ointment bases such as petrolatum, polyethylene glycols, lanolin, and poloxamers, which are block copolymers of polyoxyethylene and polyoxypropylene and may also be used as surfactants or emulsifiers.

Preservatives are used to protect the pharmaceutical compositions of the present invention from the degradative attack of environmental microbes and include, for example, benzalkonium chloride, benzethonium chloride, alkyl esters of parahydroxybenzoic acid, hydantoin derivatives, cetylpyridinium chloride, monothioglycerol, phenol, phenoxyethanol, methyl parahydroxybenzoate, imidazolidinyl urea, sodium dehydroacetate, propyl parahydroxybenzoate, quaternary ammonium compounds, especially polymers such as polixetonium chloride, potassium benzoate, sodium formaldehyde sulfoxylate, sodium propionate and thimerosal.

Chelating agents are used to improve the stability of the pharmaceutical compositions of the present invention and include, for example, cyclodextrins, a family of natural cyclic oligosaccharides capable of forming inclusion complexes with a variety of substances, and the size of the rings is variable, wherein these compounds with 6-, 7-and 8-glucose residues in the rings are commonly referred to as alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin, respectively. Suitable cyclodextrins include, for example, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, delta-cyclodextrin and cationized cyclodextrins.

Solvents useful in preparing the pharmaceutical compositions of the present invention include, for example, acetone, ethanol, pentene hydrate, butanol, corn oil, cottonseed oil, ethyl acetate, glycerol, hexylene glycol, isopropyl alcohol, isostearyl alcohol, methanol, methylene chloride, mineral oil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether, propylene glycol diacetate, sesame oil, and purified water.

Suitable stabilizers for use include, for example, calcium saccharate and thymol.

Hardeners commonly used in topical formulations to provide the desired viscosity and application properties include, for example, cetyl esters wax, myristyl alcohol, paraffin, emulsifying wax, microcrystalline wax, white wax and yellow wax.

Sugars are commonly used to impart various desirable properties to the compositions of the present invention and to improve the results obtained. Such sugars include, for example, monosaccharides, disaccharides, and polysaccharides such as glucose, xylose, fructose, reose, ribose, pentose, arabinose, allose, talose, arabinose , mannose, galactose, lactose, sucrose, erythrose, glyceraldehyde, or any combination thereof.

Surfactants are used to provide stability to the multicomponent pharmaceutical compositions of the present invention, to enhance existing properties of these compositions, and to impart new desirable properties to the compositions. Surfactants can be used as wetting agents, antifoaming agents for reducing the surface tension of water, as well as emulsifiers, dispersants and penetrants, and include, for example, lapinium chloride; lauryl ether 4, i.e., α -dodecyl- ω -hydroxy-poly (oxy-1, 2-ethylene) or polyethylene glycol monododecyl ether; lauryl ether 9, a mixture of polyethylene glycol monododecyl ethers containing an average of about 9 ethylene oxide groups per molecule; monoethanolamine; nonoxynol 4, 9 and 10, i.e., polyethylene glycol mono (p-nonylphenyl) ether; nonoxynol 15, i.e., α - (p-nonylphenyl) - ω -hydroxypenta (oxyethylene); nonoxynol 30, i.e., α - (p-nonylphenyl) - ω -hydroxytriacontanoi (oxyethylene); poloxamene, a nonionic polymer of the polyethylene-propylene glycol type, having a MW of about 3000; poloxamers, see discussion above in ointment base; polyoxyl 8, 40 and 50 stearates, i.e., poly (oxy-1, 2-ethanediylidene), α -hydro- ω -hydroxy; esters of stearic acid; polyoxyl 10 oleyl ether, i.e. poly (oxy-1, 2-ethanediylidene), α - [ (Z) -9-octadecenyl- ω -hydroxy-; polysorbate 20, i.e. sorbitan, mono-eicosanoate, poly (oxy-1, 2-ethaneylidene); polysorbate 40, i.e., sorbitan, cetyl esters, poly (oxy-1, 2-ethylidene); polysorbate 60, i.e. sorbitan, monostearates, poly (oxy-1, 2-ethaneylidene); polysorbate 65, i.e. sorbitan, trioctadecanoate, poly (oxy-1, 2-ethaneylidene); polysorbate 80, i.e., sorbitan, mono-9-monododecanoate, poly (oxy-1, 2-ethanediylidene); polyoxyethylene ether 85, i.e., sorbitan, tri-9-octadecenoate, poly (oxy-1, 2-ethenylene); sodium lauryl sulfate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; sorbitan stearate; sorbitan sesquioleate and sorbitan tristearate.

The pharmaceutical compositions of the present invention may be prepared by simple methods well known to those skilled in the art. When the pharmaceutical composition of the invention is a simple aqueous and/or other solvent solution, the different components of the total composition are mixed together in any practical order, which requirement is mainly considered for simplicity. Those components having low water solubility but sufficient solubility in the same cosolvent containing water can be dissolved in the cosolvent, and then the cosolvent solution is added to the aqueous portion of the carrier, whereupon the solute will dissolve in water. To facilitate this dispersion/dissolution process, surfactants may be used.

When the pharmaceutical composition of the present invention is in the form of an emulsion, the components of the pharmaceutical composition are mixed according to the following general method. The continuous aqueous phase is first heated to a temperature of from about 60 ℃ to about 95 ℃, preferably from about 70 ℃ to about 85 ℃, the temperature used being selected depending on the physicochemical properties of the components constituting the oil-in-water emulsion. Once the continuous aqueous phase has reached the selected temperature, the final composition components to be added in this step are mixed with water and dispersed therein under high speed stirring. The water temperature is then reduced to about its initial temperature and the composition ingredients comprising the next step are then added to the above compositional mixture under moderate agitation and mixing is continued for about 5 to about 60 minutes, preferably about 10 to about 30 minutes, depending on the first two steps of ingredients. Followed by passive or active cooling of the compositional mixture to about 20 c to about 55 c to add any components in the remaining steps, followed by addition of sufficient water to reach its predetermined original concentration in the total composition.

According to the present invention, the pharmaceutical composition may be in the form of a sterile injectable preparation, for example, an aqueous or oily sterile injectable suspension. Such suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable excipients and solvents used may be water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, bland fixed oils which may be employed include synthetic mono-or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives are also useful in the preparation of injectables, especially in their polyoxyethylated versions, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as Rh, HCIX or similar alcohols.

The pharmaceutical compositions of the present invention may be administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For capsules for oral administration, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. They can be prepared by mixing the active ingredient with suitable non-irritating excipients which are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the invention may also be administered topically, particularly where the target of treatment includes a site or organ accessible by topical administration, including diseases of the eye, skin, or lower intestinal tract. For these sites or organs, suitable topical formulations suitable for them are readily prepared.

For topical administration to the lower intestinal tract, this may be accomplished in the form of rectal suppositories or in the form of suitable enema preparations as described above. Topically active transdermal patches may also be used.

For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. In another aspect, the pharmaceutical compositions of the present invention may also be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate, cetyl esters wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol and water.

Within the scope of the present invention, pharmaceutical compositions include those wherein a therapeutically effective amount of the active ingredient (including a compound of the present invention) needed for the treatment or prevention of diseases, disorders and conditions mediated by PDE4 activity or associated with the modulation of PDE4 activity is provided in a dosage form suitable for systemic administration. Such pharmaceutical compositions comprise the active ingredient in a suitable liquid form for administration in the following manner: (1) intra-arterial, intradermal or transdermal, subcutaneous, intramuscular, intraspinal, intrathecal or intravenous injection or infusion wherein the active ingredient: (a) contained in the solution as a solute; (b) included in a discontinuous emulsion phase or a discontinuous phase of an invert emulsion (invert emulsion) by injection or infusion, the emulsion containing a stable emulsifier; or (c) as a suspended solid in the form of colloids or microparticles in a suspension containing a suitable suspending agent; (2) injected or infused into body tissues or cavities as a depot, wherein the composition provides storage of the active ingredient followed by delayed-, sustained-, and/or controlled release of the active ingredient for systemic distribution; (3) instilling, inhaling or insufflating the pharmaceutical composition in a suitable solid form into body tissue or cavities, wherein the active ingredient: (a) contained within a solid implant composition capable of delayed-, sustained-, and/or controlled release of the active ingredient; (b) contained in a particulate composition that can be inhaled into the lungs; or (c) contained in a particulate composition capable of being insufflated into an appropriate body tissue or cavity, wherein said composition is optionally capable of delayed-, sustained-, and/or controlled release of said active ingredient; or (4) ingesting the pharmaceutical composition in a suitable solid or liquid form suitable for oral administration of the active ingredient, wherein the active ingredient is included within a solid dosage form; or (b) contained in a liquid dosage form.

Specific dosage forms of the above pharmaceutical compositions include (1) suppositories as a special kind of implant comprising a matrix which is solid at room temperature but is capable of melting at body temperature, so that the active ingredient impregnated in the matrix can be slowly released into the surrounding tissues of the body where it can be absorbed and transported, thereby achieving systemic administration; (2) a solid oral dosage form selected from: (a) sustained release oral tablets, capsules, caplets, lozenges, troches and multiparticulates; (b) enteric coated tablets and capsules which are resistant to release and absorption in the stomach, thereby facilitating their delivery to the distal side of the stomach of a patient being treated; (c) sustained release oral tablets, capsules and microgranules capable of systemic delivery of the active ingredient in a controlled manner over a period of up to 24 hours; (d) (ii) a fast dissolving tablet; (e) encapsulating the solution; (f) oral paste; (g) a particulate form that has been incorporated or is capable of being incorporated into the food of a patient to be treated; and (h) an oral liquid dosage form selected from the group consisting of solutions, suspensions, emulsions, invert emulsions, elixirs, extracts, tinctures, and concentrates.

Within the scope of the present invention are included pharmaceutical compositions wherein a therapeutically effective amount of an active ingredient, including a compound of the present invention, required for the treatment or prevention of diseases, disorders and conditions mediated by PDE4 activity or associated with modulation of PDE4 activity as described herein is provided in a formulation suitable for topical administration to a subject in need thereof, wherein said pharmaceutical composition comprises said active ingredient in a suitable liquid form for administration of said active ingredient in the following manner: (1) injection or infusion by intra-arterial, intra-articular, intra-chondral, intracostal, intracapsular, intradermal or transdermal, intrafascicular (intrafascicular), intralesional, intramedullary, intramuscular, intranasal, intraneural, intraocular-i.e., ocular administration, intraosseous, intrapelvic, intrapericardial, intraspinal, intrasternal, intrasynovial, intratarsal, or intrathecal administration to a local site; comprising a component capable of providing delayed, controlled and/or sustained release of the active ingredient to the topical site; wherein the active ingredient: (a) contained in the solution as a solute; (b) contained within the discontinuous phase of an emulsion containing a stable emulsifier or within the discontinuous phase of an invert emulsion inverted by injection or infusion; or (c) as a suspended solid in the form of colloids or microparticles in a suspension containing a suitable suspending agent; or (2) as a depot injection or infusion for delivery of the active ingredient to the local site, wherein the composition provides storage of the active ingredient followed by delayed-, sustained-, and/or controlled release of the active ingredient to the local site, and wherein the composition further comprises components which ensure that the active ingredient is predominantly locally active and is less active for systemic administration; or wherein the pharmaceutical composition comprises the active ingredient in a suitable solid form for administration of the inhibitor in the following manner: (3) instillation, inhalation or insufflation to a topical site, wherein the active ingredient: (a) contained within a solid graft composition that can be placed in a topical location, said composition optionally providing delayed-, sustained-, and/or controlled release of said active ingredient to said topical location; (b) contained in a particulate composition that is inhaled into a localized site, including the lungs; or (c) in a particulate composition which can be insufflated into a suitable topical site, wherein said composition comprises components which ensure that said active ingredient is predominantly topically active, is poorly active for systemic administration, and that such components can optionally delay-, sustain-, and/or provide controlled release of said active ingredient to said topical site. For ophthalmic use, the pharmaceutical compositions of the present invention may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably as solutions in isotonic, pH adjusted sterile saline with or without preservatives such as benzalkonium chloride. On the other hand, for ophthalmic use, the pharmaceutical composition may also be formulated as an ointment, such as petrolatum ointment.

The pharmaceutical compositions of the present invention may also be administered by nasal aerosol form, or by inhalation using a nebulizer, dry powder inhaler or metered dose inhaler. Such compositions are prepared by methods well known in the pharmaceutical arts and may be prepared as physiological saline solutions employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons, and/or other conventional solubilizing or dispersing agents.

