HK1119164A

HK1119164A - Azole derivatives in the form of lipase and phospholipase inhibitors

Info

Publication number: HK1119164A
Application number: HK08110619.2A
Authority: HK
Inventors: Gerhard Zoller; Stefan Petry; Günter Müller; Hubert Heuer; Norbert Tennagels
Original assignee: Sanofi-Aventis
Priority date: 2005-04-20
Filing date: 2006-04-13
Publication date: 2009-02-27

Description

pyrrole derivatives in the form of lipase and phospholipase inhibitors

the invention relates to pyrrole derivatives of general formula (I), their pharmaceutically acceptable salts and their use as pharmaceutical substances.

WO2003/0051842A2 describes compounds useful for inhibiting hormone sensitive lipase. These compounds include benzisoxazole derivatives and benzisothiazole derivatives. Benzisoxazole derivatives useful for inhibiting glycogen synthase kinase 3 are described in WO 2004/058749.

It is an object of the present invention to provide alternative compounds which have an inhibitory effect on hormone sensitive lipase or endothelial lipase.

The invention relates to pyrrole derivatives of general formula I

Wherein the meanings are as follows:

a is S, O;

w is- (C ═ O) -, - (S ═ O) -, - (SO)₂)-；

X is, identically or differently, ═ C (-R) -or ═ N-;

y is-O-or-NR 1-;

r is hydrogen, halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃) -alkoxy- (C)₁-C₃) Alkylene, hydroxy, (C)₁-C₆) Alkylthio, amino, (C)₁-C₆) Alkylamino, di- (C)₂-C₁₂) Alkylamino, mono- (C)₁-C₆) -alkylaminocarbonyl, di- (C)₂-C₈) -alkylaminocarbonyl, COOR4, trifluoromethyl, (C)₁-C₆) -alkylsulfonyl, (C)₁-C₆) -alkylsulfinyl, aminosulfonyl, nitro, pentafluorothio, (C)₆-C₁₀) Aryl, CO-NR2R3, O-CO-NR2R3, O-CO- (C)₁-C₆) alkylene-CO-O- (C)₁-C₆) Alkyl, O-CO- (C)₁-C₆) alkylene-CO-OH, O-CO- (C)₁-C₆) alkylene-CO-NR 2R3 or unsubstituted or mono-or poly-F-substituted (C)₁-C₆) -an alkoxy group;

r1 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

r2 is (C)₅-C₁₆) Alkyl radicals, (C)₁-C₄) -alkyl- (C)₆-C₁₀) -aryl, wherein aryl may be optionally substituted one or more times by: halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃) -alkoxy, hydroxy, (C)₁-C₆) Alkylthio, amino, (C)₁-C₆) Alkylamino, di- (C)₂-C₁₂) Alkylamino, mono- (C)₁-C₆) -alkylaminocarbonyl, di- (C)₂-C₈) -alkylaminocarbonyl, (C)₁-C₆) Alkoxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, (C)₁-C₆) -alkylsulfonyl, aminosulfonyl, nitro;

r3 is hydrogen, (C)₁-C₆) -an alkyl group; or

R2 and R3 together with the nitrogen atom which carries them may form a monocyclic, saturated or partially unsaturated 4-to 7-membered or bicyclic, saturated or partially unsaturated 8-to 14-membered ring system, each member of which may be substituted by 1 to 3 substituents selected from-CHR 5-, -CR5R5-, - (C ═ R5) -, -NR5-, -C (═ O) -, -O-, -S-, -SO ═ O ═ R5-₂-is replaced by an atom or group provided that two are selected from-O-, -S-, -SO₂-the units may not be contiguous;

r4 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

r5 is (C)₁-C₆) -alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene;

tautomeric forms of the compounds and their physiologically tolerated salts.

Preferred compounds of formula I are those wherein W is- (C ═ O) -.

Further preferred compounds of the formula I are those in which the radicals have the following meanings:

w is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-O-, -NR 1-;

r is hydrogen, halogen, (C)₁-C₆) Alkyl, hydroxy, ammoniaGroup, COOR4, trifluoromethyl group, (C)₁-C₆) Alkylsulfonyl, nitro, pentafluorothio, (C)₆-C₁₀) Aryl, CO-NR2R3, O-CO-NR2R3 or O-CO- (C)₁-C₆) alkylene-CO-O- (C)₁-C₆) -an alkyl group;

r1 is hydrogen, (C)₁-C₆) -an alkyl group;

r2 is (C)₆-C₁₀) Alkyl radicals, (C)₁-C₃) -alkyl- (C)₆-C₁₀) -aryl, wherein aryl may be optionally substituted one or more times by: halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃) -alkoxy, hydroxy, amino, (C)₁-C₆) -alkylamino, trifluoromethyl, nitro;

r3 is hydrogen, (C)₁-C₆) -an alkyl group; or

R2 and R3 together with the nitrogen atom which carries them may form a monocyclic saturated 5-to 6-membered ring system or a bicyclic saturated or partially unsaturated 9-to 10-membered ring system, each member of which may be replaced by 1 to 3 atoms or groups selected from-CHR 5-, -CR5R5-, - (C ═ R5) -, -NR5-, -O-, -S-, with the proviso that two units selected from-O-, -S-may not be adjacent;

r4 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

r5 is (C)₁-C₆) -alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene.

