HK1081538A - 2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof - Google Patents

Description

2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof

Technical Field

The present invention relates to compounds from the group of 2-thia-dibenzoazulenes, to their pharmacologically acceptable salts and solvates, to processes and intermediates for the preparation thereof and to their anti-inflammatory effects, in particular to the inhibition of tumor necrosis factor-alpha (TNF-alpha) production and the inhibition of interleukin-1 (IL-1) production as well as to their analgetic action.

Prior Art

1-thia-dibenzoazulenes substituted in the 2-position by methyl, methyl ketone, nitro or carboxyl derivatives have been described so far in the literature (Cagniant PG, C.R. Hebd. sciences Acad. Sci., 1976, 283: 683-686). Certain 1, 3-diaza-dibenzoazulene derivatives and salts thereof are known as a new class of compounds with anti-inflammatory action (US3,711,489, US 4,198,421 and CA 967,573). 1-thia-dibenzoazulene derivatives with an alkoxy substituent in position 2 (WO 01/878990) also have a strong anti-inflammatory effect. However, to date, the structure of 2-thiadibenzoazulenes is generally unknown, and therefore the anti-inflammatory effects and analgesic effects of derivatives derived from such structures as inhibitors of TNF- α secretion and inhibitors of IL-1 secretion are unknown, based on our knowledge and available literature data.

In 1975, TNF- α was defined as an endotoxin-induced serum factor induced by endotoxin and resulting in tumor necrosis in vitro and in vivo (Carswell EA et al, Proc. Natl.Acad. Sci. U.S.A., 1975, 72: 3666-3670). In addition to antitumor activity, TNP- α has several other biological activities that are important in both homeostasis and pathophysiological conditions. The main sources of TNF- α are monocyte-macrophages, T-lymphocytes and mast cells.

The discovery that anti-TNFa antibodies (cAZ) are effective in the treatment of Rheumatoid Arthritis (RA) patients (Elliott M et al, Lancet (Lancet), 1994, 344: 1105-1110) has enhanced interest in finding new TNF- α inhibitors as potentially effective RA drugs. Rheumatoid arthritis is an autoimmune chronic inflammatory disease characterized by irreversible joint pathology. In addition to RA, TNF- α antagonists may also have application in several pathological conditions and diseases such as spondylitis, osteoarthritis, gout and other joint inflammations, sepsis, septic shock, toxic shock syndrome, atopic dermatitis, contact dermatitis, psoriasis, glomerulonephritis, lupus erythematosus, scleroderma, asthma, cachexia, chronic obstructive pulmonary disease, congestive heart failure, insulin resistance, pulmonary fibrosis, multiple sclerosis, crohn's disease, ulcerative colitis, viral infections and AIDS.

Evidence of the biological importance of TNF- α has been obtained in vivo experiments in mice in which TNF- α or its receptor genes are inactivated. Such animals are resistant to collagen-induced arthritis (Mori L et al, J.Immunol., 1996, 157: 3178-. In animal experiments with increased levels of TNF- α, chronic inflammatory polyarthritis appeared (Georgopoulos S et al, J.Inflamm., 1996, 46: 86-97; Keffer J et al, EMBO J., 1991, 10: 4025-. The treatment of such inflammatory and pathological conditions often involves the use of non-steroidal anti-inflammatory drugs, although gold salts, D-penicillamine or methotrexate are given in severe cases. The medicine can not stop the pathological process in symptomatic treatment. New approaches in the treatment of rheumatoid arthritis have been established, for example based on tinib-daru, leflunomide, cyclosporin, FK-506 and biomolecules neutralizing the effects of TNF-alpha. Currently, fusion proteins of soluble TNF-alpha receptor, named etanercept (Enbrel, immunox/Wyeth), and mouse and human chimeric monoclonal antibodies, named Infliximab (Remicade, Centocor), are available on the market. In addition to RA therapy, etanercept and Infliximab have also been demonstrated for the treatment of crohn's disease (exp. opin. invest. drugs, 2000, 9: 103).

In addition to the inhibitory effect of TNF- α secretion, inhibition of IL-1 secretion is also important in RA therapy, since IL-1 represents an important cytokine in cellular regulation, immune regulation and pathophysiological conditions, such as inflammation (Dinarello CA et al, Rev. infection. disease, 1984, 6: 51). The biological activities of IL-1 are known as: activation of T cells, induction of temperature elevations, stimulation of prostaglandin or collagenase secretion, chemotaxis of neutrophils, and reduction of plasma iron levels (Dinarello CA, J.clinical immunology, 1985, 5: 287). IL-1 is known to bind to two receptors: IL-1RI and IL-1 RII. IL-1RI transmits signals in cells, while IL-1RII is present on the cell surface and does not transmit signals in cells. Since IL1-RII binds to both IL-1 and IL1-RI, it is therefore able to act as a negative regulator of the action of IL-1. In addition to the mentioned signal transmission regulation mechanisms, another natural IL-1 receptor antagonist (IL-1ra) is present in the cell. This protein binds to IL-1RI, but does not transmit any signal. It is not as potent in signaling inhibition, so its concentration must be 500 times higher than IL-1 to interrupt signaling. Recombinant human IL-1RA (Amgen) was tested clinically (Bresenihan B et al, Arthrit. Rheum., 1996, 39: 73) and the results demonstrated that 472 patients with RA had improved symptoms relative to placebo. These results indicate the importance of IL-1 activity inhibition in the treatment of diseases, such as RA, in which IL-1 production is disrupted. Due to the presence of a synergistic effect of TNF- α with IL-1, 2-thia-dibenzoazulenes may be used for the treatment of disorders and diseases associated with increased secretion of TNF- α and IL-1.

Solution to the technical problem

The present invention relates to 2-thia-dibenzoazulenes of formula I and to pharmacologically acceptable salts and solvates thereof:

wherein

X may be CH₂Or heteroatoms such as O, S, S (═ O), S (═ O)₂Or NR^aWherein R is^aIs hydrogen or a protecting group;

y and Z independently of one another represent one or more identical or different substituents attached to any available carbon atom and may be halogen, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, trifluoromethyl, halo C₁-C₄Alkyl, hydroxy, C₁-C₄Alkoxy, trifluoromethoxy, C₁-C₄Alkanoyl, amino-C₁-C₄Alkyl radical, C₁-C₄Alkylamino, N- (C)₁-C₄Alkyl) amino, N-di (C)₁-C₄Alkyl) amino, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, carboxy, C₁-C₄Alkoxycarbonyl, cyano, nitro;