As mentioned before, the active ingredient of formula (1.0.0) according to the invention can be administered systemically to the patient to be treated by injection or infusion in the form of a pharmaceutical composition in a suitable liquid form. The presence of multiple sites and organ systems within a patient allows the properly formulated pharmaceutical composition to penetrate the entire body and all organ systems of the patient being treated after injection or infusion. Injection is typically a single dose of a pharmaceutical composition that is forced into the relevant tissue using a syringe. The most common types of injection are intramuscular, intravenous and subcutaneous. Infusion, in contrast, is the gradual addition of a pharmaceutical composition into the relevant tissue. The most common type of infusion is intravenous infusion. Other types of injection or infusion include intra-arterial, intradermal or transdermal (including subcutaneous), or intraspinal, especially intrathecal. In these liquid pharmaceutical compositions, the active ingredient may be contained in solution as a solute. This is the most common and most preferred class of such compositions, but requires the active ingredient to be in the form of a salt, which has excellent water solubility. Obviously water (brine) is the most preferred solvent for such compositions. Occasionally, supersaturated solutions can also be used, but these solutions have stability problems that make them difficult to achieve for everyday use.

If some of the compounds of formula (1.0.0) are not available in a form having the desired water solubility, although they may be present, one skilled in the art can prepare emulsions by dispersing a finely divided liquid droplet (discontinuous or internal phase) into a second liquid immiscible therewith (continuous or internal phase). The two liquids are maintained in an emulsified state by the use of a pharmaceutically acceptable emulsifier. For example, when the active ingredient is a water-insoluble oil, it may be administered as a discontinuous phase emulsion. Also, emulsions may be used when the active ingredient is water-insoluble but soluble in a water-miscible solvent. While the active ingredient is most commonly used as the discontinuous or internal phase, known as an oil-in-water emulsion, it may also be used as the discontinuous or internal phase of an invert emulsion (commonly referred to as a water-in-oil emulsion). The active ingredients are herein water-soluble and can be administered in the form of simple aqueous solutions. The invert emulsion, however, is inverted by injection or infusion into an aqueous medium such as blood, giving the advantage of being able to disperse the active ingredient more rapidly and effectively into the aqueous medium (compared to the advantages obtained using aqueous solutions). The invert emulsion is prepared using pharmaceutically acceptable suitable emulsifiers well known in the art. In the case of active ingredients having limited aqueous solubility, it may also be administered in solid form suspended in colloidal particles or microgranules in a suspension prepared using a suitable pharmaceutically acceptable suspending agent. The suspended solids containing the active ingredient may also be formulated in the form of delayed-, sustained-, and/or controlled-release compositions.

Although systemic administration is most commonly carried out by means of injection or by means of an auxiliary liquid, it is in many cases advantageous, or even necessary, to administer the active ingredient in solid form. Systemic administration of solids is accomplished by instillation, inhalation or insufflation of pharmaceutical compositions in the form of suitable solids containing the active ingredient. Instillation of the active ingredient may require placement of the solid implant composition into the appropriate body tissue or cavity. The implant comprises a matrix of biocompatible and bioerodible material in which solid active ingredient particles are dispersed, or possibly pellets or ex vivo cells with liquid active ingredient entrapped therein. The matrix is preferably degradable and can be completely absorbed by the body. It is also preferred to select such matrix compositions that are capable of providing a controlled-, sustained-, and/or delayed release of the active ingredient over a long period of time, even over a period of up to several months.

The term "implant" is most commonly used to refer to a solid pharmaceutical composition containing an active ingredient, while the term "depot" often refers to a liquid pharmaceutical composition containing an active ingredient that is placed in any suitable tissue or cavity to form a depot or pool that slowly migrates into surrounding tissues and organs and eventually becomes systemically distributed. These limits are not always strictly adhered to in the art and therefore it is considered within the scope of the present invention to include both liquid implants and solid reservoirs and for each to be even a mixture of solid and liquid. Suppositories can be considered as implant types because they comprise a matrix which is solid at room temperature but melts at the patient's body temperature, thereby enabling slow release of the active ingredient impregnated in the matrix into the surrounding body tissues of the patient, whereupon the active ingredient is absorbed and transported, thereby enabling systemic administration.

Systemic administration can also be accomplished by inhalation or insufflation of powders, i.e., particulate compositions containing the active ingredient. For example, the active ingredient in powder form may be inhaled into the lungs using conventional means for aerosolizing particulate formulations. The active ingredients in the form of granular formulations may also be administered by insufflation, i.e. by simple dusting or by conventional means for atomising granular formulations for insufflation or dispersion into the appropriate body tissue or cavity. These particulate compositions may also be formulated to release the active ingredient in a delayed-, sustained-, and/or controlled manner using well known principles and materials.

Other systemic modes of administration in which the active ingredient of the invention is in liquid or solid form that may be used include transdermal, intranasal and ocular routes. In particular transdermal patches prepared according to well-known administration techniques, which patches are applied to the skin of a patient to be treated and the active agent then migrates across the epidermis, according to its formulated solubility characteristics, into the skin layers of the patient's skin where it is absorbed as part of the patient's normal circulation and ultimately provides for systemic distribution of the active ingredient over a desired extended period. Also included are implants that are placed beneath the epidermal layer of the skin of the patient being treated, i.e., between the epidermal layer and the dermis. Such implants are formulated using principles well known in the art and materials for such administration techniques, and may be formulated to provide controlled-, sustained-, and/or prolonged release of the active ingredient into the systemic circulation of the patient. Such sub-epidermal implants provide the same ease of device and efficacy of administration as transdermal patches, but overcome the limitations of being susceptible to degradation, damage or accidental removal by application to the outer layers of the patient's skin.

In the above description of the pharmaceutical composition containing an active ingredient, the equivalent expressions "administration", "administration" and "administration" are used for the pharmaceutical composition. Thus, as used herein, these terms refer to providing a pharmaceutical composition of the present invention to a patient in need of treatment by providing the route of administration described herein, wherein the active ingredient is a compound of formula (1.0.0), a prodrug, derivative, or metabolite thereof, which is useful for treating a disease, disorder or condition in said patient mediated by PDE4 activity or associated with modulation of PDE4 activity. Thus, any other compound which when administered to a patient is capable of forming, directly or indirectly, a compound of formula (1.0.0) is included within the scope of the invention. These compounds are referred to as prodrugs and a number of established methods have been used to prepare these prodrug forms of the compounds of formula (1.0.0).

The amount and single dose of a compound of the invention effective for the treatment or prevention of a disease, disorder or condition mediated by PDE4 activity or associated with the modulation of PDE4 activity will depend on a variety of factors, such as the nature of the inhibitor, the weight of the patient, the therapeutic goal, the nature of the disease being treated, the particular composition used, and the discretion and judgment of the attendant physician.

For example, for oral dosage forms such as tablets or capsules, a suitable dosage level of the compound of formula (1.0.0) is from about 0.1 μ g/kg to about 50.0mg/kg body weight per day, preferably from about 5.0 μ g/kg to about 5.0mg/kg body weight per day, more preferably from about 10.0 μ g/kg to about 1.0mg/kg body weight per day, and most preferably from about 20.0 μ g/kg to about 0.5mg/kg body weight per day of the active ingredient.

Where the dosage form is for topical administration to the bronchi and lungs, for example using a powder inhaler or nebulizer, a suitable dosage level of the compound of formula (1.0.0) is from about 0.001 μ g/kg to about 10.0mg/kg body weight per day, preferably from about 0.5 μ g/kg to about 0.5mg/kg body weight per day, more preferably from about 1.0 μ g/kg to about 0.1mg/kg body weight per day, and most preferably from about 2.0 μ g/kg to about 0.05mg/kg body weight per day of the active ingredient.

To illustrate the above daily dosage ranges for oral administration using representative body weights of 10kg and 100kg, suitable dosage levels for the compound of formula (1.0.0) are about 1.0-10.0 μ g and 500.0-5000.0mg, preferably about 50.0-500.0 μ g and 50.0-500.0mg, more preferably about 100.0-1000.0 μ g and 10.0-100.0mg, and most preferably about 200.0-2000.0 μ g and about 5.0-50.0mg per day of the active ingredient comprising the compound of formula (1.0.0). These dosage ranges represent the total dose of active ingredient for a particular patient per day. The number of daily administrations depends on pharmacological and pharmacokinetic factors such as half-lives reflecting the catabolism and clearance rates of the active ingredients, as well as the minimum and optimal plasma or other body fluid concentrations reached by the active ingredients in the patient, which are necessary for the therapeutic effect.

Various other factors are necessary in determining the number of administrations per day and the amount of active ingredient administered per dose. Other factors of greater importance are the individual response of the treated patient. For example, when the active ingredient is used in the treatment or prophylaxis of asthma and is administered topically by aerosol inhalation to the lungs, 1 to 4 doses per day consisting of the acitations of the dispenser, i.e., the "spray" of the inhaler, may be administered, each dose containing from about 50.0 μ g to about 10.0mg of the active ingredient.

Detailed Description

11.0 preparation examples and examples

Preparation example 1

2- [ benzo [2, 1, 3 ] of formula (5.0.1)]Oxadiazol-5-yloxy]-ethyl nicotinate:

a mixture of 5.5g (29.4mmol) ethyl 2-chloronicotinate, 4.0g (29.4mmol) 5-hydroxybenzofuran and 20.1g (61.7mmol) caesium carbonate in 125ml dry dimethylformamide is heated at 90 ℃ for a total of 5 days. The mixture was poured into water and extracted with ethyl acetate. Combining the ethyl acetate extracts; washing with sodium bicarbonate solution, water, and brine in sequence; then dried (Na)₂SO₄) (ii) a Concentration in vacuo afforded a solid. Recrystallization from ether/pentane gave 2.2g (26%) of a solid.

¹H-NMR(CDCl₃)：δ8.3(m，2H)，7.8(d，1H，J＝10 Hz)，7.2(m，3H)，4.4(q，2H，J＝7Hz)，1.4(t，

3H，J＝7Hz)

GC-MS(m/z)：285(M⁺，20)，122(100)

Preparation example 2

2- [ benzo [2, 1, 3 ] of formula (5.0.2)]Oxadiazol-5-yloxy]-nicotinic acid:

A mixture of 2.2g (7.7mmol) of ethyl 2- [ benzo [2, 1, 3] oxadiazol-5-yloxy ] -nicotinic acid with 23.1ml (23.1mmol) of 1MLiOH in 75ml of tetrahydrofuran is stirred at room temperature overnight. Tetrahydrofuran was evaporated in vacuo and the mixture was then acidified with 1n hcl. The resulting solid was filtered and dried to yield 1.9g (96%) of a solid.

¹H-NMR(CH₃OD)：δ8.4(d，1H，J＝8Hz)，8.3(dd，1H，J＝2，5Hz)，8.0(d，1H，J＝9Hz)，7.6(s，

1H)，7.5(d，1H，J＝9Hz)，7.2(dd，1H，5，8Hz).

MS(m/z)：257(M⁺，20)，256(100).

Preparation example 3

2- [ benzo [2, 1, 3] of formula (5.0.3)]Oxadiazol-5-yloxy]-N- [4- [ 2-methyl- [1, 3]]Dioxolan-2-yl radical]-benzyl radical]-nicotinamide:

prepared analogously to example 1 by replacing 4- [ 2-methyl- [1, 3] dioxolan-2-yl ] -benzylamine (Korytnyk et al, J.Med.chem., 21, 507, 1978).

¹H-NMR(CDCl₃)：δ8.6(dd，1H，J＝2，8Hz)，8.2(dd，1H，J＝2，5Hz)，7.8(m，1H)，7.5(d，1H，

J＝2Hz)，7.4(m，2H)，7.3(m，5H)，4.7(d，2H，J＝6Hz)，4.0(m，2H)，3.7(m，2H)，1.6(s，3H).

Preparation example 4

(+ -) -1- [ 5-aminomethyl-thiophen-2-yl group represented by the formula (5.0.4)]-ethanol:

to a solution of 400mg (2.61mmol) (+ -) -1- [ 5-cyano-thiophen-2-yl group at 0 deg.C]8ml (8.10mmol) of a 1.0M solution of lithium aluminium hydride in tetrahydrofuran are added dropwise to a stirred solution of ethanol in 20ml of tetrahydrofuran. The mixture was refluxed for 1 hour, cooled to 0 ℃ and quenched by the addition of methanol. The mixture was diluted with chloroform and washed with water. The resulting emulsion was filtered through celite and the filtrate layer was separated. Drying (MgSO)₄) The organic extract was then concentrated in vacuo to give 310mg (76%) of an oil.

¹H-NMR(CDCl₃)：δ6.8(m，1H)，6.7(m，1H)，5.0(q，1H，J＝6Hz)，4.0(s，2H)，1.6(d，3H，J＝6

Hz).