Preferred compounds of the formula I are also those in which the radicals have the following meanings:

w is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-O-, -NR 1-;

r is hydrogen, halogen, (C)₁-C₆) -alkyl, hydroxy, amino, COOR4. Trifluoromethyl, (C)₁-C₆) Alkylsulfonyl, nitro, pentafluorothio, (C)₆-C₁₀) Aryl, CO-NR2R3, O-CO-NR2R3 or O-CO- (C)₁-C₆) alkylene-CO-O- (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -an alkoxy group;

r1 is hydrogen, (C)₁-C₆) -an alkyl group;

r3 is hydrogen, (C)₁-C₆) -an alkyl group; or

r4 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

Particularly preferred compounds of the formula I are those in which the radicals have the following meanings:

w is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-O-;

r is hydrogen, halogen, nitro, hydroxy or (C)₁-C₆) -an alkyl group;

r2 is (C)₆-C₁₀) -alkyl or benzyl, wherein benzyl may optionally be substituted by halogen, (C)₁-C₆) -alkyl or trifluoromethyl substitution;

r3 is hydrogen, (C)₁-C₆) -an alkyl group; or

R2 and R3 together with the nitrogen atom which carries them may form a monocyclic saturated 5-to 6-membered ring system, each member of which may be replaced by 1-2 atoms or groups selected from-CHR 5-, -NR 5-; and is

R5 is (C)₁-C₆) -alkyl or cyclopropyl.

Further particularly preferred embodiments are compounds of the formula I in which the radicals have the following meanings:

w is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-O-;

r is hydrogen, halogen, nitro, hydroxy, (C)₁-C₃) -alkoxy or (C)₁-C₆) -an alkyl group;

r3 is hydrogen; or

R5 is (C)₁-C₆) -alkyl, trifluoromethyl or cyclopropyl.

Another particularly preferred embodiment are compounds of the formula I in which the radicals have the following meanings:

w is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-NR 1-;

r is hydrogen, halogen, nitro, hydroxy or (C)₁-C₆) -an alkyl group;

r1 is hydrogen, (C)₁-C₆) -an alkyl group;

r3 is hydrogen, (C)₁-C₆) -an alkyl group; or

R5 is (C)₁-C₆) -alkyl or cyclopropyl.

w is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-NR 1-;

r1 is hydrogen, (C)₁-C₆) -an alkyl group;

r3 is hydrogen; or

R5 is (C)₁-C₆) -alkyl, trifluoromethyl or cyclopropyl.

In one embodiment of the invention, a in the compounds of the formula I has the meaning O.

In another embodiment of the invention, a in the compounds of the formula I has the meaning S.

In another embodiment of the invention, Y in the compounds of the formula I has the meaning O.

In another embodiment of the invention, Y in the compounds of the formula I has the meaning NR1, where R1 may have the above-mentioned meaning.

Very particularly preferred compounds of the formula I are those in which the radicals have the following meanings: NR2R3 is a piperidine containing the atom member CHR5 at the 4-position.

x is, identically or differently, ═ C (-R) -.

x is, identically or differently, ═ C (-R) -or ═ N-, with the proviso that only one X is ═ N-.

x is, identically or differently, ═ C (-R) -, in the 4, 5 and 6 positions, and ═ N-in the 7 position.

x is ═ C (-R) -, where R is hydrogen, at the 4, 5 and 7 positions, and R is not hydrogen at the 6 position.

x is ═ C (-R) -, where R is hydrogen, at the 4 and 5 positions, and R is not hydrogen at the 6 position.

The present invention relates to compounds of formula I in the form of salts, racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.

The alkyl groups in the substituents R, R1, R2, R3, R4, R5 may be linear or branched. Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

Aryl means an aromatic carbocyclic mono-or bicyclic ring system comprising 6 to 10 atoms in the ring.

Heteroaryl is a mono-or bicyclic aromatic ring system having 5 to 12 ring members, wherein at least one atom in the ring system is a heteroatom selected from N, O and S.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications because of their higher water solubility than the starting or base compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and salts of organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable base salts are ammonium, alkali metal (e.g. sodium and potassium) and alkaline earth metal (e.g. magnesium and calcium) salts and salts of tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with non-pharmaceutically acceptable anions such as trifluoroacetate are likewise encompassed by the scope of the present invention, as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, e.g. in vitro, applications.

The term "physiologically functional derivative" as used herein refers to any physiologically tolerated derivative of a compound of formula I according to the invention, for example an ester, which on administration to a mammal such as a human is capable of (directly or indirectly) generating a compound of formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of the compounds of the invention, for example as described in h.okada et al, chem.pharm.bull.1994, 42, 57-61. Such prodrugs can be metabolized in vivo to the compounds of the invention. These prodrugs may themselves be active or inactive.

The compounds of the present invention may also exist in various polymorphic forms, for example in amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are covered by the scope of the invention and are a further aspect of the invention.

All references hereinafter to "compounds of formula I" refer to the compounds of formula I as described above, as well as their salts, solvates and physiologically functional derivatives as described herein.

Use of

The compounds of formula I according to the invention have a surprising inhibitory effect on the Hormone Sensitive Lipase (HSL), an allosteric enzyme, in adipocytes which are inhibited by insulin, responsible for the destruction of fat in adipocytes and thus for the transfer of fat constituents into the bloodstream. Thus, inhibition of this enzyme equates to an insulin-like action of the compounds of the invention, which ultimately results in a reduction of free fatty acids in the blood and blood glucose. They are therefore useful in metabolic disorders such as non-insulin dependent diabetes mellitus, diabetic syndrome and direct pancreatic damage.