R¹can be hydrogen, halogen, optionally substituted C₁-C₇Alkyl or C₂-C₇Alkenyl radical, C₂-C₇Alkynyl, optionally substituted aryl or heteroaryl and heterocycle, hydroxy-C₂-C₇Alkenyl, hydroxy-C₂-C₇Alkynyl, C₁-C₇Alkoxy, thiol, thio C₂-C₇Alkenyl, thio C₂-C₇Alkynyl, C₁-C₇Alkylthio, amino, N- (C)₁-C₇Alkyl) amino, N-di (C)₁-C₇Alkyl) amino, C₁-C₇Alkylamino, amino-C₂-C₇Alkenyl, amino-C₂-C₇Alkynyl, amino-C₁-C₇Alkoxy radical, C₁-C₇Alkanoyl, aroyl, oxo C₁-C₇Alkyl radical, C₁-C₇Alkanoyloxy, carboxy, optionally substituted C₁-C₇Alkoxycarbonyl or aryloxycarbonyl, carbamoyl, N- (C)₁-C₇Alkyl) carbamoyl, N-di (C)₁-C₇-alkyl) carbamoyl, cyano-C₁-C₇Alkyl, sulfonyl, C₁-C₇Alkylsulfonyl, sulfinyl, C₁-C₇Alkylsulfinyl, nitro or a substituent of formula II:

wherein

R³And R⁴May be hydrogen, C simultaneously or independently of one another₁-C₄Alkyl, aryl or together with N means an optionally substituted heterocycle or heteroaryl;

m and n represent an integer of 0 to 3;

Q₁and Q₂Represents, independently of one another, oxygen, sulfur or a group:

-C≡C-

wherein the substituents are

y₁And y₂May be independently of one another hydrogen, halogen, optionally substituted C₁-C₄Alkyl or aryl, hydroxy, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, cyano, nitro or together form a carbonyl or imino group;

R²may be hydrogen, carboxyl or alkoxycarbonyl.

The term "halo", "hal" or "halogen" refers to a halogen atom which may be fluorine, chlorine, bromine or iodine.

The term "alkyl" means an alkane from which a group is derived which may be a straight or branched chain or a cyclic group or a combination of straight and branched chain and cyclic groups. For example, preferred straight or branched chain alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. Preferred cycloalkyl groups are, for example, cyclopentyl or cyclohexyl.

The term "haloalkyl" refers to an alkyl group that must be substituted with at least one halogen atom. The most common haloalkyl groups are, for example, chloromethyl, dichloromethyl, trifluoromethyl or 1, 2-dichloropropyl.

The term "alkenyl" refers to an alkenyl group having the meaning of a hydrocarbon group which may be a straight or branched chain or a cyclic group or a combination of straight and cyclic groups but which has at least one carbon-carbon double bond. The most common alkenyl groups are ethenyl, propenyl, butenyl or cyclohexenyl.

The term "alkynyl" refers to alkynyl groups having the meaning of a hydrocarbon group which is straight or branched chain and which contains at least one and up to two carbon-carbon triple bonds. The most common alkynyl groups are for example ethynyl, propynyl or butynyl.

The term "alkoxy" refers to straight or branched chain alkoxy groups. Examples of such radicals are methoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy.

The term "aryl" means aromatic ring groups such as phenyl and fused aromatic ring groups. An aryl group comprises one ring having at least 6 carbon atoms or two rings having a total of 10 carbon atoms with alternating double (resonant) bonds between the carbon atoms. The most commonly used aryl groups are for example phenyl or naphthyl. In general, the aryl group may be bonded directly or through C via any available carbon atom₁-C₄An alkylene group such as methylene or ethylene is attached to the remainder of the molecule.

The term "heteroaryl" means a monocyclic or bicyclic aromatic and partially aromatic group having 4 to 12 carbon atoms, at least one of which is a heteroatom such as O, S or N, and the available nitrogen or carbon atoms are the direct bonds of the group to the remainder of the molecule or C as defined above₁-C₄The site where the alkyl group binds. Examples of such are thienyl, pyrrolyl, imidazolyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, quinolinyl or triazinyl.

The term "heterocycle" refers to a 5-or 6-membered, fully saturated or partially unsaturated heterocyclic group containing at least one heteroatom such as O, S or N, and the available nitrogen or carbon atoms are the direct bonds between the group and the remainder of the molecule or C as defined above₁-C₄The site where the alkyl group binds. The most common examples are morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazinyl or imidazolyl.

The term "alkanoyl" relates to straight-chain acyl groups, such as formyl, acetyl or propionyl.

The term "aroyl" refers to an aromatic acyl group, such as benzoyl.

The term "optionally substituted alkyl" means that it may be optionally additionally substitutedAlkyl substituted with one, two, three or more substituents. These substituents may be halogen atoms (preferably fluorine or chlorine), hydroxy groups, C₁-C₄Alkoxy (preferably methoxy or ethoxy), thiol, C₁-C₄Alkylthio (preferably methylthio or ethylthio), amino, N- (C)₁-C₄) Alkylamino (preferably N-methylamino or N-ethylamino), N, N-di (C)₁-C₄-alkyl) -amino (preferably dimethylamino or diethylamino), sulfonyl, C₁-C₄Alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl, C₁-C₄Alkylsulfinyl (preferably methylsulfinyl).

The term "optionally substituted alkenyl" refers to alkenyl groups optionally additionally substituted with one, two or three halogen atoms. These substituents may be, for example, 2-chloroethenyl, 1, 2-dichlorovinyl or 2-bromo-propen-1-yl.

The term "optionally substituted aryl, heteroaryl or heterocycle" refers to an aryl, heteroaryl or heterocyclyl group optionally additionally substituted with one or two substituents. The substituents may be halogen (preferably chlorine or fluorine), C₁-C₄Alkyl (preferably methyl, ethyl or isopropyl), cyano, nitro, hydroxy, C₁-C₄Alkoxy (preferably methoxy or ethoxy), thiol, C₁-C₄Alkylthio (preferably methylthio or ethylthio), amino, N- (C)₁-C₄) Alkylamino (preferably N-methylamino or N-ethylamino), N-di (C)₁-C₄-alkyl) -amino (preferably N, N-dimethylamino or N, N-diethylamino), sulfonyl, C₁-C₄Alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl, C₁-C₄Alkylsulfinyl (preferably methylsulfinyl).

When X means NR^aAnd R is^aWhen a protecting group is intended, R^aRefers to the following groups: alkyl (preferably methyl or ethyl), alkanoyl (preferably acetyl), alkoxycarbonyl (preferably methoxycarbonyl or tert-butoxycarbonyl), arylmethoxyCarbonyl (preferably benzyloxycarbonyl), aroyl (preferably benzoyl), arylalkyl (preferably benzyl), alkylsilyl (preferably trimethylsilyl) or alkylsilylalkoxyalkyl (preferably trimethylsilylethoxymethyl).

When R is²And R³When taken together with N to mean heteroaryl or heterocyclic, it means that these heteroaryl or heterocyclic have at least one carbon atom substituted with a nitrogen atom through which the group is attached to the rest of the molecule. Examples of such radicals are morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, imidazol-1-yl or piperazin-1-yl.

The term "pharmaceutically suitable salts" refers to salts of compounds of formula I, including, for example, those containing C₁-C₄Salts of alkyl halides (preferably methyl bromide, methyl chloride) (quaternary ammonium salts), salts with inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulfuric acid) or salts with organic acids (tartaric acid, acetic acid, citric acid, maleic acid, lactic acid, fumaric acid, benzoic acid, succinic acid, methanesulfonic acid or p-toluenesulfonic acid).

Certain compounds of formula I may form salts with inorganic or organic acids or bases and these are also included in the present invention.

Solvates (most common hydrates) which can form compounds of formula I or salts thereof are also objects of the present invention.

Depending on the particular substituents, the compounds of formula I may have geometric isomers and one or more chiral centers and may thus exist as optical antipodes or diastereomers. The invention also relates to such isomers and mixtures thereof, including racemates.