Preparation example 5

(+ -) -1- [ 5-cyano-thiophen-2-yl group represented by formula (5.0.5)]-ethanol:

to a solution of 1.0g (6.61mmol) of 2-acetyl-5-cyanothiophene in 20ml of methanol was added 312mg of sodium borohydride with stirring at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour and then saturated NH was added₄The Cl solution was quenched. The mixture was poured into water and then extracted with ethyl acetate. Combining the organic extracts; washing with water and brine continuously; then dried (MgSO)₄) (ii) a Concentration in vacuo gave an oil. Chromatography on silica eluting with ethyl acetate/hexane (1: 4) gave 900mg (89%) of an oil.

¹H-NMR(CDCl₃)：δ7.5(d，1H，J＝4Hz)，6.9(dd，1H，J＝1，4Hz)，5.1(q，1H，J＝6Hz)，1.6(d，

1H，J＝6Hz).

Preparation example 6

(+ -) -2- [4- [ 1-amino-ethyl ] represented by formula (5.0.6)]-3-fluoro-phenyl]-propan-2-ol:

a mixture of 158mg (0.48mmol) (+ -) -2- [1- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl ] -phenyl ] ethyl ] -isoindole-1, 3-dione and 0.08ml (2.4mmol) hydrazine hydrate in 10ml methanol was stirred at room temperature overnight. The resulting precipitate was filtered, and the filtrate was concentrated to give a solid. The solid was triturated with chloroform, filtered and the filtrate was concentrated to give 110mg (100%) of an oil.

¹H-NMR(CDCl₃)：δ7.2(m，3H)，4.3(q，1H，J＝7Hz)，1.5(s，6H)，1.4 (d，3H，J＝7Hz).

Preparation example 7

(+ -) -2[2- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl ] represented by formula (5.0.7)]-phenyl radical]-ethyl radical]-isoindole-1, 3-dione

311mg (1.0mmo) (+ -) -2- [1- [ 4-acetyl-2-fluoro-phenyl group) was added thereto under stirring at 0 deg.C ]-ethyl radical]-isoindole-1, 3-dione and 296mg of (1.2mmol) of cerium (III) chloride in 20ml of anhydrous tetrahydrofuran 0.4ml (1.2mmol) of a 3.0M solution of methylmagnesium chloride in tetrahydrofuran are added dropwise. The mixture was slowly warmed back to room temperature over 4 hours; pouring into water; acidifying with 2N acetic acid; then extracted with ethyl acetate. Combining the organic extracts; washing with water and brine continuously; then drying; concentration in vacuo gave an oil. Silica gel chromatography with ethyl acetate/hexane (1: 2) as eluent gave 165mg (50%) of an oil. MS (m/z): 327 (M)⁺，100)。

Preparation example 8

(+ -) -2- [1- [ 4-acetyl-2-fluoro-phenyl ] represented by formula (5.0.8)]-ethyl radical]-isoindole-1, 3-dione:

1.09g (3.54mmol) (+ -) -2- [1- [ 4-bromo-2-fluoro-phenyl ] -was charged]-ethyl radical]A mixture of isoindole-1, 3-dione, 2.3ml (17.7mmol) of butyl vinyl ether, 1.0g (3.9mmol) of thallium (I) acetate, 1ml (7.1mmol) of triethylamine, 80mg (0.195mmol) of 1, 3-bis (diphenylphosphinopropane) and 39mg (0.18mmol) of palladium (II) acetate in 40ml of anhydrous dimethylformamide is degassed under nitrogen and then heated at 90 ℃ for 5 hours. The mixture was poured into water, followed by extraction with ethyl acetate. Combining the organic extracts; washing with water and brine continuously; then dried (MgSO) ₄) (ii) a Concentration gave an oil. This oil was dissolved in 50ml of tetrahydrofuran, then 50ml of 1.0N HCl was added, after which the mixture was stirred at room temperature for 1 hour. The mixture was poured into water and extracted with ethyl acetate. Combining the organic extracts; washing with water and brine in sequence; then dried (MgSO)₄) (ii) a Concentration in vacuo gave an oil. Chromatography with ethyl acetate/hexane (1: 2) as eluent gave 330mg (30%) of a solid.

¹H-NMR(CDCl₃)：δ7.7(m，6H)，7.5(d，1H，J＝11Hz)，5.8(q，1H，7Hz)，2.5(s，3H)，1.9(d，

3H，J＝7Hz)

Preparation example 9

(+ -) -2- [1- [ 4-bromo-2-fluoro-phenyl ] represented by the formula (5.0.9)]-ethyl radical]-isoindole-1, 3-dione:

to a volume of 1.2g (5.5mmol) (+ -) -1- [ 4-bromo-2-fluoro-phenyl group at room temperature under stirring]A solution of ethanol, 886mg (6.0mmol) of phthalimide and 1.6g (6.0mmol) of triphenylphosphine in 20ml of anhydrous THF is added dropwise to a solution of 1.0ml (6.6mmol) of diethyl azodicarboxylate. The mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed successively with water, brine and then dried (MgSO₄) And concentrated to give an oil. Chromatography on silica gel with ethyl acetate/hexane (1: 4) as eluent gave 1.1g (58%) of a solid.

MS(m/z)：347/349(M⁺，100).

Preparation example 10

(+ -) -1- [ 4-bromo-2-fluoro-phenyl ] represented by formula (5.0.10)]-ethanol:

to a solution of 5.0g (0.025mol) of 4-bromo-2-fluorobenzaldehyde in 50ml of anhydrous tetrahydrofuran at 0 ℃ was added dropwise, with stirring, 10ml of a 3.0M solution of methylmagnesium chloride in tetrahydrofuran. The mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 2 hours. The mixture was cooled to 0 ℃ and quenched by addition of methanol. The mixture was poured into water, acidified with 1N HCl and then extracted with ethyl acetate. The combined organic extracts were washed sequentially with water, brine and then dried (MgSO) ₄) And concentrated in vacuo to give an oil. Chromatography on silica gel eluting with ethyl acetate/hexane (1: 4) gave 3.2g (58%) of an oil.

¹H-NMR(CDCl₃)：δ7.3(m，3H)，5.1(q，1H，J＝6Hz)，1.4(d，3H，J＝6Hz).

Example 11

(R) -diallyl- [1- (4-bromo-phenyl) -ethyl ] represented by formula (5.0.11)]-an amine:

a mixture of 2.0g (10.0mmol) of (R) -1- (4-bromo-phenyl) -ethylamine and 30ml of toluene (anhydrous) is cooled to 0 ℃. 5.2ml (30.0mmol) of di-isopropylethylamine were then added dropwise, followed by 7.4ml (85mmol) of allyl bromide. The resulting mixture was warmed to room temperature and then heated at 95 ℃ for 2.5 hours. The mixture was filtered. The precipitate was then washed with toluene, and the filtrate and washings were combined and then concentrated in vacuo to give a reddish brown oil. Silica gel chromatography using 15% ethyl acetate/hexane gave 2.76g (99%) of an oil.

¹H-NMR(CDCl₃)：δ7.40(d，2H，J＝8Hz)，7.22(d，2H，J＝8Hz)，5.79(m，2H)，5.10(m.4H)，3.83

(q，1H，J＝7Hz)，3.03(m，4H)，1.27(d，3H，J＝7Hz).

Preparation example 12

(R) -2- [4- (1-diallylamino-ethyl) -phenyl ] represented by formula (5.0.12)]-propan-2-ol:

under nitrogen 2.76g (9.9mmol) of (R) -diallyl- [1- (4-bromo-phenyl) -ethyl]The amine is dissolved in 30ml THF. The mixture was then cooled to-78 ℃ and 5.0ml (12mmol) of 2.5m n-BuLi in hexane was added dropwise. The mixture was then cooled to-90 deg.C, acetone was added, and cooling continued at-90 deg.C for 10 minutes with stirring. The mixture was then warmed to room temperature and quenched with MeOH. Then, water was added, and the resulting mixture was extracted with diethyl ether. Mixing the ether extracts; washing with water and brine; MgSO (MgSO) ₄Drying; filtered and concentrated in vacuo. Silica gel chromatography using 15% ethyl acetate/hexane gave 1.6g (46%) of the desired end product.

¹H-NMR(CDCl₃)：δ7.35(d，2H，J＝8Hz)，7.23(d，2H，J＝8Hz)，5.76(m，2H)，5.09(m，4H)，3.82

(q，1H，J＝7Hz)，3.00(m，4H)，1.48(s，6H)，1.27(d，3H，J＝7Hz).

MS(m/z)260(M⁺+1，100).

Preparation example 13

(R) -2- [4- (1-amino-ethyl) -phenyl ] represented by formula (5.0.13)]-propan-2-ol:

0.63g (0.54mmol) Pd (PPh) were mixed₃)₄A mixture of NDMBA (25.3 mg, 162mmol) was placed under nitrogen. 7.0g (27mmol) of (R) -2- [4- (1-diallylamino-ethyl) -phenyl are subsequently added]-propan-2-ol in 140ml dichloromethane. The resulting mixture was then refluxed for 2 hours under nitrogen atmosphere. The crude reaction mixture was placed on crude silica gel. Silica gel chromatography with 7.5% MeOH/CH₂Cl₂And 2% NH₄OH/10％MeOH/CH₂Cl₂The subsequent elution gave 4.5g (93%) of the desired product.

¹H-NMR(CDCl₃)：δ7.39(d，2H，J＝8Hz)，7.26(d，2H，J＝8Hz)，4.11(q，1H，J＝7Hz)，1.52(s，

6H)，1.42(d，3H，J＝7Hz).

Preparation example 14

(S) -diallyl- [1- (4-bromo-phenyl) -ethyl ] represented by formula (5.0.14)]-an amine:

prepared analogously to preparation 11 by replacing (S) -1- (4-bromo-phenyl) -ethylamine.

¹H-NMR(CDCl₃)：δ7.40(d，2H，J＝8Hz)，7.22(d，2H，J＝8Hz)，5.79(m，2H)，5.10(m，4H)，3.83

(q，1H，J＝7Hz)，3.03(m，4H)，1.27(d，3H，J＝7Hz).

Preparation example 15

Represented by formula (5.0.15)(S) -2- [4- (1-diallylamino-ethyl) -phenyl]-propan-2-ol:

prepared by analogy with preparation 12 substituting (S) -diallyl- [1- (4-bromophenyl) -ethyl ] -amine.

¹H-NMR(CDCl₃)：δ7.35(d，2H，J＝8Hz)，7.23(d，2H，J＝8Hz)，5.76(m，2H)，5.09(m，4H)，3.82

(q，1H，J＝7Hz)，3.00(m，4H)，1.48(s，6H)，1.27(d，3H，J＝7Hz).

MS(m/z)260(M⁺+1，100).

Preparation example 16

(S) -2- [4- (1-amino-ethyl) -phenyl ] represented by formula (5.0.16)]-propan-2-ol:

Prepared analogously to preparation 13 by replacing (S) -2- [4- (1-diallylamino-ethyl) phenyl ] -propan-2-ol.

¹H-NMR(CDCl₃)：δ7.39(d，2H，J＝8Hz)，7.26(d，2H，J＝8Hz)，4.11(q，1H，J＝7Hz)，1.52(s，

6H)，1.42(d，3H，J＝7Hz).

Preparation example 17

(S) -2- [4- (1-hydroxy-1-methyl-ethyl) -cyclohex-1-enylmethyl of formula (5.0.17)]-isoindole-1, 3-dione

2.2g (16mmol) of K are stirred at room temperature₂CO₃1.2g (8.4mmol) of phthalimide in 40ml of DMF for 0.5 hour. Thereafter, 1.7g (7.4mmol) of (S) -2- (4-bromomethylcyclohex-3-enyl) -propan-2-ol (Bull et al, Aust. J. chem. 461869, 1993) are added and the resulting mixture is stirred at room temperature for 72 hours.Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Combining the ethyl acetate extracts; washing with water and brine; drying (MgSO)₄) (ii) a Filtration and concentration in vacuo. Silica gel chromatography using 20% ethyl acetate/hexane afforded 0.62g (28%) of the desired product.

MS(m/z)300(M⁺+1，5)，282(100).

Preparation example 18

(S) -2- (4-aminomethyl-cyclohex-3-enyl) -propan-2-ol represented by formula (5.0.18):

cool 0.62g (2.1mmol) of (S) -2- [4- (1-hydroxy-1-methyl-ethyl) -cyclohex-1-enyl-methyl]-mixture of isoindole-1, 3-dione with 20ml MeOH to 0 ℃. Then 0.2ml (6mmol) of hydrazine hydrate was added and the resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo; with CHCl ₃Development; filtration and concentration of the filtrate gave 0.31g (63%) of the product as a solid.

MS(m/z)211(100)，170(M⁺+1，55).

Preparation example 19

(R) -2- [4- (1-hydroxy-1-methyl-ethyl) -cyclohex-1-enylmethyl group represented by the formula (5.0.19)]-isoindole-1, 3-dione:

prepared by analogy with preparation 17, replacing (R) -2- (4-bromomethylcyclohex-3-enyl) -propan-2-ol (Bull et al, supra).