The compounds of formula I of the present invention may also have an inhibitory effect on Endothelial Lipase (EL). For EL, the preferred substrate is HDL, which has anti-atherosclerotic activity. The reduction of HDL levels leads to the progression of atherosclerosis and its sequelae such as metabolic syndrome and coronary heart disease. Inhibition of EL should therefore lead to the prevention of atherosclerotic disorders.

The compounds of formula I of the present invention may also have an inhibitory effect on triglyceride lipase.

It has also been found that the inhibition by the compounds of formula I according to the invention is selective with respect to other lipases.

The compounds are particularly suitable for the treatment and/or prophylaxis

1. Disorders of fatty acid metabolism and glucose utilization

2. Insulin selective disorder (insulin resistance) -metabolic syndrome of muscle cells, adipocytes and liver cells.

3. Diabetes, particularly type 2 diabetes, includes the prevention of its associated sequelae.

In this case, the specific aspects are

-a high blood sugar level,

-an improvement in insulin resistance, and,

-an improvement in glucose tolerance,

protection of pancreatic beta cells

Prevention of macrovascular and microvascular disorders

4. Dyslipidemia and its sequelae such as atherosclerosis, coronary heart disease, cerebrovascular disorders, and the like, particularly (but not limited to) those characterized by one or more of the following factors:

-high plasma triglyceride concentration, high postprandial plasma triglyceride concentration,

low HDL cholesterol concentration

Low ApoA lipoprotein concentration

High LDL cholesterol concentration

Low density LDL cholesterol particles

High ApoB lipoprotein concentration

5. Various other conditions that may be associated with metabolic syndrome, such as:

obesity (overweight), including central obesity

Thrombosis, hypercoagulability and prothrombotic stages (arteries and veins)

-hypertension

Heart failure, such as (but not limited to) myocardial infarction, hypertensive heart disease or heart failure after cardiomyopathy

6. Among other disorders or conditions that may, for example, involve inflammatory responses or cell differentiation are:

atherosclerosis, such as (but not limited to) coronary arteriosclerosis, including angina pectoris or myocardial infarction, stroke

Restenosis or reocclusion of blood vessels

Chronic inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis

-pancreatitis

Other inflammatory states

Retinopathy of the retina

-adipose cell tumors

Adipose cell carcinoma, such as liposarcoma

Solid tumors and neoplasms, such as (but not limited to) gastrointestinal cancer, liver cancer, bile duct cancer and pancreatic cancer, endocrine tumors, lung cancer, kidney and urinary tract cancer, genital tract cancer, prostate cancer and the like

Acute and chronic myeloproliferative disorders and lymphomas

Angiogenesis

-neurodegenerative disorders

-Alzheimer's disease

Multiple sclerosis

Parkinson's disease

Erythrosquamous dermatoses (erythro-squamous dermatoses), such as psoriasis

Acne vulgaris

Other skin disorders and dermatological conditions modulated by PPAR

-eczema and neurodermatitis

Dermatitis, such as seborrheic dermatitis or solar dermatitis

Keratitis and keratoses, such as seborrheic keratosis, senile keratosis, actinic keratosis, photo-induced keratosis (photo-induced keratoses) or follicular keratosis

Keloid and keloid prevention

Warts, including condyloma or condyloma acuminata

Human Papillomavirus (HPV) infections such as venereal papilloma (venereal papillomas), viral warts such as molluscum contagiosum, leukoplakia

Papular dermatitis, e.g. lichen planus

Skin cancer, e.g. basal cell carcinoma, melanoma or cutaneous T-cell lymphoma

Localized benign epidermal tumors, such as keratoderma, epidermal nevi

Chilblain

-hypertension

Syndrome X

Polycystic ovarian syndrome (PCOS)

-asthma

-osteoarthritis

Lupus Erythematosus (LE) or inflammatory rheumatic disorders, such as rheumatoid arthritis

Vasculitis

Emaciation (cachexia)

Gout (gout)

Ischemia/reperfusion syndrome

-Acute Respiratory Distress Syndrome (ARDS)

Preparation

The amount of a compound of the invention necessary to achieve a desired biological effect will depend on a variety of factors, such as the particular compound selected, the intended use, the mode of administration, and the clinical condition of the patient. The daily dose is generally in the range 0.3mg to 100mg (usually 3mg to 50mg) per day per kilogram body weight, for example 3-10 mg/kg/day. The intravenous dose may be, for example, from 0.3mg to 1.0mg/kg, which may suitably be administered in an infusion of from 10ng to 100 ng/kg/minute. Suitable infusions for these purposes may contain, for example, 0.1ng to 10mg, usually 1ng to 10mg per ml. Single doses may contain, for example, from 1mg to 10g of active ingredient. Thus, ampoules for injection may contain, for example, from 1mg to 100mg, and orally administrable single-dose preparations such as tablets or capsules may contain, for example, from 0.05 to 1000mg, usually from 0.5 to 600 mg. For the treatment of the above conditions, the compounds of formula I may be used as the compounds themselves, but they are preferably in the form of a pharmaceutical composition containing an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the health of the patient. The carrier may be a solid or a liquid or both, and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05 to 95% by weight of the active ingredient. Other pharmaceutically active substances, including other compounds of the invention, may also be present. The pharmaceutical compositions of the present invention may be prepared by known pharmaceutical methods which consist essentially of admixing the ingredients with a pharmacologically acceptable carrier and/or excipient.