The invention also relates to all possible tautomeric forms of the specific compounds of formula I.

Other objects of the present invention relate to the preparation of compounds of formula I according to the following process comprising:

a) for compounds of formula I, wherein R¹And R²Independent of each otherIs a carboxyl group, C₁-C₆Alkoxycarbonyl, aryloxycarbonyl or arylalkoxycarbonyl,

cyclizing an alpha-diketone of the formula III with a compound of the formula IV

b) For compounds of formula I, wherein Q₁meaning-O-,

reacting an alcohol of formula V

With compounds of the formula VI

Wherein R is⁵Meaning a leaving group;

c) for compounds of formula I, wherein Q₁meaning-O-, -NH-, -S-or-C.ident.C-,

reacting a compound of formula Va with a compound of formula VIa

Wherein L is¹Meaning a leaving group

d) For compounds of formula I, wherein Q₁meaning-O-, -NH-or-S-,

reacting a compound of formula Vb

With a compound of the formula VI, wherein R⁵Meaning a leaving group;

e) for compounds of formula I, wherein Q₁meaning-C ═ C-, where Q is₁Meaning that the compound of formula Vb of the carbonyl group is reacted with a phosphonium ylide.

The preparation method comprises the following steps:

a) an alpha-diketone of the formula III and a compound of the formula IV (wherein R¹And R²Simultaneously or independently of one another represent C₁-C₆-alkoxycarbonyl, aryloxycarbonyl or arylalkoxycarbonyl) is accomplished by the disclosed methods of preparing analogous compounds (Chadwick DJ et al, j.chem.soc.perkin trans.i, 1972, 2079-81). The cyclization reaction is carried out in an alcohol (most commonly in t-butanol) in the presence of an alcoholate (preferably potassium t-butoxide).

The starting compounds for this reaction are known or may be prepared by methods used to prepare analogous compounds: for example, for the α -diketones of formula III, Leonard n.j. et al, j.am.chem.soc., 1955, 77: 5078, U.S. Pat. No. 3,711,489 or LombardioJ.G, J. heterocyclic chem., 1974, 11: 17-21; or, for example, for the thioethers of formula IV, using the overhead berger c.g. et al, j.am.chem.soc., 1950, 72: 4958-61. The resulting compound may be purified, isolated and characterized, or it may be further converted without isolation.

b) The compounds of the formula I according to the process of the invention can be prepared by reacting an alcohol of the formula V with a compound of the formula VI, where R is⁵Meaning a leaving group which may be a halogen atom (most commonly bromine, iodine or chlorine) or a sulfonyloxy group (most commonly trifluoromethylsulfonyloxy or p-toluenesulfonyloxy). The condensation reaction can be carried out according to the methods disclosed for the preparation of analogous compounds (Menozzi G et al, J.Heterocyclic chem., 1997, 34: 963-968 or WO 01/87890). The reaction is at 20At temperatures of from DEG C to 100 ℃ in the presence of a phase transfer catalyst, preferably benzyltriethylammonium chloride, benzyltriethylammonium bromide, cetyltribromomethane, in a two-phase system, preferably containing 50% NaOH/toluene, in 1-24 hours. After working up the reaction mixture, the product formed is isolated by recrystallization or silica gel column chromatography.

The starting compounds for preparing the alcohols of the formula V are compounds of the formula I in which R is¹And R²Independently of one another, means a carboxyl group or an ester group (ethoxycarbonyl, methoxycarbonyl), by decarboxylation to give a compound of the formula I, in which R²Means hydrogen, and R¹Meaning an ester group, by reducing the compound to give the alcohol of formula V. Decarboxylation is accomplished by pyrolysis at 250-300 ℃ in the presence of a metal, preferably copper. The reduction is accomplished by using a metal hydride such as lithium aluminum hydride or sodium hydride. Furthermore, the alcohols of the formula V can be prepared by hydrolysis of the corresponding esters (in basic or acidic medium).

The starting compounds of formula VI are known or may be prepared according to published procedures for preparing analogous compounds.

c) Compounds of formula I may be prepared according to the methods of the invention by a compound of formula Va (wherein L is¹Means above with respect to R⁵A defined leaving group) and a compound of formula VIa (wherein Q is₁Meaning oxygen, nitrogen, sulfur or-C.ident.C-). The most suitable condensation reaction is a nucleophilic substitution reaction on saturated carbon atoms as disclosed in the literature.

The starting compound of formula Va (most commonly the halide) can be prepared by reaction with a conventional halogenating agent (e.g., hydrobromic acid, PBr)₃、SOCl₂Or PCl₅) The alcohol of formula V is halogenated (e.g., brominated or chlorinated) using literature published methods. The resulting compounds may be used, with or without isolation, as suitable intermediates for the preparation of compounds of formula I.

The starting compounds of formula VIa are known or may be prepared according to published procedures for preparing analogous compounds.

d) A compound of formula I (wherein Q)₁Meaning that the heteroatom-O-, -NH-or-S-) can be prepared by condensing a compound of formula Vb with a compound of formula VI⁵Meaning a leaving group as defined above. The reaction can be carried out under the reaction conditions disclosed in process b) or under the nucleophilic substitution reaction conditions disclosed in the literature. The starting alcohols, amines and mercaptans can be obtained by reacting water, amines or hydrogen sulphide with compound Va according to literature published methods.

e) The alcohol of structure V may be oxidized to the corresponding compound of formula Vb, wherein Q₁Meaning a carbonyl group, which can further lead to an extended chain and form an alkenyl substituent containing a carbonyl or ester group as disclosed in HR patent application 20000310 by reaction with the corresponding ylide reagent.

In addition to the above reactions, the compounds of formula I may be prepared by conversion of other compounds of formula I. It is to be understood that the invention also includes such compounds and methods. A specific example of a functional group modification is the reaction of an aldehyde group with the selected phosphonium ylide resulting in an extended chain and the formation of an alkenyl substituent containing a carbonyl or ester group as disclosed in HR patent application 20000310. These reactions are carried out in a solvent such as benzene, toluene or hexane at elevated temperatures (most commonly boiling).

The compounds of formula I are obtained by reacting a compound of formula Va with a 1-alkyne in a basic medium (e.g. sodium amide in aqueous ammonia), wherein Q₁is-C.ident.C-. The reaction conditions for this process are disclosed in the literature. Under similar reaction conditions (nucleophilic substitution), different ether, thioether or amine derivatives can be prepared.

Formation of compounds of formula I by such means as Vilsmeier acylation or reaction of n-BuLi with dimethylformyl is another example of a conventional transformation. The reaction conditions for these processes are known in the literature.

Compounds having carboxyl groups can be prepared by hydrolysis of compounds of formula I having nitrile, amide or ester groups, which are suitable intermediates for the preparation of other compounds having novel functional groups, such as esters, amides, halides, aldehydes, alcohols or amines.