MS(m/z)300(M⁺+1，5)，282(100).

Preparation example 20

(R) -2- (4-aminomethyl-cyclohex-3-enyl) -propan-2-ol represented by formula (5.0.20):

prepared by a similar procedure as preparation 18, substituting (R) -2- [4- (1-hydroxy-1-methyl-ethyl) -cyclohex-1-enylmethyl ] -isoindole-1, 3-dione.

MS(m/z)211(100)，170(M⁺+1，55).

Preparation example 21

4- (1-hydroxy-cyclopropyl) -benzonitrile of formula (5.0.21):

a solution of 2.9ml (2.67mmol) of di-isopropylamine in dry THF (5.0ml) was cooled to-78 deg.C and treated with 8.26ml of n-BuLi (2.5M, 20.67 mmol). After stirring for 0.5 h at-78 ℃ a solution of 2.0g (13.78mmol) of 4-acetyl-benzonitrile in 10ml of anhydrous THF is added by syringe at-78 ℃ followed by a solution of 8.37g (0.1M, 20.7mmol) of samarium diiodide in THF. The reaction mixture was then stirred at-78 ℃ for 10 minutes, then 10.95g (41.34mmol) of diiodomethane were added and the reaction mixture was stirred for 16 hours and allowed to warm to room temperature. The reaction mixture was quenched with 1N HCl, THF removed in vacuo, and extracted with EtOAc. The combined extracts were washed with brine and dried (Na) ₂SO₄) And concentrated in vacuo to give a dark oil. Silica gel chromatography using ethyl acetate/hexane (1: 4) gave 0.57g (26%) of a pale yellow solid.

¹H-NMR(CDCl₃)：δ7.57(d，2H，J＝9Hz)，7.30(d，2H，J＝9Hz)，1.37(m，2H)，1.09(m，2H).

Preparation example 22

1- (4-aminomethyl-phenyl) -cyclopropanol of formula (5.0.22):

prepared analogously to preparation 4 by replacing 4- (1-hydroxy-cyclopropyl) -benzonitrile.

¹H-NMR(CDCl₃)：δ7.25(m，4H)，3.83(s，2H)，1.78(br，2H)，1.24(m，2H)，1.01(m，2H).

Preparation example 23

4-acetyl-2-fluoro-benzonitrile of formula (5.0.23):

prepared analogously to preparation 10 by replacing 4-cyano-3-fluoro-benzoic acid methyl ester.

¹H-NMR(CDCl₃)：δ7.78(m，3H)，2.61(s，3H).

Preparation example 24

2-fluoro-4- (1-hydroxy-cyclopropyl) -benzonitrile of formula (5.0.24):

prepared analogously to preparation 21 by replacing 4-acetyl-2-fluoro-benzonitrile.

¹H NMR(CDCl₃)：δ7.50(m，1H)，7.15(d，1H，J＝10Hz)，7.01(d，1H，J＝8Hz)，2.60(s，1H)，1.42(m，2H)，1.11(m，2H).

Preparation example 25:

1- (4-aminomethyl-3-fluoro-phenyl) -cyclopropanol of formula (5.0.25):

prepared analogously to preparation 4 by replacing 2-fluoro-4- (1-hydroxy-cyclopropyl) -benzonitrile.

¹H NMR (CDCl₃)：δ7.23(m，1H)，7.18(m，2H)，3.81(s，2H)，1.22(m，2H)，0.95(m，2H).

Preparation example 26

(+ -) -diallyl- [1- (4-bromo-phenyl) -ethyl group represented by formula (5.0.26)]-an amine:

prepared by following a similar procedure to preparation 11, substituting (+/-) -1- (4-bromo-phenyl) -ethylamine.

¹H-NMR(CDCl₃)：δ7.40(d，2H，J＝8Hz)，7.22(d，2H，J＝8Hz)，5.79(m，2H)，5.10(m，4H)，3.83(q，1H，J＝7Hz)，3.03(m，4H)，1.27(d，3H，J＝7Hz).

Preparation example 27

(+ -) -2- [4- (1-diallylamino-ethyl) -phenyl group represented by formula (5.0.27)]-propan-2-ol:

prepared by analogy with preparation 12, substituting (+/-) -diallyl- [1- (4-bromo-phenyl) -ethyl ] -amine.

¹H-NMR(CDCl₃)：δ7.35(d，2H，J＝8Hz)，7.23(d，2H，J＝8Hz)，5.76(m，2H)，5.09(m，4H)，3.82(q，1H，J＝7Hz)，3.00(m，4H)，1.48(s，6H)，1.27(d，3H，J＝7Hz).

Preparation example 28

(+ -) -2- [4- (1-amino-ethyl) -phenyl group represented by the formula (5.0.28)]-propan-2-ol:

prepared by analogy with preparation 13 using (+/-) -2- [4- (1-diallylamino-ethyl) -phenyl ] -propan-2-ol instead.

¹H-NMR(CDCl₃)：δ7.39(d，2H，J＝8Hz)，7.26(d，2H，J＝8Hz)，4.11(q，1H，J＝7Hz)，1.52(s，6H)，1.42(d，3H，J＝7Hz).

Preparation example 29

Benzo- [2, 1, 3] of the formula (5.0.29)]-thiadiazole-5-ol:

5-methoxy-benzo- [2, 1, 3] -thiadiazole (4.09g, 24.6mmol) was stirred with hydrobromic acid (60ml, 165mmol, 30% in acetic acid) at 80 ℃ for 5 days. The mixture was cooled to 0 ℃ and filtered. The solid was purified by short column chromatography (50% ethyl acetate/hexane). The solvent was removed in vacuo to yield 1.0g of a yellow solid (27% yield).

¹H-NMR(CD₃OD)：δ7.81(d，1H，J＝2Hz)，7.79(d，1H，J＝2Hz)，7.30(s，1H).

Preparation example 30

2- (benzo- [2, 1, 3] of the formula (5.0.30)]-thiadiazol-5-yloxy) -nicotinic acid ethyl ester:

a mixture of ethyl 2-chloro-nicotinate (0.516g, 3mmol), benzo- [2, 1, 3] -thiadiazol-5-ol (0.46g, 3mmol) and cesium carbonate (2.07g, 6.3mmol) was stirred in 40ml of N, N-dimethylformamide at 80 ℃ for 48 h. The dark orange mixture was cooled, poured into water (600ml) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, and dried over sodium sulfate. The mixture was concentrated in vacuo to give 0.74g of a yellow solid (82% yield).

MS(m/z)：302(M⁺，20)，227(100).

Preparation example 31

2- (benzo- [2, 1, 3] of the formula (5.0.31)]-thiadiazol-5-yloxy) -nicotinic acid:

a solution of ethyl 2- (benzo [2, 1, 3] thiadiazol-5-yloxy) -nicotinic acid (0.74g, 2.5mmol) in tetrahydrofuran (2.78ml) and 1M LiOH (2.7ml) was stirred overnight. The mixture was diluted with water, then acidified to pHl with 2N hydrochloric acid and filtered to give a pale yellow solid (160 mg).

¹H-NMR(CD₃OD)：δ8.37(d，1H，J＝6Hz)，8.26(dd，1H，J＝2Hz，5Hz)，8.00(d，1H，J＝9Hz)，7.60(t，1H，J＝2Hz)，7.50(t，1H，J＝2Hz)，7.26(d，1H，J＝8Hz).

Example 1

2- [ benzo [2, 1, 3] of the formula (5.5.1)]Oxadiazol-5-yloxy]-N- [4- [ 1-hydroxy-1-methyl-ethyl]-benzyl radical]-nicotinamide:

to a volume of 2.0g (7.8mmol) of 2- [ benzo [2, 1, 3] with stirring]Oxadiazol-5-yloxy]To a solution of nicotinic acid, 1.3g (7.8mmol)2- (4-aminomethyl-phenyl) -propan-2-ol and 1.2g (8.6mmol) 1-hydroxybenzotriazole Hydrate (HOBT) in 200ml DMF was added 1.8g (9.3mmol)1- [3- (dimethylamino) propyl ] -propan-2-ol]3-Ethylcarbodiimide hydrochloride (EDCI), the reaction mixture being stirred at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with 1N NaOH, water, and brine, and then dried (Na)₂SO₄) And vacuum concentrating to obtain solid. Silica gel chromatography using ethyl acetate/hexane (1: 1) afforded a solid. Further recrystallization from ethyl acetate/hexane gave 2.1g (68%) of a solid, mp149-151 ℃.

¹H-NMR(CDCl₃)：δ8.6(dd，1H，J＝2，8Hz)，8.2(dd，1H，J＝2，5Hz)，7.8(m，2H)，7.5(m，2H)，

7.2(m，5H)，4.7(d，2H，J＝6Hz)，1.6(s，6H).

MS(m/z)：405(M⁺，5)，387(100).

Example 2

2- [ benzo [2, 1, 3 ] of the formula (5.5.2)]Oxadiazol-5-yloxy]-N- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl]-benzyl radical]-nicotinamide:

prepared in analogy to example 1 substituting 2- (4-aminomethyl-3-fluoro-phenyl) -propan-2-ol.

MP160-1℃.

MS(m/z)：423(M⁺+1，25)，405(100).

Example 3

Trans-2- [ benzo [2, 1, 3 ] of formula (5.5.3)]Oxadiazol-5-yloxy]-N- [4- [ 1-hydroxy-1-methyl-ethyl]-cyclohexylmethyl group]-nicotinamide:

prepared in analogy to example 1 by substituting 2- (4-aminomethyl-cyclohex-3-enyl) -propan-2-ol.

¹H-NMR(CDCl₃)：δ8.6(dd，1H，J＝2，8Hz)，8.2(dd，1H，J＝2,5Hz)，7.9(d，1H，J＝10Hz)，7.6(m，2H)，7.3(m，4H)，3.4(m，3H)，1.9(m，4H)，1.6(m，2H)，1.2(m，10H).

MS(m/z)：410(M⁺，30)，409(100).

Example 4

2- (benzo [2, 1, 3 ] of the formula (5.5.4)]Oxadiazol-5-yloxy) -N- [4- (1-hydroxy-cyclobutyl) -benzyl]-nicotinamide:

prepared in analogy to example 1 by replacing 2- (4-aminomethyl-phenyl) cyclobutanol.

¹H-NMR(CDCl₃)：δ8.6(ddd，1H，J＝2.4，8Hz)，8.2(ddd，1H，2.4，5Hz)，7.8(m，2H)，7.5(m，3H)，7.3(m，4H)，4.7(d，2H，J＝6Hz)，2.5(m，2H)，2.1(m，2H)，2.0(m，1H)，1.7(m，1H).MS(m/z)：417(M⁺+1,20)，399(100).

Example 5

(+ -) -2- [ benzo [2, 1, 3 ] of formula (5.5.5)]Oxadiazol-5-yloxy]-N- [4- [2, 2, 2-trifluoro-1-hydroxy-ethyl]-benzyl radical]-nicotinamide:

prepared in analogy to example 1 substituting (±) -4- (2, 2, 2-trifluoro-ethoxy) -benzylamine.

Mp164-6℃.

Elemental analysis C₂₁H₁₅N₄O₄F₃: calculated values: c, 56.76; h, 3.40; n, 12.61 found: c, 56.66; h, 3.47; n, 12.51.

Example 6

(+ -) -2- [ benzo [2, 1, 3 ] of formula (5.5.6)]Oxadiazol-5-yloxy]-N- [5- [ 1-hydroxy-ethyl]-thien-2-ylmethyl]-nicotinamide:

prepared by analogy with example 1 using (. + -.) -1- [ 5-aminomethyl-thiophen-2-yl ] -ethanol instead.

Mp81-3℃.

Elemental analysis C₁₉H₁₆N₄O₄S: calculated values: c, 57.57; h, 4.07; n, 14.13. found: c, 57.74; h, 4.00; n, 14.15.

Example 7

N- [ 4-acetyl-benzyl ] of formula (5.5.7)]-2- [ benzo [2, 1, 3 ]]Oxadiazol-5-yloxy]-nicotinamide:

466mg (1.08mmol) of 2- [ benzo [2, 1, 3 ] are stirred at room temperature]Oxadiazol-5-yloxy]-N- [4- [ 2-methyl- [1, 3 ]]-dioxolan-2-yl]-benzyl radical]A mixture of nicotinamide in 20ml of tetrahydrofuran and 10ml of 1.0N HCl for a total of 2 hours. The mixture was then poured into water, neutralized, and then extracted with ethyl acetate. Combining the organic extracts, washing with water and brine in sequence; then dried (MgSO)₄) And vacuum concentrating to obtain solid. Silica gel chromatography using ethyl acetate/hexane (2: 1) as eluent gave a solid. Further using ethyl acetate/hexaneRecrystallization of the alkane gave 340mg (75%) of a solid.