The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula I used in each case. Coated formulations and coated sustained release formulations are also encompassed by the scope of the present invention. Acid-and gastric juice-resistant preparations are preferred. Suitable coatings resistant to gastric juices include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration may be in the form of individual units such as capsules, cachets, suckable tablets (suckable tablets) or tablets, each containing a defined amount of a compound of formula I; in the form of a powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical process which includes a step in which the active ingredient is brought into contact with a carrier, which may contain one or more additional ingredients. Compositions are generally prepared by uniformly and homogeneously mixing the active ingredient with liquid and/or finely divided solid carriers, after which the product is shaped, if desired. Thus, for example, a tablet may be prepared by compressing or molding a powder or granules of the compound (and where appropriate one or more additional ingredients). Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, which may be mixed as appropriate with binders, glidants, inert diluents and/or one or more surfactants/dispersants. Molded tablets may be prepared by molding the compound in powder form and moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for oral (sublingual) administration include sucking tablets containing a compound of formula I and a flavoring agent, usually sucrose and acacia or tragacanth, and pastilles (pastilles) comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, but may also be administered by subcutaneous, intramuscular or intradermal injection. These formulations can preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of active compound.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. They may be prepared by mixing a compound of formula I with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers which may be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present at a concentration of 0.1 to 15%, for example 0.5 to 2% by weight of the composition.

It can also be administered transdermally. Pharmaceutical compositions suitable for transdermal use may be in the form of a single patch suitable for prolonged intimate contact with the epidermis of a patient. Such patches suitably contain the active ingredient dissolved and/or dispersed in an adhesive or dispersed in a polymer in an aqueous solution, buffered as appropriate. Suitable active ingredient concentrations are about 1% to 35%, preferably about 3% to 15%. The active ingredient can be released in particular by electrotransport or iontophoresis, such as, for example, Pharmaceutical Research, 2 (6): 318 (1986).

The compounds of formula I are characterized by a favourable effect on metabolic disorders. They beneficially influence lipid and sugar metabolism, in particular they reduce triglyceride levels, and are suitable for the prevention and treatment of type II diabetes and arteriosclerosis and their various sequelae.

Combinations with other drugs

The compounds of the invention may be administered alone or in combination with one or more additional pharmacologically active substances which, for example, have a beneficial effect on metabolic disorders or disorders frequently associated therewith. Examples of such drugs are

1. Hypoglycemic agents, antidiabetics,

2. an active ingredient for the treatment of dyslipidemia,

3. an anti-atherosclerotic medicament,

4. an anti-obesity agent which is an anti-obesity agent,

5. an anti-inflammatory active ingredient, which is,

6. an active component for treating malignant tumor,

7. an anti-thrombotic active ingredient, which is,

8. an active ingredient for the treatment of hypertension,

9. active ingredients for the treatment of heart failure, and

10. active ingredients for the treatment and/or prevention of complications resulting from or associated with diabetes.

They can be used in combination with the compounds of the formula I according to the invention, in particular to achieve a synergistic increase in the effect. The administration of the active ingredient combination can be carried out by separate administration of the active ingredients to the patient or in the form of a combination product in which a plurality of active ingredients are present in one pharmaceutical preparation.

Examples which may be mentioned are:

antidiabetic agent

Suitable antidiabetic agents are disclosed, for example, in Rote Liste 2001, noChapter 12 or the USP compatibility of USAN and International Drug Names, US Pharmacopeia, Rockville 2003. Antidiabetic agents include all insulins and insulin derivatives, e.g. Lantus^®(see www.lantus.com) or Apidra^®And other rapid acting insulins (see US6,221,633), GLP-1 receptor modulators as described in WO01/04146 and the like, such as those disclosed in WO98/08871 to novo nordiska/S.

Orally active hypoglycemic active ingredients preferably include sulfonylureas which act on the ATP-dependent potassium channel of beta cells (as disclosed, for example, in WO97/26265 and WO 99/03861), biguanides, meglitinides, glucagon antagonists, oral GLP-1 agonists, DPP-IV inhibitors, insulin sensitizers such as PPAR and PXR modulators and active ingredients such as oxadiazolidinediones, thiazolidinediones, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake such as glucosidase inhibitors, compounds which alter lipid metabolism and lead to a change in the composition of blood lipids, compounds which reduce food intake or food absorption.

In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.

In one embodiment of the invention, the compounds of the formula I are administered in combination with substances which influence hepatic glucose production, for example glycogen phosphorylase inhibitors (cf. WO01/94300, WO02/096864, WO03/084923, WO03/084922, WO 03/104188).

In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, for example sulfonylureas (e.g. tolbutamide, glyburide, glipizide, glimepiride) or glinides (e.g. repaglinide).

In one embodiment, the compounds of formula I are administered in combination with a biguanide, for example, metformin.

In one embodiment, the compounds of formula I are administered in combination with a PPAR γ agonist or a thiazolidinedione such as ciglitazone, pioglitazone, rosiglitazone or a compound disclosed in WO97/41097 of dr. reddy's Research Foundation, in particular 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl ] methyl ] -2, 4-thiazolidinedione.