The oxidation or reduction reaction may also alter the substituents of the compounds of formula I. The most commonly used oxidizing agents are peroxides (hydrogen peroxide, m-chloroperbenzoic acid or benzoyl peroxide) or permanganate, chromate or perchlorate ions. Thus, for example, aldehyde groups are formed by oxidation of alcohols with pyridine based dichromate or pyridyl chlorochromate, which groups can be converted to carboxyl groups by further oxidation. Wherein R is substituted with a catalytic amount of benzoyl chloride by using lead tetraacetate in acetic acid or with N-bromosuccinimide¹The oxidation of compounds of formula I, meaning alkyl, gives the corresponding carbonyl derivatives.

Alkylsulfinyl or alkylsulfonyl can be prepared by selective oxidation of an alkylthio group.

The amino compound can be prepared by reducing the compound with a nitro group. The reaction is completed under conventional catalytic hydrogenation conditions or electrochemically. The alkenyl substituents can be converted to alkyl ketones or the nitrile groups to aminoalkyl groups by catalytic hydrogenation using palladium on carbon.

Substituents of different aromatic structures can be introduced into the compounds of formula I by standard substitution reactions or by conventional alteration of individual functional groups. Examples of such reactions are aromatic substitution, alkylation, halogenation, hydroxylation and oxidation or reduction of substituents.

The reagents and reaction conditions are known from the literature. Thus, for example, the nitro group is introduced by aromatic substitution in the presence of concentrated nitric acid and sulfuric acid. The acyl or alkyl group may be introduced by using an acyl halide or an alkyl halide. The reaction is carried out in the presence of a Lewis acid such as aluminum trichloride or iron under Friedel-crafts reaction conditions. By reduction of the nitro group to give an amino group, conversion of the amino group to a suitable starting group by diazotisation, which group may be substituted with one of the following groups: H. CN, OH and Hal.

In order to prevent undesired interactions in chemical reactions, it is often necessary to protect certain groups, such as hydroxyl, amino, sulfur or carboxyl groups. For this purpose, a number of protecting Groups [ Green TW, Wuts PGH, Protective Groups in Organic Synthesis, John Wiley and Sons, 1999] can be used, and their selection, use and removal are routine methods in chemical Synthesis.

Conventional protecting groups for amino or alkylamino are groups such as: alkanoyl (acetyl), alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl); arylmethoxycarbonyl (benzyloxycarbonyl), aroyl (benzoyl) or alkylsilyl (trimethylsilyl or trimethylsilylethoxymethyl) groups. The conditions for removing the protecting group depend on the choice and nature of such group. Thus, for example, an acyl group such as an alkanoyl group, an alkoxycarbonyl group or an aroyl group can be removed by hydrolysis in the presence of a base (sodium hydroxide or potassium hydroxide), a tert-butoxycarbonyl group or an alkylsilyl group (trimethylsilyl group) can be removed by treatment with an appropriate acid (hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid), and an arylmethoxycarbonyl group (benzyloxycarbonyl group) can be removed by hydrogenation using a catalyst such as palladium supported on carbon.

Salts of the compounds of formula I can be prepared by known methods, for example by reacting a compound of formula I with the corresponding base or acid in the presence of a suitable solvent or solvent mixture, such as an ether (diethyl ether) or an alcohol (ethanol, propanol or isopropanol).

Another object of the invention relates to the use of the compounds of the invention in the treatment of inflammatory diseases and conditions, such as all diseases and conditions induced by excessive secretion of TNF- α and IL-1.

The inhibitor of the production of cytokines or inflammatory mediators or a pharmacologically acceptable salt thereof, which is the object of the present invention, can be used for the preparation of a medicament for the treatment and prevention of any pathological condition or disease induced by an excessive unregulated production of cytokines or inflammatory mediators, which should contain an effective dose of the inhibitor.

The invention is particularly directed to effective dosages of TNF- α inhibitors, which may be determined by conventional methods.

Furthermore, the present invention relates to a pharmaceutical composition comprising an effective non-toxic dose of a compound of the present invention and a pharmaceutically acceptable carrier or solvent.

The preparation of the pharmaceutical composition may include mixing, granulating, tableting, and dissolving the ingredients. The chemical carrier may be a solid or a liquid. The solid carrier can be lactose, sucrose, talc, gelatin, agar, pectin, magnesium stearate, fatty acids, etc. The liquid carrier may be syrup, oil such as olive oil, sunflower oil or soybean oil, water, etc. Similarly, the carrier may also contain a component for the extended release of the active ingredient, such as glyceryl monostearate or glyceryl distearate. Pharmaceutical formulations in different dosage forms may be used. Thus, if a solid carrier is used, the dosage form may be a tablet, a hard gelatin capsule, a powder or granules which may be administered orally in a capsule. The amount of solid carrier may vary, but is generally from 25mg to 1 g. If a liquid carrier is used, the preparation is in the form of syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as ampule or nonaqueous liquid suspension.

The compounds according to the invention can be administered orally, parenterally, topically, intranasally, intrarectally and intravaginally. The parenteral route here denotes intravenous, intramuscular and subcutaneous application. Suitable formulations of the invention can be used for the prevention and treatment of a variety of diseases and pathological inflammations induced by an over-unregulated production of cytokines or inflammatory mediators, primarily TNF-alpha. They include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other joint conditions and diseases, eczema, psoriatic and other skin inflammations (e.g. burns induced by UV radiation (sun exposure and similar UV light sources)), inflammatory eye diseases, crohn's disease, ulcerative colitis and asthma.

The inhibitory effect of the compounds of the invention on TNF- α and IL-1 secretion was determined by the following in vitro and in vivo experiments.

Determination of TNF-alpha and IL-1 secretion in human peripheral blood mononuclear cells in vitro

Human peripheral blood mononuclear cells (PMBC) are in Ficoll-Paque^TMPMBC were isolated on Plus (Amersham-Pharmacia) and prepared from heparinized whole blood. To determine TNF-. alpha.levels, 3.5-5X 10 were plated on microtiter flat-bottom plates (96-well, Falcon)⁴Cells were cultured in 200. mu.l of PRMI1640 medium for 18 to 24 hours, to which 10% FBS (bovine fetal serum, Biowhittaker), 100 units/ml penicillin, 100mg/ml streptomycin and 20mM HEPES (GIBCO), previously inactivated at 54 ℃/30 minutes, were added. At 37 ℃ in a solution containing 5% CO₂The cells were cultured in an atmosphere of 90% humidity. Negative control cells were cultured in medium (NC) only, while positive control cells were stimulated for TNF-. alpha.secretion by addition of 1ng/ml lipopolysaccharide (LPS, E.coli serotype 0111: B4, SIGMA) (PC). The effect (TS) of test substances on TNF-alpha secretion was investigated after addition of them to cell cultures stimulated with LPS. According to manufacturer (R)&D Systems) by measuring TNF- α levels in cell supernatants by ELISA. The sensitivity of the assay was < 3pg/ml TNF-. alpha.. Under the same conditions. Using the same number of cells and the same concentration of stimulus, by ELISA (R)&D Systems) to determine IL-1 levels. Percent inhibition of TNF- α or IL-1 production was calculated by the following equation:

inhibition [% 1- (TS-NC)/(PC-NC) ] × 100

IC₅₀Is defined as the concentration of the substance that inhibits 50% of the production of TNF-alpha.

IC₅₀Compounds at 20 μ M or less are considered active.