Mp154-6℃.

Elemental analysis C₂₁H₁₆N₄O₄: calculated values: c, 64.94; h, 4.15; n, 14.43. found: c, 64.93; h, 4.11; n, 14.52.

Example 8

(+ -) -2- (benzo [2, 1, 3) represented by formula (5.5.8)]Oxadiazol-5-yloxy) -N- {1- [ 2-fluoro-4- (1-hydroxy-1-methyl-ethyl) -phenyl]-ethyl } -nicotinamide:

prepared in a similar manner to example 1 substituting (+ -) -2- [4- [ 1-amino-ethyl ] -3-fluoro-phenyl ] -propan-2-ol.

Mp128-130℃.

Elemental analysis C₂₃H₂₁N₄O₄F: calculated values: c, 63.30; h, 4.85; n, 12.84. found: c, 63.20; h, 4.88; n, 12.77.

Example 9

2- (benzo [2, 1, 3 ] of the formula (5.5.9)]Oxadiazol-5-yloxy) -N- [ 2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl]-nicotinamide:

prepared in analogy to example 1 substituting 2- (4-aminomethyl-3-chloro-phenyl) -propan-2-ol.

Mp171-3℃.

MS(m/z)439(M⁺+1，5)，421(100).

Example 10

(+ -) -2- (benzo [2, 1, 3) represented by formula (5.5.10)]Oxadiazol-5-yloxy) -N- [4- (1-hydroxy-ethyl) -benzyl]-nicotinamide:

prepared in analogy to example 1 by substituting 1- (4-aminomethyl-phenyl) -ethanol.

¹H-NMR(CDCl₃)：δ8.65(dd，1H，J＝2Hz，8Hz)，8.21(dd，1H，J＝2Hz，5Hz)，7.84(m，2H)，

7.51(m，1H)，7.28(m，5H)，4.87(q，1H，J＝6Hz)，4.70(d，2H，J＝6Hz)，1.45(d，3H，J＝6Hz).

MS(m/z)：391(M⁺+1，5)，373(100).

Example 11

(-) -2- (benzo [2, 1, 3) represented by the formula (5.5.11)]Oxadiazol-5-yloxy) -N- {1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-ethyl } -nicotinamide:

prepared in analogy to example 1 by replacing (R) -2- [4- (1-amino-ethyl) -phenyl ] -propan-2-ol.

¹H-NMR(CDCl₃)：δ8.57(dd，1H，J＝2Hz，8Hz)，8.18(dd，1H，J＝2Hz，5Hz)，7.84(dd，1H，

J＝1Hz，9Hz)，7.51(m，1H)，7.41(d，2H，J＝8Hz)，7.30(d，2H，J＝8Hz)，7.22(m，2H)，5.31

(m，1H)，1.56(d，3H，J＝7Hz)，1.51(s，6H).

MS(m/z)：417(M^--1，100).

[α]²⁵ _D＝-66.74°(4.45，CHCl₃).

Example 12

(+) -2- (benzo [2, 1, 3 ] benzo [2 ] benzo [ 5.5.12 ] th e formula]Oxadiazol-5-yloxy) -N- {1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-ethyl } -nicotinamide:

prepared in analogy to example 1 by replacing (S) -2- [4- (1-amino-ethyl) -phenyl ] -propan-2-ol.

¹H-NMR(CDCl₃)：δ8.57(dd，1H，J＝2Hz，8Hz)，8.18(dd，1H，J＝2Hz，5Hz)，7.84(dd，1H，

J＝1Hz，9Hz)，7.51(m，1H)，7.41(d，2H，J＝8Hz)，7.30(d，2H，J＝8Hz)，7.22(m，2H)，5.31

(m，1H)，1.56(d，3H，J＝7Hz)，1.51(s，6H).

MS(m/z)：417(M^--1，100)

[α]²⁵ _D＝+67.43°(5.65，CHCl₃).

Example 13

(+) -2- (benzo [2, 1, 3 ] benzo [2 ] benzo [ 5.5.13 ] th e formula]Oxadiazol-5-yloxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohexyl-1-alkenylmethyl]-nicotinamide:prepared in analogy to example 1 by substituting (R) -2- (4-aminomethyl-cyclohex-3-enyl) -propan-2-ol.

MS(m/z)：409(M⁺+1，5)，391(100).

[α]²⁵ _D＝+0.45(0.013，CHCl₃).

Example 14

(-) -2- (benzo [2, 1, 3) represented by the formula (5.5.14)]Oxadiazol-5-yloxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -cyclohex-1-enylmethyl]-nicotinamide:

prepared in analogy to example 1 by substituting (S) -2- (4-aminomethyl-cyclohex-3-enyl) -propan-2-ol.

MS(m/z)：409(M⁺+1，5)，391(100).

[α]²⁵ _D＝-1.01(0.0033，CHCl₃).

Example 15

2- (benzo [2, 1, 3 ] of the formula (5.5.15)]Oxadiazol-5-yloxy) -N- [4- (1-hydroxy-cyclopropyl) -benzyl]-nicotinamide:

prepared in analogy to example 1 by substituting 1- (4-aminomethyl-phenyl) -cyclopropanol.

¹H NMR(d₆-DMSO)：δ8.94(s，1H)，8.24(m，1H)，8.13(d，1H，J＝7Hz)，8.09(d，1H，J＝9Hz)，

7.47(d，1H，J＝2Hz)，7.31(t，1H，J＝5Hz)，7.20(d，2HJ＝8Hz)，7.09(d，2H，J＝8Hz)，5.83(s，

1H)，4.42(d，2H，J＝5Hz)，1.01(m，2H)，0.82(m，2H).

MS(m/z)：402(M^--1，100).

Example 16

2- (benzo [2, 1, 3 ] of the formula (5.5.16)]Oxadiazol-5-yloxy) -N- [ 2-fluoro-4- (1-hydroxy-cyclopropyl) -benzyl ]-nicotinamide:

prepared in analogy to example 1 by substituting 1- (4-aminomethyl-3-fluoro-phenyl) -cyclopropanol.

¹H NMR(CDCL₃)：δ8.50(d，1H，J＝8Hz)，8.13(m，1H)，7.94(m，1H)，7.80(d，1H，J＝10Hz)，

7.48(s，1H)，7.24(m，1H)，7.17(m，1H)，6.95(dd，1H，J＝12Hz，2Hz)，6.84(dd，1H，J＝12

Hz，2Hz)，4.61(d，2H，J＝6Hz)，1.17(d，2H，J＝2Hz)，0.87(d，2H，J＝2Hz).

Mp155-156℃.

Example 17

(+ -) -2- (benzo [2, 1, 3) represented by formula (5.5.17)]Oxadiazol-5-yloxy) -N- {1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-ethyl } -nicotinamide:

prepared analogously to example 1 by replacing (+/-) -2- [4- (1-amino-ethyl) -phenyl ] -propan-2-ol.

¹H-NMR(CDCl₃)：δ8.57(dd，1H，J＝2Hz，8Hz)，8.18(dd，1H，J＝2Hz，5Hz)，7.84(dd，1H，

J＝1Hz，9Hz)，7.51(m，1H)，7.41(d，2H，J＝8Hz)，7.30(d，2H，J＝8Hz)，7.22(m，2H)，5.31

(m，1H)，1.56(d，3H，J＝7Hz)，1.51(s，6H).MS(m/z)：417(M^--1，100).

Mp116-117℃.

Example 18

(+ -) -2- (benzo [2, 1, 3) represented by formula (5.5.18)]Oxadiazol-5-yloxy) -N- [4- (1-hydroxy-1, 2, 2, -trimethyl-propyl) -benzyl]-nicotinamide:

5.0g (34.4mmol) of 4-acetylbenzonitrile are dissolved in anhydrous THF and then added at 0 ℃ to a solution of 60ml of anhydrous THF and 21.0ml of 2M tert-butylmagnesium chloride (41.2 mmol). The reaction mixture was stirred at 0 ℃ for 0.5 h and then quenched by addition of 10ml of methanol. The mixture is then diluted with water and acidified with oxalic acid. The mixture was then extracted with ether, the organic layers combined and washed with water and brine; then MgSO 2₄Drying; filtering; and (5) concentrating. Silica gel chromatography using 20% ethyl acetate/hexane afforded 2.60g (37%) of the crude product.The crude product from the chromatographic separation (12.8mmol) was dissolved in anhydrous THF and cooled to 0 deg.C. Thereafter, 38.4ml of 1.0MLiAlH were added dropwise ₄(38.4mmol) and then the reaction mixture was warmed to room temperature and refluxed for an additional 1 hour. The mixture was then cooled to 0 ℃ and 15ml of methanol were added. With CHCl₃And the mixture was diluted with water, then filtered through celite, and the layers were separated. The organic layer was MgSO₄Drying, filtering and concentrating. The crude product was isolated in an amount of 0.76g (3.67 mmol). The crude product was then used in the next reaction and the final product was prepared analogously as described in example 1.

¹H-NMR(CDCl₃)：δ8.54(dd，1H，J＝2Hz，8Hz)，8.20(dd，1H，J＝2Hz，5Hz)，7.88(m，1H)，

7.76(d，1H，J＝6Hz)，7.45(s，1H)，7.35(d，2H，J＝8Hz)，7.20(m，3H)，4.63(d，2H，J＝5Hz)，

1.50(s，3H)，0.82(s，9H).

MS(m/z)：445(M^--1，100).

Example 19

(+ -) -2- (benzo [2, 1, 3) represented by formula (5.5.19)]Oxadiazol-5-yloxy) -N- [4- (1-hydroxy-1, 2-dimethyl-propyl) -benzyl]-nicotinamide:

prepared in a similar manner to example 18 substituting isopropyl magnesium chloride.

¹H-NMR(CDCl₃)：δ8.64(dd，1H，J＝2Hz，8Hz)，8.22(dd，1H，J＝2Hz，5Hz)，7.82(m，2H)，

7.52(s，1H)，7.22(m，5H)，4.69(d，2H，J＝5Hz)，1.98(m，1H)，1.48(s，3H)，0.84(d，3H，J＝7

Hz)，0.75(d，3H，J＝7Hz).MS(m/z)：415(M⁺-18，100).

Example 20

2- (benzo [2, 1, 3 ] of the formula (5.5.20)]Oxadiazol-5-yloxy) -N- [4- (1-cyano-1-methyl-ethyl) -benzyl]-nicotinamide:to 2- (benzo [2, 1, 3 ] cooled to 0 DEG C]Oxadiazol-5-yloxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl]To a solution of nicotinamide (300mg, 0.74mmol) in dichloromethane (1.5ml) was added trimethylsilyl cyanide (1ml, 7.4mmol) followed by slow addition of tin tetrachloride (7 drops of 1.0M dichloromethane solution). The reaction mixture was warmed to room temperature overnight. Potassium carbonate (300mg, 2.10mmol) and potassium fluoride dihydrate (120mg, 2.10mmol) were added, followed by dropwise addition of water. The reaction mixture was stirred vigorously for 90 minutes, after which silica gel (600mg) was added. The mixture was filtered and washed thoroughly with dichloromethane. The filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate, filtered and concentrated to give 124mg of a pale yellow solid. The product was recrystallized from ethyl acetate/hexane to give 96mg (31% yield) of a pale yellow solid.

¹H NMR(CDCl3)：δ8.66(dd，1H，J＝2Hz，8Hz)，8.22(dd，1H，J＝2Hz，4Hz)，7.87(dd，2H，

J＝1Hz，10Hz)，7.55-7.19(m，6H)，4.72(d，2H，J＝6Hz)，1.69(s，6H).

MS(m/z)：414(M⁺+1，100).

Example 21

2- (benzo [2, 1, 3] of the formula (5.5.21)]Thiadiazol-5-yloxy) -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl]-nicotinamide:

2- (benzo [2, 1, 3] -thiadiazol-5-yloxy) -nicotinic acid (30.8mg, 0.11mmol), 2- (4-aminomethyl-phenyl) -propan-2-ol (18.6mg, 0.11mmol), 1-hydroxybenzotriazole hydrate (16.8mg, 0.12mmol) and 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride (25.9mg, 0.14mmol) were dissolved in N, N-dimethylformamide (10ml) and stirred at room temperature overnight. The resulting solution was poured into water (30ml), which was extracted with ethyl acetate. The combined organic layers were washed successively with 1N NaOH, water and brine, then dried over sodium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash column chromatography (1: 1 ethyl acetate/hexanes) to give a white foam (29mg, 0.07 mmol).

MS(m/z)：419(M^-，100).