In one embodiment, the compounds of formula I are used in combination with DPPIV inhibitors such as WO98/19998, WO99/61431, WO99/67278, WO99/67279, WO01/72290, WO02/38541, those described in WO03/040174, in particular P93/01 (1-cyclopentyl-3-methyl-1-oxo-2-pentanaminium chloride), P-31/98, LAF237(1- [2- [ 3-hydroxyadamantan-1-ylamino ] acetyl ] pyrrolidine-2- (S) -carbonitrile), TS021((2S, 4S) -4-fluoro-1- [ [ (2-hydroxy-1, 1-dimethylethyl) amino ] acetyl ] pyrrolidine-2-carbonitrile monobenzenesulfonate).

In one embodiment, the compounds of the formula I are administered in combination with compounds having an inhibitory effect on SGLT-1 and/or 2, such as those disclosed directly or indirectly in WO2004/007517, WO2004/052902, WO2004/052903 and WO 2005/121161.

In one embodiment, the compounds of the formula I are administered in combination with an α -glucosidase inhibitor, for example miglitol or acarbose.

In one embodiment, the compound of formula I is administered in combination with more than one of the above compounds, e.g., in combination with sulfonylureas and metformin, in combination with sulfonylureas and acarbose, in combination with repaglinide and metformin, in combination with insulin and sulfonylureas, in combination with insulin and metformin, in combination with insulin and troglitazone, in combination with insulin and lovastatin, and the like.

Lipid modulators

In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor such as lovastatin, fluvastatin, pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.

In one embodiment of the invention, the compounds of formula I are administered in combination with a bile acid absorption inhibitor (see, e.g., US6,245,744, US6,221,897, US6,277,831, EP0683773, EP 0683774).

In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid absorber, for example cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I are administered in combination with cholesterol absorption inhibitors such as those described in WO02/50027 or ezetimibe, tiquinan, pamabrin.

In one embodiment of the invention, the compounds of formula I are administered in combination with an LDL receptor inducing agent (see, e.g., US6,342,512).

In one embodiment, the compound of formula I is administered in combination with a bulking agent, preferably an insoluble bulking agent (see, e.g., Carob/Caromax ® (Zunft H J et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (9-10 months 2001), 18(5), 230-6.) Caromax is a Carob-containing product provided by Nutrinova, Nutrition specialties & Food Ingredients GmbH, Industiepark Hoechst, 65926 Frankfurt/Main). The combination with Caromax ® may be achieved in one formulation or by separate administration of the compound of formula I and Caromax ®. Caromax ® may also be administered herein in the form of a food product, for example in the form of a bakery product or breakfast bar (muesli bar).

In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR α agonist.

In one embodiment of the invention, the compounds of formula I are administered in combination with a mixed PPAR α/γ agonist such as those described in AZ 242(tesaglitazar, (S) -3- (4- [2- (4-methanesulfonyloxyphenyl) ethoxy ] phenyl) -2-ethoxypropionic acid), BMS 298585(N- [ (4-methoxyphenoxy) carbonyl ] -N- [ [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy ] phenyl ] methyl ] glycine) or WO99/62872, WO99/62871, WO01/40171, WO01/40169, WO96/38428, WO01/81327, WO01/21602, WO03/020269, WO00/64888 or WO 00/64876.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as fenofibrate, gemfibrozil, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I are administered in combination with nicotinic acid or nicotinic acid.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example CP-529, 414 (torcetrapib).

In one embodiment of the invention, the compounds of the formula I are administered in combination with ACAT inhibitors.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, for example, inputapi.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein (a) antagonist.

Anti-obesity agent

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, for example orlistat.

In one embodiment, the additional active ingredient is fenfluramine or dexfenfluramine.

In another embodiment, the additional active ingredient is sibutramine.

In another embodiment, the compounds of formula I are administered in combination with: CART modulators (see "Cocaine-amphetamine-regulated transcript-in-synthesis, and anxiety and structural-encoding in mice," Asakawa, A et al, M.: Hormone and Metabolic Research (2001), 33(9), 554), 558), NPY antagonists such as naphthalene-1-sulfonic acid {4- [ (4-aminoquinazolin-2-ylamino) methyl ] cyclohexylmethyl } amide hydrochloride (CGP 71683A)), MC4 agonists such as 1-amino-1, 2, 3, 4-tetrahydronaphthalene-2-carboxylic acid [2- (3A-benzyl-2-methyl-3-oxo-2, 3, 3A, 4, 6, 7-hexahydropyrazolo [4, 3-c ] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl ] amide (WO01/91752)) (see, Anorectic (orexin) antagonists (e.g., 1- (2-methylbenzoxazol-6-yl) -3- [1, 5] naphthyridin-4-ylurea hydrochloride (SB-334867-A)), H3 agonists (3-cyclohexyl-1- (4, 4-dimethyl-1, 4, 6, 7-tetrahydroimidazo [4, 5-c ] pyridin-5-yl) propan-1-one oxalate (WO00/63208)), TNF agonists, CRF antagonists (e.g., [ 2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-1, 3, 9-triazafluoren-4-yl ] dipropylamine (WO00/66585)), CRF BP antagonists (e.g., urocortin (urocortin)), (CRF (TM)), (S (R))), Urocortin agonists, beta 3 agonists (e.g. 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) ethylamino ] ethanol hydrochloride (WO01/83451)), MSH (melanotropin) agonists, CCK-A agonists (e.g. trifluoroacetate {2- [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) thiazol-2-ylcarbamoyl ] -5, 7-dimethylindol-1-yl } acetate (WO99/15525), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed serotonergic and noradrenergic compounds (e.g. WO00/71549), 5HT agonists such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO01/09111), bombesin agonists, galanin antagonists, growth hormones (e.g. human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylaminoethylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO01/85695)), TRH agonists (see, e.g., EP 04884), uncoupling protein 2 or 3 modulators, leptin (leptin) agonists (see, e.g., Lee, Daniel W.; Leinung, Matthew C.; Rozhakkaya-Arena, Marina; Grasso, Patricia. leptin as a potential pro-a to the peptide of formula I2001, D.A.A.A. beta., Doprexin), lipase/amylase inhibitors (e.g., WO00/40569), PPAR modulators (e.g., WO00/78312), RXR modulators, or TR-beta agonists.