Determination of TNF-alpha and IL-1 secretion by peritoneal macrophages in mice in vitro

To obtain peritoneal macrophages, male Balb/C mice 8 to 12 weeks old were injected intraperitoneally with 300 μ g of a Phosphate Buffered Saline (PBS) of maternal polysaccharide (SIGMA) in a total volume of 0.1 ml/mouse. After 24 hours, mice were euthanized according to Laboratory Animals Welfare Act (Laboratory animal Welfare Act). The abdominal cavity was washed with sterile saline (5 ml). Washing the obtained peritoneal macrophages with sterile saline twice, and finally isolatingAfter hearts (350g/10 min), they were resuspended in RPMI1640 to which 10% FBS fraction was added. To determine TNF-. alpha.secretion, 5X 10 cells were plated on microtiter flat-bottom plates (96-well, Falcon)⁴Cells/well were cultured in a total volume of 200. mu.l RPMI1640 medium for 18 to 24 hours, to which heat-inactivated 10% FBS (bovine fetal serum, Biowhittaker), 100 units/ml penicillin, 100 units/ml streptomycin, 20mM HEPES and 50. mu.M 2-mercaptoethanol (both from GIBCO) were added. At 37 ℃ in a solution containing 5% CO₂The cells were cultured in an atmosphere of 90% humidity. Negative control cells were cultured in medium (NC) only, while the addition of 10ng/ml lipopolysaccharide (LPS, E.coli serotype 0111: B4, SIGMA) (PC) to the positive control stimulated secretion of TNF- α. The effect (TS) of test substances on TNF-alpha secretion was investigated after addition of them to cell cultures stimulated with LPS. By ELISA (R)&DSystems, Biosource) measures TNF-alpha levels in cell supernatants. ELISA method (R) in the same assay as the TNF-. alpha.assay&D Systems) to determine IL-1 levels. Percent inhibition of TNF- α or IL-1 production was calculated by the following equation:

inhibition [% 1- (TS-NC)/(PC-NC) ] × 100

IC₅₀Is defined as the concentration of the substance that inhibits 50% of the production of TNF-alpha.

IC₅₀Compounds at 10 μ M or less are considered active.

In vivo model of LPS-induced mouse TNF-alpha or IL-1 hypersecretion

TNF-. alpha.or IL-1 secretion was induced in mice as described previously (BadgerAM et al, J.Pharmac.Env.Therap., 1996, 279: 1453-one 1461). Male Balb/c mice 8 to 12 weeks old were used for the experiment, 6-10 animals per group. Animals were treated orally with solvent alone (negative and positive controls) or with test solution, 30 minutes later treated intraperitoneally with LPS (E.coli serotype 0111: B4, Sigma) at a dose of 25. mu.g/animal. After 2 hours, the animals were euthanized by intraperitoneal injection of Roumpun (Bayer) and Ketanest (Parke-Davis). Blood samples were collected from each animal in Vacutainer tubes (becton dickinson) and plasma was isolated according to the manufacturer's recommendations. TNF-. alpha.levels in plasma were determined by ELISA (Biosource, R & D Systems) according to the manufacturer's instructions. The sensitivity of the assay was < 3pg/ml TNF-. alpha.. IL-1 levels were determined by ELISA (R & D Systems). Percent inhibition of TNF- α or IL-1 production was calculated by the following equation:

inhibition [% 1- (TS-NC)/(PC-NC) ] × 100

Compounds that inhibited TNF- α production by 30% or more at a dose of 10mg/kg were considered active.

Distortion test for analgesic Activity

In this test, a stimulant, most commonly acetic acid, was injected intraperitoneally into mice to induce pain. Animal reactions are characteristically distorted and therefore the name of the test was obtained (Collier HOJ et al, Pharmac. Chemothers., 1968, 32: 295-; Fukawa K et al, J. Pharmacol. meth., 1980, 4: 251-; 259; Schweizer A et al, AgentsActions, 1988, 23: 29-31). This assay is suitable for determining the analgesic activity of a compound. The method comprises the following steps: male Balb/c mice (Charles River, Italy) 8 to 12 weeks old were used. Methylcellulose was orally administered to the control group, acetic acid was administered at a concentration of 0.6% in the peritoneal membrane 30 minutes later, and a methylcellulose solution of the standard substance (acetylsalicylic acid) or the test substance was orally administered to the test group. After 30 minutes 0.6% acetic acid (volume 0.1ml/10g) was administered intraperitoneally. Mice were placed individually under a glass funnel and the number of twists recorded for each animal over 20 minutes. Percent inhibition of distortion was calculated according to the following equation:

inhibition%

Compounds with analgesic activity equal to or better than that of acetylsalicylic acid are considered active.

In vivo model of LPS induced mouse shock

Male Balb/C mice (Charles River, Italy) 8 to 12 weeks old were used. LPS (Sigma, L-6136) isolated from Serratia marcescens (Serratie marcescens) was diluted in sterile saline. The first LPS injection was given intradermally at a dose of 4. mu.g/mouse. After 18 to 24 hours, LPS was administered intravenously at a dose of 200. mu.g/mouse. Two LPS injections were given to the control group in the manner described above. The test subjects were administered orally half an hour prior to each LPS administration. Survival after 24 hours was observed.

Compounds that resulted in 40% or better survival at a dose of 30mg/kg were considered active.

The compound of example 14 demonstrated activity in at least two studies. However, these results are merely illustrative of the biological activity of the compounds and in no way limit the invention.

Preparation method and examples

The invention is illustrated by the following examples, which are not intended to limit the invention in any way.

Example 1

8-oxa-2-thia-dibenzo [ e, h ] azulene-1, 3-dicarboxylic acid monoethyl ester (1)

Dibenzo [ b, f ] in tert-butanol]Oxepine (oxepin) -10, 11-dione (III; X ═ O, Y ═ Z ═ H) (0.004mole) and thioether (IV; R)⁵Et) (0.008mole) was added to a potassium butoxide solution (0.013mole) in 5ml of tert-butanol (10ml) and heated to 60 ℃. After stirring for 30 minutes at 60 ℃ the reaction mixture was cooled and acidified with 5M aqueous HCl (10ml) and most of the solvent was evaporated at a temperature of 30 ℃ and a pressure of 30 hPa. Ether (20ml) was added to the residue, followed by 2M NH₄OH (10ml) extract solution. The combined extracts were acidified with dilute HCl to the acid reactant and the dicarboxylate was obtained in the form of brown crystals.

Example 2

5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene-1, 3-dicarboxylic acid 1-methyl ester (2)

5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene-1, 3-dicarboxylic acid 3-methyl ester (3)

The method according to example 1, starting from 2-chloro-dibenzo [ b, f]Oxacycloheptene-10, 11-diones (III; X ═ O, Y ═ 2-Cl, Z ═ H) and thioethers (IV; R)⁵Me) to give a mixture of dicarboxylic acid esters as a brown oil.

Example 3

2, 8-Dithia-dibenzo [ e, h ] azulene-1, 3-dicarboxylic acid monoethyl ester (4)

Starting from dibenzo [ b, f ] thiacycloheptene (tiepin) -10, 11-dione (III; X ═ S, Y ═ Z ═ H) and thioether (IV; R ═ Et), the dicarboxylate is obtained in the form of brown crystals according to the process of example 1.