¹H NMR(CDCl₃)：δ8.66(d，1H，J＝8Hz)，8.19(dd，1H，J＝5，2Hz)，7.99(m，2H)，7.70(d，1H，

J＝2Hz)，7.41(m，3H)，7.31(d，1H，J＝8Hz)，7.23(m，1H)，4.70(d，2H，J＝5Hz)，1.53(s，

6H).

Example 22

2- (benzo [2, 1, 3] of the formula (5.5.22)]Thiadiazol-5-yloxy) -N- [ 2-fluoro-4- (1-hydroxy-1-methyl-ethyl) -benzyl]-nicotinamide:

prepared analogously to example 21 by replacing 2- (4-aminomethyl-3-fluoro-phenyl) -propan-2-ol (66% yield), m.p.: 124-.

¹H NMR(CDCl₃)：δ8.65(d，1H，J＝6Hz)，8.21(m，2H)，8.03(d，1H，J＝10Hz)，7.76(s，1H)，

7.45(d，1H，J＝10Hz)，7.39(t，1H，J＝8Hz)，7.23(d，1H，J＝6Hz)，7.20(d，1H，J＝10Hz)，

4.74(d，2H，J＝6Hz)，1.53(s，6H).

Claims (15)

1. A compound of formula (1.0.0) or a pharmaceutically acceptable salt thereof:wherein

-m is 0, 1 or 2;

-n is 1 or 2;

-W is-O-; -S (═ O)_t-, where t is 0, 1 or 2; or-N (R)³)-，R³Have the meanings as described below;

-Y is ═ C (R)^E) -, or- [ N → (O)]-；

Wherein

--R^ESelected from-H, -F, -Cl, -CN, -NO₂、-(C₁-C₄) Alkyl, (C)₂-C₄) Alkynyl, fluoro- (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, fluoro (C)₁-C₃) Alkoxy, -OH and-C (═ O) NR¹²R¹³Wherein R is¹²And R¹³As defined below;

-R^Aand R^BEach independently selected from-H, -F, -CF₃、-(C₁-C₆) Alkyl, - (C)₃-C₇) Cycloalkyl, phenyl, benzyl; and a heterocyclic group selected from: pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl and thiadiazolyl; wherein said alkyl, cycloalkyl, phenyl, benzyl or heterocyclyl is each independently substituted with 0-3 substituents R¹⁰Substituted;

with the proviso that

For R^AAnd R^BThe above and all other meanings of (A) are to be regarded as R^AOr R^BSubstituent R of¹⁰having-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³In the meaning of (A), the said-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³And means OR¹²The positional relationship of Z of (a) is not vicinal;

Wherein

--R¹⁰Selected from-F, -Cl, -CF₃、-CN、(C₁-C₂) Alkyl, -OR¹²、-C(＝O)OR¹²、-O-C(＝O)R¹³、-C(＝O)NR¹²R¹³、-O-C(＝O)NR¹²R¹³、-NR¹²R¹³、-NR¹²C(＝O)R¹³、-NR¹²C(＝O)OR¹³、-NR¹²S(＝O)₂R¹³、-S(＝O)₂NR¹²R¹³；

Wherein

--R¹²And R¹³Each independently selected from-H, - (C)₁-C₄) Alkyl, (C)₂-C₄) Alkenyl, (C)₃-C₆) Cycloalkyl, phenyl, benzyl, and monocyclic heterocyclyl, including (C) in which the nitrogen heteroatom replaces one carbon atom₃-C₆) Cycloalkyl, a 5-or 6-membered heterocyclyl optionally substituted at a second nitrogen heteroatom by a second carbon atom and a 5-or 6-membered heterocyclyl further optionally substituted at an oxygen heteroatom by a third carbon atom; wherein said alkyl, alkenyl, cycloalkyl, phenyl, benzyl, or mono-heterocyclyl is substituted with 0-3 substituents selected from F and Cl;

-or-

Under the condition that m is 1, -R^AAnd R^BTogether form a spiro group of formula (1.1.0):

wherein

-r and s are independently 0 to 4, with the proviso that the sum of r + s is at least 1 but not more than 5;

-and-

--Q^AIs selected from-CH₂-、-CHF、-CF₂、-NR¹²-, -O-, and-S (═ O)_t-, where t is 0, 1 or 2; any one or more carbon atoms of said spiro group, including Q^ADefinition of middle-CH₂Carbon atom of (A) by 0 to 3 substituents R¹⁰Is substituted in which R¹⁰And R¹²Having the meaning as defined above, with the proviso that for R^AAnd R^BThe above meanings of and R^AAnd R^BAll other meanings as R^AOr R^BR of the substituent(s)¹⁰having-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR ¹²R¹³In the meaning of (A), the said-OR¹²、-O-C(＝O)R¹³or-OC (═ O) NR¹²R¹³And means OR¹²The positional relationship of Z of (a) is not vicinal;

-R^Cand R^DHaving the above-mentioned R^AAnd R^BMeaning defined, only R^CAnd R^DAt least one mustIs H; they are selected independently of one another from R^AAnd R^B；

-Q is phenyl, pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, oxazolyl, monocyclic (C)₅-C₇) Cycloalkyl, monocyclic (C) ring selected from cyclopentenyl, cyclohexenyl and cycloheptenyl₅-C₇) Cycloalkenyl, or bicyclic- (C)₇-C₁₀) Cycloalkyl or- (C)₇-C₁₀) Cycloalkenyl, preferably norbornyl, norbornenyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.1]Octyl, bicyclo [3.3.0]Octyl, bicyclo [2.2.2]Oct-5-enyl, bicyclo [2.2.2]Oct-7-enyl, bicyclo [3.3.1]Nonyl and adamantyl;

-R¹and R²Each independently selected from-H, -F, -Cl, -R¹²、-OR¹²、-S(＝O)_pR¹²、-C(＝O)OR¹²、-OC(＝O)R¹²、-CN、-NO₂、-C(＝O)NR¹²R¹³、-OC(＝O)NR¹²R¹³、-NR¹⁴C(＝O)NR¹⁵R¹²、-NR¹⁴C(＝NR¹⁴)NR¹⁵R¹²、-NR¹⁴C(＝NCN)NR¹⁵R¹²、-NR¹⁴C(＝N-NO₂)NR¹⁵R¹²、-C(＝NR¹⁴)NR¹⁵R¹²、-OC(＝NR¹⁴)NR¹⁵R¹²、-OC(＝N-NO₂)NR¹⁵R¹²、-NR¹⁵R¹²、-CH₂NR¹⁵R¹²、-NR¹⁴C(＝O)R¹²、-NR¹⁴C(＝O)OR¹²、-NR¹⁴S(＝O)_pR¹³(ii) a and-S (═ O)_pNR¹²R¹³(ii) a Wherein p is 0, 1 or 2; r¹²And R¹³Have the meaning as defined above; and R is¹⁴And R¹⁵Have the meaning defined below;

-R³is-H, - (C)₁-C₃) Alkyl, - (C)₁-C₃) Alkoxy, -OH, phenyl or benzyl;

-R⁴is aEach group independently selected from the following groups: - (a) -H, -F, -CI, - (C)₂-C₄) Alkynyl, -R¹²、-OR¹²、-S(＝O)_pR¹²、-C(＝O)OR¹²、-OC(＝O)R¹²、-CN、-NO₂、-C(＝O)NR¹⁵R¹²、-OC(＝O)NR¹⁵R¹²、-NR¹⁴C(＝O)NR¹⁵R¹²、-NR¹⁴C(＝NR¹⁴)NR¹⁵R¹²、-NR¹⁴C(＝NCN)NR¹⁵R¹²、-NR¹⁴C(＝N-NO₂)NR¹⁵R¹²、-C(＝NR¹⁴)NR¹⁵R¹²、-OC(＝NR¹⁴)NR¹⁵R¹²、-OC(＝N-NO₂)NR¹⁵R¹²、-NR¹⁵R¹²、-S(＝O)_pNR¹⁵R¹²and-CH₂C(＝NR¹⁴)NR¹⁵R¹²Wherein p is 0, 1 or 2; r ¹²Have the meaning as defined above;

wherein

--R¹⁴Is selected from-H, -CH₃and-CH₂CH₃；

--R¹⁵Independently selected from-H, -C (═ O) OR¹²、-C(＝O)NR¹²R¹³、-(C₁-C₄) Alkyl, - (C)₂-C₄) Alkenyl, - (C)₁-C₂) Alkoxy, - (C)₃-C₇) Cycloalkyl and phenyl; wherein R is¹²And R¹³Have the meaning as defined above; the alkyl group, the alkenyl group; alkoxy, cycloalkyl and phenyl substituted by 0-2 substituents R²¹Substituted;

wherein

-R²¹Independently selected from-F, -CI, -C (═ O) OR²³Wherein R is²³And R²⁴Has the meaning defined as-OH, -CN, -C (═ O) NR²³R²⁴、-NR²³R²⁴、-NR²³C(＝O)R²⁴、-NR²³C(＝O)OR²⁴、-NR²³S(＝O)_pR²⁴and-S (═ O)_pNR²³R²⁴Wherein p has the meaning as defined above, - (C)₁-C₄) Alkyl (including dimethyl) and- (C)₁-C₄) An alkoxy group; wherein said alkyl and alkoxy groups are each independently substituted with 0-3 substituents independently selected from the group consisting of: -F and-CI, - (C)₁-C₂) Alkoxycarbonyl, - (C)₁-C₂) Alkanoyl and- (C)₁-C₂) An alkylcarbonyloxy group;

wherein

R²³And R²⁴Independently is-H or- (C)₁-C₂) An alkyl group;

-R⁴further (b) is independently selected from- (C)₁-C₄) Alkyl and- (C)₁-C₄) An alkoxy group; wherein said alkyl and alkoxy are each independently substituted with 0-3 substituents-F or-Cl; or by 0 or 1 substituents (C)₁-C₂) Alkoxycarbonyl-, (C)₁-C₂) Alkylcarbonyl-or- (C)₁-C₂) Alkylcarbonyloxy;

-R⁴yet further- - (c) an aryl or heterocyclic group independently selected from: phenyl, benzyl, furyl, tetrahydrofuryl, oxetanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, pyrazolyl, pyrazolidinyl, oxadiazolyl, thiadiazolyl, imidazolyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, triazolyl, triazinyl, tetrazolyl, pyranyl, azetidinyl, morpholinyl, p-thiazinyl, indolyl, indolinyl, benzo [ b ]Furyl, 2, 3-dihydrobenzofuryl, 2-H-benzopyranyl, chromanyl, benzothienyl, 1-H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, 2, 3-naphthyridinyl, quinazolinyl, quinoxalinyl, and purinyl;

wherein the alkyl, alkoxy, aryl and heterocyclyl are each independently substituted with 0-3 substituents R¹⁰Is substituted in which R¹⁰Have the meaning as defined above; -R⁵And R⁶Together form a group selected from the group consisting of the radicals of the partial formulae (1.1.1) to (1.1.5):

wherein

-R⁷And R⁸Each independently is-H, -CH₃、-OR¹⁴Wherein R is¹⁴Have the meaning as defined above; or they are absent, in which case the dotted line- - - -represents a double bond;

-and-

-Z is independently selected from-OR¹²、-C(＝O)R¹²and-CN, wherein R¹²Have the meaning as defined above.

2. A compound according to claim 1, wherein m is 1, n is 1; r^AAnd R^Bis-H, -F, -CF₃Or by 0 or 1-F, -Cl, -CF₃、-CN、-NH₂Or C (═ O) NH₂Substituted- (C)₁-C₆) Alkyl, or together form a substituted or unsubstituted radical of 0 or 1-F, -Cl, -CF₃or-CN substituted spiro- (C)₃-C₆) A cycloalkyl group; r^cAnd R^DOne is-H, the other is-H, - (C)₁-C₄) Alkyl or phenyl, each of which is substituted by 0 or 1-F, -Cl or-CN; w is-O-; y is ═ C (R) ^E) Wherein R is^Eis-H, -F, -Cl, -CN, -CH₃or-OCH₃；R¹And R²is-H, -F, -Cl, -CN, -NO₂、-OH、-CH₃、-OCH₃、-OCHF₂Or OCF₃；R³is-H or-CH₃；R⁴is-H, -F, -CN, -NO₂、-OH、-CH₃or-OCH₃；R⁵And R⁶Together form a group of the sub-formula (1.1.1), the sub-formula (1.1.4) or the sub-formula (1.1.5), wherein R⁷And R⁸In each of said formulae is absent, -H or-CH₃(ii) a Q is phenyl, norbornyl, furyl, thienyl, pyrimidinyl, cyclohexenyl or cyclohexyl; z is OR¹²or-C (═ O) R¹²Wherein R is¹²is-H, -CH₃、-CH₂CH₃or-C (CH)₃)₃(ii) a Or Z is-CN.