In one embodiment of the invention, the further active ingredient is leptin.

In one embodiment, the additional active ingredient is dextroamphetamine, amphetamine, mazindole, or phentermine.

In one embodiment, the additional active ingredient is one or more antidiabetic agents, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR γ agonists, PPAR α/γ agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymerized bile acid absorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists, lipase inhibitors, insulin groups, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α -glucosidase inhibitors, active ingredients acting on ATP-dependent potassium channels of β cells, CART agonists, NPY agonists, MC4 agonists, orexin antagonists, H3 agonists, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof, TNF agonists, CRF antagonists, CRF BP antagonists, urocortin agonists, β 3 agonists, MSH (melanotropin) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR- β agonists or amphetamines.

In one embodiment, the compounds of formula I are administered in combination with drugs having an effect on the coronary circulation and vascular system, such as ACE inhibitors (e.g., ramipril), drugs acting on the angiotensin-renin system, calcium antagonists, beta blockers, and the like.

In one embodiment, the compounds of the formula I are administered in combination with a drug having an anti-inflammatory action.

In one embodiment, the compounds of formula I are administered in combination with a drug that is used for cancer treatment and cancer prevention.

It is to be understood that every suitable combination of a compound of the invention with one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances is to be considered as falling within the scope of the present invention.

The activity of the compounds of the invention was tested in the following enzyme assay system:

HSL inhibition assay

1.1. Preparation of partially purified HSL:

isolated rat adipocytes were obtained from epididymal adipose tissue from untreated male rats (Wistar, 220-. Adipocytes from 10 rats were washed three times by floating each time with 50ml of homogenization buffer (25ml Tris/HCl, pH7.4, 0.25M sucrose, 1mM ETDA, 1mM DTT, 10. mu.g/ml leupeptin, 10. mu.g/ml antipain, 20. mu.g/ml pepstatin) and finally added to 10ml of homogenization buffer. Adipocytes were homogenized for 10 strokes at 1500rpm and 15 ℃ in a Teflon-in-glass homogenizer (Braun-Melsungen). The homogenate was centrifuged (Sorvall SM24 tube, 5000rpm, 10 min, 4 ℃). The lower clear liquid between the top fat layer and the pellet was removed and centrifugation repeated. The thus obtained subnatant was centrifuged again (Sorvall SM24 tube, 20000rpm, 45 min, 4 ℃). The lower layer clear solution was removed and 1g heparin-Sepharose (Pharmacia-Biotech, CL-6B, 5X washed with 25mM Tris/HCl, pH7.4, 150mM NaCl) was added. After incubation at 4 ℃ for 60 minutes (shaking at 15 minute intervals), the mixture was centrifuged (Sorvall SM24 tube, 3000rpm, 10 minutes, 4 ℃). The supernatant was adjusted to pH5.2 by adding glacial acetic acid and incubated at 4 ℃ for 30 minutes. The precipitate was collected by centrifugation (Sorvall SS34, 12000rpm, 10 minutes, 4 ℃) and suspended in 2.5ml of 20mM Tris/HCl, pH7.0, 1mM EDTA, 65mM NaCl, 13% sucrose, 1mM DTT, 10. mu.g/ml leupeptin/antipain. The suspension was dialyzed overnight at 4 ℃ against 25mM Tris/HCl, pH7.4, 50% glycerol, 1mM DTT, 10. mu.g/ml leupeptin, pepstatin, antipain, and then loaded onto a hydroxyapatite (hydroxyapatite) column (0.1 g per 1ml suspension, equilibrated with 10mM potassium phosphate, pH7.0, 30% glycerol, 1mM DTT). The column was washed with four volumes of equilibration buffer at a flow rate of 20-30 ml/h. HSL was eluted with one volume of equilibration buffer containing 0.5M potassium phosphate, then dialyzed (see above) and concentrated 5-to 10-fold by ultrafiltration (Amicon Diaflo PM 10 Filter) at 4 ℃. Partially purified HSL can be stored at-70 ℃ for 4-6 weeks.