Example 4

8-oxa-2-thia-dibenzo [ e, h ] azulene-1-carboxylic acid ethyl ester (5)

8-oxa-2-thia-dibenzo [ e, h ] azulene (9)

A homogeneous mixture of dicarboxylate 1(200mg) and copper (150mg) was heated at 30 ℃ for 2 hours. After cooling the reaction mixture, diethyl ether was added thereto and the insoluble copper oxide was filtered off. The filtrate was evaporated under reduced pressure and the product mixture was separated by column chromatography. Isolating compounds 5 and 9 in crystalline form.

Example 5

5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene-1-carboxylic acid methyl ester (6)

11-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene-1-carboxylic acid methyl ester (7)

5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene (10)

Starting from a mixture of dicarboxylates 2 and 3 according to the procedure of example 4, a mixture of two monocarboxylic esters, 6 and 7, of compound 10 is obtained. Compound 10 is isolated from the monocarboxylic acid ester mixture by column chromatography. Separation of carboxylic acidsEsters 6 and 7, and two close peaks by GC-MS, and m/z 314 (MH)⁺)。

Example 6

2, 8-Dithia-dibenzo [ e, h ] azulene-1-carboxylic acid ethyl ester (8)

2, 8-dithia-dibenzo [ e, h ] azulenes (11)

Compounds 8 and 11 were prepared according to the procedure of example 4, starting from dicarboxylate 4. The mixture of compounds was separated by column chromatography to give the product in two crystalline forms.

Example 7

1, 3-dibromo-2, 8-dithia-dibenzo [ e, h ] azulene (12)

To a solution of compound 11 in dichloromethane (0.38mmole in 2ml dichloromethane) cooled to 0 ℃ was added dropwise bromine (100 μ l). The reaction mixture was stirred at the same temperature for an additional 45 minutes. By adding 10% Na₂S₂O₃An aqueous solution (10ml) was used to react excess bromine. The product was extracted with dichloromethane, the solvent was evaporated under reduced pressure and purified by column chromatography to give the dibromo derivative in the form of white crystals.

Example 8

(8-oxa-2-thia-dibenzo [ e, h ] azulen-1-yl) -methanol (13)

To LiALH in anhydrous ether (10mmoles in 15ml of anhydrous ether)₄The suspension of ester 5(2mmoles in 15ml of anhydrous ether) is added dropwise to an ethereal solution. The reaction mixture was stirred at room temperature for 4 hours. After the entire amount of ester had reacted (the course of the reaction was followed by thin layer chromatography), the excess LiAIH was decomposed by addition of diethyl ether and water₄. The resulting white precipitate was filtered off and washed with anhydrous Na₂SO₄After drying the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography to give the pure product as yellow crystals.

Example 9

(5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-yl) -methanol (14)

(11-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-yl) -methanol (15)

The mixture of the title compounds was prepared according to the procedure for example 8 starting from a mixture of esters 6 and 7 and the mixture was separated by column chromatography to give the pure material in the form of yellow crystals.

Example 10

(2, 8-dithia-dibenzo [ e, h ] azulen-1-yl) -methanol (16)

According to the procedure of example 8, the alcohol is prepared in the form of brown crystals starting from the corresponding ester 8.

TABLE 1

Compound (I)	X	Y	Z	R1	R2	1H NMR(ppm)
							1	O	H	H	CO2H	CO2Et	1.33(t，3H)；4.32(m，2H)；7.14-7.19(m，2H)；7.31-7.42(m，7.54-7.64(m，

						2H)(CDCl3)
							2	O	5-Cl	H	CO2H	CO2Me
3	O	H	11-Cl	CO2H	CO2Me
							4	S	H	H	CO2H	CO2Et	1.15(t，3H)；4.22(m，2H)；7.29-7.40(m，4H)；7.54-7.58(m，7.63-7.66(m，2H)；13.5(bs，1H)(DMSO-d6)
5	O	H	H	H	CO2Et	1.32(t，3H)；4.33(m，2H)；7.17-7.67(m，9H)(CDCl3)
							6	O	5-Cl	H	H	CO2Me
7	O	H	11-Cl	H	CO2Me
							8	S	H	H	H	CO2Et	1.25(t，3H)；4.26(m，2H)；7.24-7.35(m，4H)；7.50-7.54(m，2H)；7.58(s，1H)；7.62-7.67(m，2H)(CDCl3)
9	O	H	H	H	H	7.24-7.30(m，2H)；7.37-7.41(m，4H)；7.66-7.69(m，2H)；7.97(s，2H)(DMSO-d6)
							10	O	5-Cl	H	H	H	7.19-7.58(m，9H)(CDCl3)
11	S	H	H	H	H	7.25-7.37(m，4H)；7.49(s，2H)；7.53-7.57(m，2H)；7.64-7.68(m，2H)(CDCl3)
							12	S	H	H	Br	Br	7.28-7.40(m，4H)；7.61-7.68(m，4H)(CDCl3)
13	O	H	H	H	CHOH	1.76(bs，1H)；4.97(bd，2H)；7.17-7.38(m，6H)；7.46(s，1H)；7.54-7.60(m，2H)(CDCl3)
							14	O	5-Cl	H	H	CH2OH	4.88(bs，1H)；4.93(s，2H)；7.27-7.43(m，5H)；7.67-7.70(m，2H)；7.80(s，1H)(CD3COCD3)
15	O	H	11-Cl	H	CH2OH	4.93(bs，3H)；7.23-7.29(m，1H)；7.36-7.46(m，4H)；7.65-7.68(m，1H)；7.73(s，1H)；7.82(d，1H)(CD3COCD3)
							16	S	H	H	H	CHOH	1.84(bs，1H)；4.13(m，2H)；7.23-7.38(m，4H)；7.40(s，1H)；7.48-7.50(m，2H)；7.62-7.72(m，2H)(CDCl3)

Example 11

a) Dimethyl- [3- (8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propyl ] -amine

To a solution of 3-dimethylaminopropyl chloride-hydrochloride (2.5mmoles) in 50% sodium hydroxide (3ml) was added a solution of benzyltriethylammonium chloride (0.3mmole) and alcohol 13(0.25mmole) in toluene. The reaction mixture was heated under vigorous stirring and refluxed for 4 hours. It was then cooled to room temperature, diluted with water and extracted with dichloromethane. Purification by column chromatography gave an oil product.

¹H NMR(ppm，CDCl₃)：2.08(m，2H)；2.58(s，6H)；2.84(m，2H)；3.69(m，2H)；4.75(bd，2H)；7.16-7.36(m，6H)，7.46(s，1H)；7.47-7.56(m，2H)。

b) Dimethyl- [2- (8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -ethyl ] -amine

Starting from alcohol 13(0.25mmole) and 2-dimethylaminoethyl chloride-hydrochloride (2.5mmoles), an oil product was obtained.

¹H NMR(ppm，CDCl₃)：2.52(s，6H)；2.86(bs，2H)；3.85(bs，2H)；4.80(bd，2H)；7.16-7.36(m，6H)；7.46(s，1H)；7.49-7.56(m，2H)。

c)3- (8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propylamine

Starting from alcohol 13(0.25mmole) and 3-chloropropylamine-hydrochloride (2.5mmoles), an oil product is obtained.