3. A compound according to claim 2, wherein R^AAnd R^BAre all-CH₃Or one is-CH₃And the other is-CH (CH)₃)₂or-C (CH)₃)₃Or one is-H and the other is-CH₃or-CF₃Or together form a spirocyclopropyl or spirobutyl; r^cAnd R^DOne is-H and the other is-H or-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H, -F or-Cl; r¹And R²is-H, -F or-Cl; r³is-H; r⁴is-H; r⁵And R⁶Together form a group of the sub-formula (1.1.1) or the sub-formula (1.1.4), wherein R⁷And R⁸Are not present; q is phenyl, thienyl, cyclohexenyl or cyclohexyl; z is OR¹²Wherein R is¹²is-H, or Z is-C (═ O) R¹²Wherein R is¹²is-H or-CH₃Or Z is-CN.

4. A compound according to claim 3, wherein R^AAnd R^BAre all-CH₃Or together form a spirocyclopropyl group; r^cAnd R^DOne is-H and the other is-H or-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H, -F or-Cl; r¹And R²is-H, -F or-Cl; r³is-H; r⁴is-H; r⁵And R⁶Together form a group of the formula (1.1.1), wherein R⁷And R⁸Are not present; z is OR¹²Wherein R is¹²is-H.

5. A compound according to claim 4, wherein R^AAnd R^BAre all-CH₃；R^cAnd R^DAre all-H; y is ═ C (R)^E) Wherein R is^Eis-H; r¹And R²One is-H and the other is-F.

6. A compound according to claim 2, wherein Y is ═ C (R)^E) Wherein R is^Eis-F; r¹And R²Are all-H.

7. A compound according to claim 6, wherein R⁵And R⁶Together form a group of the sub-formula (1.1.4), and wherein R^AAnd R^BAre all-CH₃Or one is-H and the other is-CH₃Or together form a spirocyclopropyl group; r^cAnd R^DOne of which is-H and the other is H or-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H or-F; r¹And R²is-H, -F or-Cl; r³is-H; r⁴is-H; r⁷And R⁸Are not present; q is phenyl, norbornyl, furyl, thienyl, pyrimidinyl or cyclohexyl; z is OR¹²Wherein R is¹²is-H.

8. A compound according to claim 1, wherein m is 1, n is 1; r^AAnd R^Bis-H, -CF₃Or by 0 or 1-F, -Cl, -CF₃、-CN、-NH₂or-C (═ O) NH₂Substituted- (C)₁-C₆) Alkyl, or together form a substituted or unsubstituted radical of 0 or 1-F, -Cl, -CF₃or-CN substituted spiro- (C)₃-C₆) A cycloalkyl group; r^cAnd R^DOne is-H, the other is-H, - (C)₁-C₄) Alkyl or phenyl, each of which is substituted by 0 or 1-F, -Cl or-CN; w is-O-; y is ═ C (R)^E) Wherein R is^Eis-H, -F, -Cl, -CN, -CH₃or-OCH₃；R¹And R²is-H, -F, -Cl, -CN, -NO₂、-OH、-CH₃、-OCH₃、-OCHF₂Or OCF₃；R³is-H; r⁴is-H, -F, -CN, -NO₂、-OH、-CH₃or-OCH₃；R⁵And R⁶Together form a group of the partial formula (1.1.5), wherein R⁷is-H or-CH₃(ii) a Q is phenyl, norbornyl, furyl, thienyl, pyrimidinyl, cyclohexenyl or cyclohexyl; z is OR¹²or-C (═ O) R¹²Wherein R is¹²is-H, -CH₃、-CH₂CH₃or-C (CH)₃)₃Or Z is-CN.

9. A compound according to claim 1, wherein R^AAnd R^BAre all-CH₃Or one is-CH₃And the other is-CH (CH)₃)₂or-C (CH)₃)₃Or one is-H and the other is-CH₃or-CF₃Or together form a spirocyclopropyl or spirobutyl; r^cAnd R^DOne is-H and the other is-H or-CH₃(ii) a Y is ═ C (R)^E) Wherein R is^Eis-H, -F or-Cl; r ¹And R²is-H, -F or-Cl; r³is-H; r⁴is-H; q is phenyl, thienyl, cyclohexenyl or cyclohexyl; z is OR¹²Wherein R is¹²is-H, or Z is-C (═ O) R¹²Wherein R is¹²is-H or-CH₃Or Z is-CN.

10. A compound according to claim 1, selected from:

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- [ I-hydroxy-1-methyl-ethyl ] -benzyl ] -nicotinamide of formula (5.5.1);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl ] -benzyl ] -nicotinamide of formula (5.5.2);

trans-2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -cyclohexyl-methyl ] -nicotinamide of formula (5.5.3);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- (1-hydroxy-cyclobutyl) -benzyl ] -nicotinamide of formula (5.5.4);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- [2, 2, 2-trifluoro-1-hydroxy-ethyl ] -benzyl ] -nicotinamide of formula (5.5.5);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-ethyl ] -thiophen-2-yl-methyl ] -nicotinamide of formula (5.5.6);

n- [ 4-acetyl-benzyl ] -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -nicotinamide of formula (5.5.7);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- {1- [ 2-fluoro-4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -ethyl } -nicotinamide of formula (5.5.8);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [ 2-chloro-4- (1-hydroxy-1-methyl-ethyl) -benzyl ] -nicotinamide of formula (5.5.9);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- (1-hydroxy-ethyl) -benzyl ] -nicotinamide of formula (5.5.10);

(-) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- {1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -ethyl } -nicotinamide of formula (5.5.11);

(+) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- {1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -ethyl } -nicotinamide of formula (5.5.12);

(+) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -cyclohex-1-enylmethyl ] -nicotinamide of formula (5.5.13);

(-) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -cyclohex-1-enylmethyl ] -nicotinamide of formula (5.5.14);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- (1-hydroxy-cyclopropyl) -benzyl ] -nicotinamide of formula (5.5.15);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [ 2-fluoro-4- (1-hydroxy-cyclopropyl) -benzyl ] -nicotinamide of formula (5.5.16);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- {1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -ethyl } -nicotinamide of formula (5.5.17);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- (1-hydroxy-1, 2, 2-trimethyl-propyl) -benzyl ] nicotinamide of formula (5.5.18);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- (1-hydroxy-1, 2-dimethyl-propyl) -benzyl ] -nicotinamide of formula (5.5.19);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- (1-cyano-1-methyl-ethyl) -benzyl ] -nicotinamide of formula (5.5.20);

2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl ] -nicotinamide of formula (5.5.21);

2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl ] -benzyl ] -nicotinamide of formula (5.5.22);

2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- [4- (1-hydroxy-cyclobutyl) -benzyl ] -nicotinamide of formula (5.5.23);

(+) -2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- {1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -ethyl } -nicotinamide of formula (5.5.24);

(+) -2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -cyclohex-1-enylmethyl ] -nicotinamide of formula (5.5.25);

2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- [ 2-fluoro-4- (1-hydroxy-cyclopropyl) -benzyl ] -nicotinamide of formula (5.5.26);

(±) -2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- [4- (1-hydroxy-1, 2, 2-trimethyl-propyl) -benzyl ] -nicotinamide of formula (5.5.27);

2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl ] -benzyl ] -nicotinamide of formula (5.5.28);

(±) -2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- [4- [2, 2, 2-trifluoro-1-hydroxy-ethyl ] -benzyl ] -nicotinamide of formula (5.5.29);

(-) -2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- {1- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -ethyl } -nicotinamide of formula (5.5.30);

2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- [4- (1-cyano-1-methyl-ethyl) -benzyl ] -nicotinamide of formula (5.5.31);

2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- [ 2-fluoro-4- (1-hydroxy-cyclopropyl) -benzyl ] -nicotinamide of formula (5.5.32);

trans-2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -cyclohexyl-methyl ] -nicotinamide of formula (5.5.33);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -cyclopent-1-enylmethyl ] -nicotinamide of formula (5.5.34);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [3- [ 1-hydroxy-1-methyl-ethyl ] -norbornan-6-yl-methyl ] -nicotinamide of formula (5.5.35);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [3- [ 1-hydroxy-1-methyl-ethyl ] -7-fluoro-norborn-5-en-6-yl-methyl ] -nicotinamide of formula (5.5.36);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [2- [2, 2, 2-trifluoro-1-yl-ethyl ] -bicyclo [2, 2, 2] -octan-5-yl-methyl ] -nicotinamide of formula (5.5.37);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [ 3-acetyl-bicyclo [2, 2, 2] -oct-7-en-5-yl-methyl ] -nicotinamide of formula (5.5.38);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [8- [ 1-hydroxy-1-methyl-ethyl ] -bicyclo [3, 2, 1] -octan-3-yl-methyl ] -nicotinamide of formula (5.5.39);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-ethyl ] -furan-2-yl-methyl ] -nicotinamide of formula (5.5.40);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-1-methyl-ethyl ] -pyridin-2-yl-methyl ] -nicotinamide of formula (5.5.41);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-1-methyl-ethyl ] -oxazol-2-yl-methyl ] -nicotinamide of formula (5.5.42);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-1-methyl-ethyl ] -thiazol-2-yl-methyl ] -nicotinamide of formula (5.5.43);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [6- [ 1-hydroxy-1-methyl-ethyl ] -pyridin-3-yl-methyl ] -nicotinamide of formula (5.5.44);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-cyclopropyl ] -pyridin-2-yl-methyl ] -nicotinamide of formula (5.5.45);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-1, 2-dimethyl-propyl ] -oxazol-2-yl-methyl ] -nicotinamide of formula (5.5.46);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-oxy ] -N- [5- [ 1-cyano-1-methyl-ethyl ] -thiazol-2-yl-methyl ] -nicotinamide of formula (5.5.47);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-sulfanyl ] -N- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl ] -benzyl ] -nicotinamide of formula (5.5.48);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-sulfanyl ] -N- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl ] -benzyl ] -nicotinamide of formula (5.5.49);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-sulfanyl ] -N- {1- [ 2-fluoro-4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -ethyl } -nicotinamide of formula (5.5.50);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-sulfanyl ] -N- [ 2-fluoro-4- (1-hydroxy-cyclopropyl) -benzyl ] -nicotinamide of formula (5.5.51);

2- [ benzo [2, 1, 3] thiadiazol-5-yl-sulfanyl ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -benzyl ] -nicotinamide of formula (5.5.52);

2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-sulfanyl ] -N- [ 2-fluoro-4- [ 1-hydroxy-1-methyl-ethyl ] -benzyl ] -nicotinamide of formula (5.5.53);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-sulfanyl ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -cyclopent-1-enylmethyl ] -nicotinamide of formula (5.5.54);

2- [ benzo [2, 1, 3] oxadiazol-5-yl-sulfanyl ] -N- [3- [ 1-hydroxy-1-methyl-ethyl ] -7-fluoro-norborn-5-en-6-yl-methyl ] -nicotinamide of formula (5.5.55);

(±) -2- [ benzo [2, 1, 3] oxadiazol-5-yl-thio ] -N- [5- [ 1-hydroxy-ethyl ] -furan-2-yl-methyl ] -nicotinamide of formula (5.5.56);

2- [ benzo [2, 1, 3] thiadiazol-5-yl-sulfanyl ] -N- [5- [ 1-hydroxy-1-methyl-ethyl ] pyridin-2-yl-methyl ] -nicotinamide of formula (5.5.57);

2-benzo [1, 2, 3] oxadiazol-5-yl-sulfanyl ] -N- [5- [ 1-hydroxy-1-methyl-ethyl ] -oxazol-2-yl-methyl ] -nicotinamide of formula (5.5.58);

2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- [4- [ 1-hydroxy-1-methyl-ethyl ] -cyclopent-1-enylmethyl ] -nicotinamide of formula (5.5.59);

2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- [3- [ 1-hydroxy-1-methyl-ethyl ] -norbornan-6-yl-methyl ] -nicotinamide of formula (5.5.60);

2- [ benzo [2, 1, 3] thiadiazol-5-yl-sulfanyl ] -N- [3- [ 1-hydroxy-1-methyl-ethyl ] -7-fluoro-norborn-5-en-6-yl-methyl ] -nicotinamide of formula (5.5.61);

2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- [ 3-acetyl-bicyclo [2, 2, 2] -oct-7-en-5-yl-methyl ] -nicotinamide of formula (5.5.62);

(±) -2- [ benzo [2, 1, 3] thiadiazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-ethyl ] -furan-2-yl-methyl ] -nicotinamide of formula (5.5.63);

2- [ 2-methyl-benzo [1, 2, 3] triazol-5-yl-oxy ] -N- [5- [ 1-hydroxy-1-methyl-ethyl ] -pyridin-2-yl-methyl ] -nicotinamide of formula (5.5.64).

11. A method of treating a patient having a disease, disorder or condition mediated by the isozyme of PDE4, which isozyme modulates the activation and degranulation of human eosinophils, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (1.0.0) as defined in claim 1.