1.2HSL Activity assay:

to prepare the substrate, 25-50. mu. Ci [3H ] is mixed]Trioleoyl glycerol (in toluene), 6.8. mu. mol unlabelled trioleoyl glycerol and 0.6mg phospholipid (phosphatidylcholine/phosphatidylinositol 3: 1w/v), with N₂Dried and then taken up in 2ml of 0.1M KPi (pH7.0) by sonication (Branson 250, microtip, setting 1-2, 2X 1 min, time interval 1 min). After addition of 1ml of KPi and renewed sonication (4X 30 seconds on ice, 30 seconds intervals), 1ml of 20% BSA (in KPi) was added (final concentration of trioleoyl glycerol 1.7 mM). To carry out the reaction, 100. mu.l of the substrate solution was transferred to 100. mu.l of HSL solution (HSL prepared as above, diluted at 20mM KPi, pH7.0, 1mM EDTA, 1mM DTT, 0.02% BSA, 20. mu.g/ml aprotinin)Pepstatin, 10. mu.g/ml leupeptin), incubated at 37 ℃ for 30 minutes. 3.25ml of methanol/chloroform/heptane (10: 9: 7) and 1.05ml of 0.1M K were added₂CO₃0.1M boric acid (pH10.5), then mixed well and finally centrifuged (800 Xg, 20 min). After phase separation, an aliquot of the upper phase (1ml) was removed and radioactivity was determined by liquid scintillation measurement.

1.3 evaluation of HSL-inhibition:

the substances are usually tested in four separate mixtures. The inhibition of HSL enzyme activity by the test substance is determined by comparison with an uninhibited control reaction. Calculating IC from inhibition curves with concentrations of at least 10 test substances₅₀. Data were analyzed using the GRAPHIT, Elsevier-BIOSOFT software package.

EL inhibition assay:

preparation of EL

EL is released as a secreted protein by recombinant cell lines (CHO, HEK293) into cell culture medium (conditioned medium) at high concentrations. After concentration, it was used as an enzyme solution.

EL Activity assay method

The enzymatic activity of endothelial lipase and the action of inhibitors were characterized with the phospholipase-specific substrate 1, 2-bis (4, 4-difluoro-5, 7-dimethyl-4-bora-3 a, 4 a-diaza-s-indacene (═ indacene) -3-undecanoyl) -sn-glycero-3-phosphocholine (manufacturer Molecular Probes). The A1 ester bond of the phospholipid was hydrolyzed with enzyme to release the fluorescent dye Bodipy, which can be detected after separation by thin layer chromatography on HPTLC plates (silica gel 60, Merck) or directly in the reaction vessel by measuring fluorescence.

A substrate solution was prepared by absorbing 100. mu.g of 1, 2-bis (4, 4-difluoro-5, 7-dimethyl-4-bora-3 a, 4 a-diaza-s-indacene-3-undecanoyl) -sn-glycero-3-phosphocholine (manufacturer Molecular Probes), 2.4mg of glyceryl palmitate (Sigma) and 7.9mg of DOP-choline (1, 2-dioleoyl-sn-glycero-3-phosphocholine) in 393. mu.l of chloroform, and then transferring 157. mu.l to a new reaction vessel. After evaporation of the solvent, the lipid mixture was dissolved in 4ml of 200mM Tris-HCl, 150mM sodium chloride, pH7.4 by sonication twice. The subsequent enzymatic reaction was carried out at 37 ℃ for 60 minutes. For this purpose, 45. mu.l of substrate solution were incubated with 1. mu.l of the appropriate concentration of inhibitor (dissolved in DMSO, using pure DMSO solution as a control) and 5. mu.l of enzyme solution (conditioned medium). Mu.l of the assay mixture was then loaded onto HPTLC plates (silica gel 60, Merck) and the liberated fluorochrome was separated with an eluent (diethyl ether: petroleum ether: acetic acid [ 78: 22: 1]) for detection. After evaporation of the eluent, the plates were read in a fluorescence scanner. The increase in the release of the fluorescent dye in the uninhibited reaction was observed as a measure of the enzyme activity.

Evaluation of EL-inhibition:

the enzyme activity decreases as a function of the inhibitor concentration used, the concentration of inhibitor at which half the maximum enzyme activity is observed being referred to as IC₅₀。

In these assays, the compounds of the examples show the following IC₅₀The value:

examples	IC₅₀[μM] HSL	IC₅₀[μM]EL
examples	IC₅₀[μM] HSL	IC₅₀[μM]EL	1	0.12
2	0.12		1	0.12
2	0.12		3	0.1
4	0.1		3	0.1
4	0.1		5	0.1
7		14.6	5	0.1
7		14.6	8		14.6
10	0.67		8		14.6
10	0.67		11	0.26

Preparation method

The compounds of the general formula I according to the invention are prepared by methods known per se, for example by acylation of substituted or unsubstituted pyrrole II with carbamoyl chloride III (method A), or in two stages (method B) by reacting pyrrole II with phosgene or its equivalent, for example trichloromethyl chlorocarbonate, bis (trichloromethyl) carbonate or 4-nitrophenyl chloroformate and further reacting the resulting pyrrole carboxylic acid derivative with an amine IV. For compounds in which R3 is hydrogen (formula Ia), pyrrole II can also be reacted with the appropriate isocyanate V R2-N ═ C ═ O (method C).