¹H NMR(ppm，CDCl₃)：1.99(m，2H)；3.05(t，2H)；3.70(bs，2H)；4.3-4.5(b，2H)；4.72(bs，2H)；7.15-7.60(m，9H)。

Example 12

a)3- (5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propylamine

To a solution of 3-chloropropylamine-hydrochloride (2.2mmoles) in 50% sodium hydroxide (3ml) was added a solution of benzyltriethylammonium chloride (0.3mmole) and alcohol 14(0.22mmole) in toluene. The reaction mixture was heated under vigorous stirring and refluxed for 5 hours. It was then cooled to room temperature, diluted with water and extracted with dichloromethane. Purification by column chromatography gave an oil product.

MS(m/z)：372(MH⁺)。

b) [2- (5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -ethyl ] -dimethyl-amine

Starting from alcohol 14(0.29 mmoles) and 2-dimethylaminoethyl chloride-hydrochloride (2.9mmoles), an oil product was obtained.

MS(m/z)：386(MH⁺)。

c) [3- (5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propyl ] -dimethyl-amine

Starting from alcohol 14(0.22mmole) and 3-dimethylaminopropyl chloride-hydrochloride (2.2mmoles), an oil product was obtained.

MS(m/z)：400(MH⁺)；

Example 13

a) [2- (11-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -ethyl ] -dimethyl-amine

To a solution of 2-dimethylaminoethyl chloride-hydrochloride (1.8mmoles) in 50% sodium hydroxide (3ml) was added a solution of benzyltriethylammonium chloride (0.3mmole) and alcohol 15(0.18mmole) in toluene. The reaction mixture was heated under vigorous stirring and refluxed for 5 hours. It was then cooled to room temperature, diluted with water and extracted with dichloromethane. Purification by column chromatography gave an oil product.

MS(m/z)：386(MH⁺)。

b)3- (11-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propylamine

Starting from alcohol 15(0.18mmole) and 3-chloropropylamine-hydrochloride (1.8mmoles), an oil product is obtained.

¹H NMR(ppm，CD₃COCD₃)：1.82(s，2H)；1.97(t，2H)；3.36(t，2H)；3.76(bs，2H)；4.74(s，2H)；7.26-7.82(m，8H)；

MS(m/z)：372(MH⁺)。

Example 14

a) [3- (2, 8-dithia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propyl ] -dimethyl-amine

To a solution of 3-dimethylaminopropyl chloride-hydrochloride (6.7mmoles) in 50% sodium hydroxide (5ml) was added a solution of benzyltriethylammonium chloride (0.88mmole) and alcohol 16(0.67mmole) in toluene. The reaction mixture was heated under vigorous stirring and refluxed for 5 hours. It was then cooled to room temperature, diluted with water and extracted with dichloromethane. Purification by column chromatography gave an oil product.

¹H NMR(ppm，CDCl₃)：2.04(p，2H)；2.57(s，6H)；2.82(bs，2H)；3.61(m，2H)；4.67(m，2H)；7.27-7.71(m，8H)；7.40(s，1H)。

b) [2- (2, 8-dithia-dibenzo [ e, h ] azulen-1-ylmethoxy) -ethyl ] -dimethyl-amine

Starting from alcohol 16(0.67mmole) and 2-dimethylaminoethyl chloride-hydrochloride (6.7mmoles), an oil product is obtained;

¹H NMR(ppm，CDCl₃)：2.49(s，6H)；2.86(bs，2H)；3.78(m，2H)；4.72(m，2H)；7.23-7.70(m，8H)；7.40(s，1H)。

c)3- (2, 8-dithia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propylamine

Starting from alcohol 16(0.27mmole) and 3-chloropropylamine-hydrochloride (2.7mmoles), an oil product is obtained.

MS(m/z)：354(MH⁺)。

Example 15

2, 8-dithia-dibenzo [ e, h ] azulene-1-carbaldehyde

To a solution of alcohol 16(3.0mmoles in 40 ml) in dichloromethane was added bipyridine-chromium- (VI) -oxide (pyridine based dichromate, PDC, 0.006 mole). The reaction mixture was stirred at room temperature for 18 hours. Diethyl ether (50ml) was added to the reaction mixture, and the thus-diluted reaction mixture was purified by means of a Florisil column to obtain a yellow crystalline product.

¹H NMR(ppm，CDCl₃)：7.29-7.45(m，5H)；7.53-7.56(m，1H)；7.65-7.68(m，1H)；7.72-7.75(m，1H)；7.81(d，1H)；9.84(s，1H)。

Claims (14)

1. A compound of formula I and pharmacologically acceptable salts and solvates thereof:

it is characterized in that

X may be CH₂Or heteroatoms such as O, S, S (═ O), S (═ O)₂Or NR^aWherein R is^aIs hydrogen or a protecting group;

y and Z independently of one another represent one or more of the same or differentAnd may be halogen, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, trifluoromethyl, halo C₁-C₄Alkyl, hydroxy, C₁-C₄Alkoxy, trifluoromethoxy, C₁-C₄Alkanoyl, amino-C₁-C₄Alkyl radical, C₁-C₄Alkylamino, N- (C)₁-C₄Alkyl) amino, N-di (C)₁-C₄Alkyl) amino, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, carboxy, C₁-C₄Alkoxycarbonyl, cyano, nitro;

R¹can be hydrogen, halogen, optionally substituted C₁-C₇Alkyl or C₂-C₇Alkenyl radical, C₂-C₇Alkynyl, optionally substituted aryl or heteroaryl and heterocycle, hydroxy-C₂-C₇Alkenyl, hydroxy-C₂-C₇Alkynyl, C₁-C₇Alkoxy, thiol, thio C₂-C₇Alkenyl, thio C₂-C₇Alkynyl, C₁-C₇Alkylthio, amino, N- (C)₁-C₇Alkyl) amino, N-di (C)₁-C₇Alkyl) amino, C₁-C₇Alkylamino, amino-C₂-C₇Alkenyl, amino-C₂-C₇Alkynyl, amino-C₁-C₇Alkoxy radical, C₁-C₇Alkanoyl, aroyl, oxo C₁-C₇Alkyl radical, C₁-C₇Alkanoyloxy, carboxy, optionally substituted C₁-C₇Alkoxycarbonyl or aryloxycarbonyl, carbamoyl, N- (C)₁-C₇Alkyl) carbamoyl, N-di (C)₁-C₇-alkyl) carbamoyl, cyano-C₁-C₇Alkyl, sulfonyl, C₁-C₇Alkylsulfonyl radicals, alkyleneSulfonyl radical, C₁-C₇Alkylsulfinyl, nitro or a substituent of formula II:

wherein

R³And R⁴Simultaneously or independently of one another, hydrogen, C₁-C₄Alkyl, aryl or together with N means an optionally substituted heterocycle or heteroaryl;

m and n represent an integer of 0 to 3;

Q₁and Q₂Represents, independently of one another, oxygen, sulfur or a group:

wherein the substituents are

y₁And y₂May be independently of one another hydrogen, halogen, optionally substituted C₁-C₄Alkyl or aryl, hydroxy, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, cyano, nitro or together form a carbonyl or imino group;

R²may be hydrogen, carboxyl or alkoxycarbonyl.