12. A pharmaceutical composition for treating a patient having a disease, disorder or condition mediated by the isozyme of PDE4, which has a modulating effect on the activation and degranulation of human eosinophils, said composition comprising a therapeutically effective amount of a compound of formula (1.0.0) as defined in claim 1 and a pharmaceutically acceptable carrier.

13. The method according to claim 11, wherein said disease, disorder or condition comprises a condition selected from one or more of the group consisting of:

-asthma of any type, etiology or pathogenesis, or asthma selected from: atopic asthma, non-atopic asthma, allergic asthma, atopic, bronchial asthma, IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, intrinsic asthma caused by a pathophysiological disorder, extrinsic asthma caused by an environmental factor, idiopathic asthma of unexplained or nondominant cause, non-atopic asthma, bronchial asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infection, non-allergic asthma, asthma primordial, infantile asthma syndrome;

chronic or acute bronchoconstriction, chronic bronchitis, fine airway obstruction, and emphysema;

-an obstructive or inflammatory airway disease of any type, etiology or pathogenesis, or selected from the following: asthma, pneumoconiosis, chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated therewith, COPD characterized by irreversible, progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), and exacerbation of airway hyperreactivity secondary to other drug therapy;

-pneumoconiosis of any type, etiology or pathogenesis, or selected from the following: bauxite or aluminous diseases, charcoal or coal mining asthma, asbestos or steam pipework asthma, chalicosis or flint disease, ostrich pneumoconiosis caused by inhalation of ostrich smut, iron pneumoconiosis caused by inhalation of iron dust, silicosis or abrasionproof diseases, cotton scurf or cotton dust asthma, and talc pneumoconiosis;

-bronchitis of any type, etiology or pathogenesis, or selected from the group consisting of: acute bronchitis, laryngeal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal infectious bronchitis, and alveolar bronchitis;

-any type, etiology or pathogenesis of bronchiectasis, or bronchiectasis selected from: cylindrical bronchiectasis, cystic bronchiectasis, fusiform bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis;

-seasonal allergic rhinitis, perennial allergic rhinitis or sinusitis of any type, etiology or pathogenesis, or of sinusitis selected from the following: purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary or sphenoid sinusitis;

-rheumatoid arthritis of any type, etiology or pathogenesis, or selected from the following: acute arthritis, acute gouty arthritis, chronic arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, and spondyloarthritis;

-gout, fever and pain associated with inflammation;

-an eosinophil-related disorder of any type, etiology or pathogenesis, or selected from the following: eosinophilia, pulmonary infiltrative eosinophilia, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopulmonary aspergillosis, Aspergillus, eosinophil-containing rheumatic granuloma, allergic granulomatous vasculitis or Churg-Strauss syndrome, polyarticular nodules (PAN), and necrotizing systemic vasculitis;

-atopic dermatitis or allergic dermatitis, or allergic or atopic eczema;

-urticaria of any type, etiology or pathogenesis, or selected from the following: immune-mediated urticaria, complement-mediated urticaria, urticaria mediated by urticaria-causing substances, urticaria caused by physical agents, urticaria caused by stress reactions, idiopathic urticaria acute, chronic urticaria, angioedema, cholinergic urticaria, autosomal dominant cold urticaria or acquired cold urticaria, contact urticaria, giant urticaria, and papular urticaria;

-conjunctivitis of any type, etiology or pathogenesis, or selected from the group consisting of: actinic conjunctivitis, acute catarrhal conjunctivitis, acute contagious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, suppurative conjunctivitis, and vernal conjunctivitis;

-uveitis of any type, etiology or pathogenesis, or of uveitis selected from: inflammation of all or part of the uvea, anterior uveitis, iritis, cyclitis, iridocyclitis, granulomatous uveitis, non-granulomatous uveitis, phakic uveitis, posterior uveitis, choroiditis, and choroidal retinitis;

-psoriasis;

-multiple sclerosis of any type, etiology or pathogenesis, or selected from the following multiple sclerosis diseases: primary progressive multiple sclerosis, and remission of recurrent multiple sclerosis;

-autoimmune/inflammatory diseases of any type, etiology or pathogenesis, or selected from the following: autoimmune blood diseases, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, polychondritis, scleroderma, Wegner's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, endocrine eye disease, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, juvenile diabetes or type I diabetes, pre-or post-uveitis, keratoconjunctivitis, epidemic keratoconjunctivitis, diffuse interstitial or interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, psoriatic arthritis, glomerulonephritis with or without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy; inflammatory/hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, benign familial pemphigus, pemphigus erythematodes, pemphigus foliaceus, and pemphigus vulgaris;

-prevention of allograft rejection after organ transplantation;

-Inflammatory Bowel Disease (IBD) of any type, etiology or pathogenesis, or selected from the following inflammatory bowel diseases: ulcerative Colitis (UC), collagenous colitis, polypoidal colitis, transmural colitis, and Crohn's Disease (CD);

-septic shock of any type, etiology or pathogenesis, or selected from the following: renal failure, acute renal failure, cachexia, malaria cachexia, pituitary cachexia, uremic cachexia, cardiac cachexia, adrenal cachexia or Addison's disease, cancer cachexia, and cachexia resulting from infection by Human Immunodeficiency Virus (HIV);

-liver damage;

pulmonary hypertension, and pulmonary hypertension due to hypoxia;

-bone loss disease, primary osteoporosis, and secondary osteoporosis;

-a central nervous system disorder of any type, etiology or pathogenesis, or a central nervous system disorder selected from the group consisting of: depression, Parkinson's disease, cognitive and memory impairment, tardive dyskinesia, drug dependence, arteriosclerotic dementia, and dementia with Huntington's chorea, Wilson's disease, paralysis agitans and thalamottle;

Infections, especially viral infections, wherein such viruses increase the production of TNF- α in their host or are susceptible to upregulation of TNF- α in the host, whereby their replication or other activity is adversely affected; comprising a virus selected from the group consisting of: HIV-1, HIV-2 and HIV-3, cytomegalovirus, CMV, influenza, adenovirus, and herpes viruses, including herpes zoster and herpes simplex;

-yeast and fungal infections sensitive to or causing the production of TNF- α in a host, when other drugs are selected for co-administration to treat systemic yeast and fungal infections, including but not limited to polymyxin, polymyxin B; imidazoles, clotrimazole, econazole, miconazole and ketoconazole; triazoles, fluconazole and itraconazole; as well as amphotericin, amphotericin B and liposomal amphotericin B;

-ischemia reperfusion injury, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infection, lupus erythematosus, kidney and ureter diseases, genitourinary and gastrointestinal diseases, and prostate diseases;

14. a method of treatment according to claim 13, the diseases and conditions: (1) an inflammatory disease or disorder, comprising: arthritis, rheumatoid spondylitis, osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronic glomerulonephritis, dermatitis and Crohn's disease; (2) respiratory diseases and disorders, including: asthma, acute respiratory distress syndrome, chronic lung inflammatory disease, bronchitis, chronic obstructive airways disease and silicosis; (3) infectious diseases and disorders, including: sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, fever and muscle pain from bacterial, viral or fungal infections, and influenza; (4) immune diseases and disorders, including: autoimmune diabetes, systemic lupus erythematosus, graft-versus-host reactions, allograft rejection, multiple sclerosis, psoriasis, and allergic rhinitis; and (5) other diseases and disorders, including: bone resorption diseases, reperfusion injury, cachexia secondary to infection or malignancy, cachexia secondary to Acquired Immune Deficiency Syndrome (AIDS) in humans, Human Immunodeficiency Virus (HIV) infection or AIDS related syndrome (ARC), formation of leucoderma tumors, formation of leucoderma tissues, type I diabetes and leukemia.

15. A combination of a compound of formula (1.0.0) as defined in claim 1 and one or more substances selected from:

(a) leukotriene biosynthesis inhibitor: 5-lipoxygenase (5-LO) inhibitor and 5-lipoxygenase activating protein (FLAP) antagonist selected from zileuton, ABT-761, fenleutonTeposalin, Abbott-79175; abbott-85761, the N- (5-substituted) thiophene-2-alkylsulfonamides of formula (5.2.8), the 2, 6-di-tert-butylphenol hydrazones of formula (5.2.10), methoxytetrahydropyrans including Zeneca ZD-2138 of formula (5.2.11), the compound SB-210661 of formula (5.2.12) and its related compounds, the pyridyl-substituted 2-cyanonaphthalenes of L-739,010, the 2-cyanoquinolines of L-746,530, the indoles and quinolines of MK-591, MK-886 and BAYx 1005; (b) leukotriene LTB₄、LTC₄、LTD₄And LTE₄A receptor antagonist selected from: phenothiazin-3-ones belonging to L-651, 392, amidinates belonging to CGS-25019c, benzoxazololamines belonging to ontazolast, benzamidines belonging to BIIL284/260, and zafirlukast, arlukast, montelukast, pranlukast, vilukast (MK-679), RG-12525, Ro-245913, iralukast (CGP45715A), and BAYx 7195;

(c) PDE4 inhibitors, including isozyme PDE4D inhibitors;

(d) a 5-lipoxygenase (5-LO) inhibitor, or a 5-lipoxygenase activating protein (FLAP) antagonist;

(e) a dual inhibitor of 5-lipoxygenase (5-LO) and a Platelet Activating Factor (PAF) antagonist;

(f) including LTB₄、LTC₄、LTD₄And LTE₄Leukotriene antagonists (LTRAs) including antagonists;

(g) antihistaminic H₁Receptor antagonists including cetirizine, loratadine, desloratadine, fexofenadine, astemizole, nitrogen  statin, and chlorpheniramine;

(h) stomach protection H₂A receptor antagonist;

(i)α₁-and α₂-an adrenergic receptor agonist, a vasoconstrictor, a sympathomimetic agent for oral or topical administration for decongestion, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethylnorepinephrine hydrochloride;

(j) and 5-Alpha combined use of lipoxygenase (5-LO) inhibitors₁-and α₂-an adrenergic receptor agonist;

(k) anticholinergic agents including ipratropium bromide, tiotropium bromide, oxitropium bromide, perenzapine, and telenzepine;

(l)β₁-β₄-adrenergic agonists including metaproterenol, isoproterenol, albuterol, salbutamol, formoterol, salmeterol, terbutaline, metaproterenol, bitolterol mesylate, and pirbuterol;

(m) theophylline and aminophylline;

(n) cromolyn sodium;

(o) muscarinic receptor (M1, M2, and M3) antagonists;

(p) COX-1 inhibitors (NSAIDs), COX-2 selective inhibitors including rofecoxib, and nitric oxide NSAIDs;

(q) insulin-like growth factor type I (IGF-1) mimetics;

(r) ciclesonide;

(s) inhaled glucocorticoids with reduced systemic side effects including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate;

(t) tryptase inhibitors;

(u) Platelet Activating Factor (PAF) antagonists;

(v) monoclonal antibodies active against endogenous inflammatory entities;

(w)IPL576；

(x) Anti-tumor necrosis factor (TNF α) agents including Etanercept, Infliximab, and D2E 7;

(y) DMARDs including leflunomide;

(z) a TCR peptide;

(aa) Interleukin Converting Enzyme (ICE) inhibitors;

(bb) an IMPDH inhibitor;

(cc) adhesion molecule inhibitors, including VLA-4 antagonists;

(dd) cathepsin;

(ee) MAP kinase inhibitors;

(ff) glucose-6 phosphate dehydrogenase inhibitors;

(gg) kinin-B₁-and B₂-a receptor antagonist;

(hh) gold in the form of a aurothioylene group having various hydrophilic groups;

(ii) Immunosuppressive agents, such as cyclosporine, azathioprine, and methotrexate;

(jj) anti-gout agents, such as colchicine;

(kk) xanthine oxidase inhibitors, such as allopurinol;

(II) uricosuric agents, for example, probenecid, sulindac, and benzbromarone;

(mm) antineoplastic agents, especially antimitotic agents, including vinca alkaloids, such as vinblastine and vincristine;

(nn) growth hormone secretagogues;

(oo) matrix metalloproteinase inhibitors (MMPs), i.e., stromelysin, collagenase and gelatinase, and aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11);

(pp) transforming growth factor (TGF β);

(qq) Platelet Derived Growth Factor (PDGF);

(rr) fibroblast growth factors, e.g., basic fibroblast growth factor (bFGF);

(ss) granulocyte macrophage colony stimulating factor (GM-CSF);

(tt) capsaicin cream;

(uu) tachykinin NK-1, NK-1/NK-2, NK-2 and NK-3 receptor antagonists, including NKP-608C, SB-233412(talnetant) and D-4418;

(vv) elastase inhibitors, including UT-77 and ZD-0892; and

(ww) adenosine A2a receptor agonist.