2. A compound according to claim 1, characterized in that X represents S or O.

3. A compound according to claim 2, characterized in that Y and/or Z represent H or Cl.

4. Compounds and salts according to claim 3, characterized in that R¹And/or R²Represents H, Br, COOH, COOMe, COOEt.

5. A compound according to claim 3, characterized in that R¹Represents H, and R²Represents COOMe, COOEt, CHO, CH₂OH。

6. Compounds and salts according to claim 3, characterized in that R¹Represents H, and R²Has the meaning of formula II.

7. Compounds and salts according to claim 6, characterized in that m means 1, the symbol n means 1 or 2, Q₁Represents O, and Q₂Represents CH₂。

8. Compounds and salts according to claim 7, characterized in that R³And R⁴Represents H or Me.

9. A compound selected according to claim 4:

8-oxa-2-thia-dibenzo [ e, h ] azulene;

2, 8-dithia-dibenzo [ e, h ] azulene;

5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene;

1, 3-dibromo-2, 8-dithia-dibenzo [ e, h ] azulene;

8-oxa-2-thia-dibenzo [ e, h ] azulene-1, 3-dicarboxylic acid monoethyl ester;

1-methyl 5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene-1, 3-dicarboxylate;

5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene-1, 3-dicarboxylic acid 3-methyl ester;

2, 8-dithia-dibenzo [ e, h ] azulene-1, 3-dicarboxylic acid monoethyl ester.

10. A compound selected according to claim 5:

8-oxa-2-thia-dibenzo [ e, h ] azulene-1-carboxylic acid ethyl ester;

5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene-1-carboxylic acid methyl ester;

11-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulene-1-carboxylic acid methyl ester;

2, 8-dithia-dibenzo [ e, h ] azulene-1-carboxylic acid ethyl ester;

2, 8-dithia-dibenzo [ e, h ] azulene-1-carbaldehyde;

(8-oxa-2-thia-dibenzo [ e, h ] azulen-1-yl) -methanol;

(5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-yl) -methanol;

(11-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-yl) -methanol;

(2, 8-dithia-dibenzo [ e, h ] azulen-1-yl) -methanol.

11. A compound selected according to claim 8:

dimethyl- [3- (8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propyl ] -amine;

dimethyl- [2- (8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -ethyl ] -amine;

3- (8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propylamine;

3- (5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propylamine;

[2- (5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -ethyl ] -dimethyl-amine;

[3- (5-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propyl ] -dimethyl-amine;

[2- (11-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -ethyl ] -dimethyl-amine;

3- (11-chloro-8-oxa-2-thia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propylamine;

[3- (2, 8-dithia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propyl ] -dimethyl-amine;

[2- (2, 8-dithia-dibenzo [ e, h ] azulen-1-ylmethoxy) -ethyl ] -dimethyl-amine;

3- (2, 8-dithia-dibenzo [ e, h ] azulen-1-ylmethoxy) -propylamine.

12. A process for the preparation of a compound of formula I:

wherein

X may be CH₂Or heteroatoms such as O, S, S (═ O), S (═ O)₂Or NR^aWherein R is^aIs hydrogen or a protecting group;

y and Z independently of one another represent one or more identical or different substituents attached to any available carbon atom and may be halogen, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, trifluoromethyl, halo C₁-C₄Alkyl, hydroxy, C₁-C₄Alkoxy, trifluoromethoxy, C₁-C₄Alkanoyl, amino-C₁-C₄Alkyl radical, C₁-C₄Alkylamino, N- (C)₁-C₄Alkyl) amino, N-di (C)₁-C₄Alkyl) amino, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, carboxy, C₁-C₄Alkoxycarbonyl, cyano, nitro;

R¹can be hydrogen, halogen, optionally substituted C₁-C₇Alkyl or C₂-C₇Alkenyl radical, C₂-C₇Alkynyl, optionally substituted aryl or heteroaryl and heterocycle, hydroxy-C₂-C₇Alkenyl, hydroxy-C₂-C₇Alkynyl, C₁-C₇Alkoxy, thiol, thio C₂-C₇Alkenyl, thio C₂-C₇Alkynyl, C₁-C₇Alkylthio, amino, N- (C)₁-C₇Alkyl) amino, N-di (C)₁-C₇Alkyl) amino, C₁-C₇Alkylamino, amino-C₂-C₇Alkenyl, amino-C₂-C₇Alkynyl, amino-C₁-C₇Alkoxy radical, C₁-C₇Alkanoyl, aroyl, oxo C₁-C₇Alkyl radical, C₁-C₇Alkanoyloxy, carboxy, optionally substituted C₁-C₇Alkoxycarbonyl or aryloxycarbonyl, carbamoyl, N- (C)₁-C₇Alkyl) carbamoyl, N-di (C)₁-C₇-alkyl) carbamoyl, cyano-C₁-C₇Alkyl, sulfonyl, C₁-C₇Alkylsulfonyl, sulfinyl, C₁-C₇Alkylsulfinyl, nitro or a substituent of formula II:

wherein

R³And R⁴Simultaneously or independently of one another, hydrogen, C₁-C₄Alkyl, aryl or together with N means an optionally substituted heterocycle or heteroaryl;

m and n represent an integer of 0 to 3;

Q₁and Q₂Represents, independently of one another, oxygen, sulfur or a group:

wherein the substituents are

y₁And y₂May be independently of one another hydrogen, halogen, optionally substituted C₁-C₄Alkyl or aryl, hydroxy, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl, thiol, C₁-C₄Alkylthio, sulfonyl, C₁-C₄Alkylsulfonyl, sulfinyl, C₁-C₄Alkylsulfinyl, cyano, nitro or together form a carbonyl or imino group;

R²may be hydrogen, carboxyl or alkoxycarbonyl,

the preparation method is characterized by comprising the following steps:

a) for compounds of formula I, wherein R¹And R²Independently of one another, represents carboxy, C₁-C₆Alkoxycarbonyl, aryloxycarbonyl or arylalkoxycarbonyl,

cyclizing an alpha-diketone of the formula III with a compound of the formula IV

b) For compounds of formula I, wherein Q₁meaning-O-, with the alcohol of formula V

With compounds of the formula VI

Wherein R is⁵Meaning a leaving group;

c) for compounds of formula I, wherein Q₁meaning-O-, -NH-, -S-or-C.ident.C-, reacting a compound of formula Va with a compound of formula VIa

Wherein L is¹Meaning a leaving group

d) For compounds of formula I, wherein Q₁means-O-, -NH-or-S-, such that the compound of formula Vb

With a compound of the formula VI, wherein R⁵Meaning a leaving group;

e) for compounds of formula I, wherein Q₁meaning-C ═ C-, where Q is₁Meaning that the compound of formula Vb of the carbonyl group is reacted with a phosphonium ylide.

13. Use of compounds of formula I according to claims 4 and 5 as intermediates for the preparation of novel 2-thia-dibenzoazulenes having anti-inflammatory action.

14. The use of compounds of formula I according to claim 6 as inhibitors of the production of cytokines or inflammatory mediators for the treatment and prevention of any pathological condition or disease induced by an excessive unregulated production of cytokines or inflammatory mediators by oral, parenteral or topical administration of a non-toxic dose of a suitable pharmaceutical formulation.