Since acids are usually released in these reactions, it is advisable to add a base such as pyridine, triethylamine, sodium hydroxide solution or alkali metal carbonate to accelerate the reaction. The reaction can be carried out over a wide temperature range. It has generally been shown to be advantageous to work at from 0 ℃ to the boiling point of the solvent used. Examples of solvents used are dichloromethane, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, diethyl ether or pyridine. If anhydrous conditions are used, it has also been shown to be convenient to use a strong base such as lithium hydride, sodium hydride or potassium tert-butoxide in an aprotic solvent such as THF or DMF.

Pyrazole II or the corresponding aza-substituted derivatives used as starting compounds are commercially available or can be prepared by methods known from the literature (e.g.K.Bowden, G.Crank, W.J.Roos, J.chem.Soc.1968, 172-185; T.Chiyoda, K.Iida, K.Takatori, M.Kajiwara, Synlett 2000, 10, 1427-1428; M.A.Khan, F.K.Rafla, J.chem.Soc.1975, 693-694).

The following detailed examples are intended to illustrate the invention, but not to limit it.

Examples

Example 1:

4-Methylpiperidine-1-carboxylic acid 6-chlorobenzo [ d ] isoxazol-3-yl ester

200mg (1.18mmol) of 6-chlorobenzo [ d ] isoxazol-3-ol, 228.7mg (1.41mmol) of 4-methylpiperidine-1-carbonyl chloride and 164. mu.l (2.36mmol) of triethylamine are dissolved in 10ml of pyridine and stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 147mg (42%), M + H +: 295.2.

example 2:

4-methylpiperidine-1-carboxylic acid isoxazolo [5, 4-b ] pyridin-3-yl ester

125mg (0.918mmol) isoxazolo [5, 4-b ] pyridin-3-ol, 178mg (1.1mmol) 4-methylpiperidine-1-carbonyl chloride and 255. mu.l (1.84mmol) triethylamine are dissolved in 10ml pyridine and stirred at room temperature for 4 hours. A further 89mg (0.55mmol) of 4-methylpiperidine-1-carbonyl chloride and 128. mu.l (0.92mmol) of triethylamine are added and stirring is continued at room temperature for 6 hours. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 101mg (42%), M + H +: 262.1.

example 3:

4-Trifluoromethylpiperidine-1-carboxylic acid 6-chlorobenzo [ d ] isoxazol-3-yl ester

In analogy to example 1, 200mg (1.18mmol) of 6-chlorobenzo [ d ] isoxazol-3-ol are reacted with 305mg (1.41mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 229mg (56%), M + H +: 349.05.

example 4:

4-methylpiperidine-1-carboxylic acid isothiazolo [5, 4-b ] pyridin-3-yl ester

In analogy to example 1, 60mg (0.4mmol) of isothiazolo [5, 4-b ] pyridin-3-one were reacted with 76mg (0.47mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 29mg (27%), M + H +: 278.13.

example 5:

4-methylpiperidine-1-carboxylic acid benzo [ d ] isothiazol-3-yl ester

In analogy to example 1, 45mg (0.3mmol) of benzo [ d ] isothiazol-3-one are reacted with 58mg (0.36mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 26mg (32%), M + H +: 277.14.

example 6:

1-hexyl-3- (5-nitrobenzo [ d ] isothiazol-3-yl) urea

100mg (0.513mmol) of 5-nitrobenzo [ d ] isothiazol-3-ylamine are suspended in 5ml of THF. 78.1mg (0.61mmol) of 1-isocyanatohexane are added, followed by stirring at RT for 2 hours and at 70 ℃ for 2 hours. Then another 0.3mmol of 1-isocyanatohexane was added and stirring was continued at 70 ℃ for 6 hours. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 18mg (11%), M + H +: 323.15.

example 7:

1- (2-methylbenzyl) -3- (5-nitrobenzo [ d ] isothiazol-3-yl) urea

In analogy to example 6, 100mg (0.51mmol) of 5-nitrobenzo [ d ] isothiazol-3-ylamine were reacted with 90.4mg (0.61mmol) of 1-isocyanatomethyl-2-methylbenzene. Yield: 11mg (6%), M + H +: 343.16.

example 8:

1-benzo [ d ] isoxazol-3-yl-3-hexylurea

In analogy to example 6, 100mg (0.75mmol) of benzo [ d ] isothiazol-3-ylamine were reacted with 114mg (0.89mmol) of 1-isocyanatohexane. Yield: 27mg (14%), M + H +: 262.15.

example 9:

4-Trifluoromethylpiperidine-1-carboxylic acid isothiazolo [5, 4-b ] pyridin-3-yl ester

In analogy to example 1, 2.99g (9.82mmol) isothiazolo [5, 4-b ] pyridin-3-ol were reacted with 2.33g (10.81mmol) 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 1.3g (40%), M + H +: 332.09.

example 10:

4-methylpiperidine-1-carboxylic acid 6-chloroisoxazolo [5, 4-b ] pyridin-3-yl ester

In analogy to example 1, 55mg (0.32mmol) of 6-chloroisoxazolo [5, 4-b ] pyridin-3-ol are reacted with 62.7mg (0.39mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 22mg (24%), M + H +: 296.04.

example 11:

4-methylpiperidine-1-carboxylic acid 6-methylisoxazolo [5, 4-b ] pyridin-3-yl ester

In analogy to example 1, 140mg (0.93mmol) of 6-methylisoxazolo [5, 4-b ] pyridin-3-ol are reacted with 181mg (1.12mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 135mg (53%), M + H +: 276.10.

Claims

1. A compound of formula I

Wherein:

a is S, O;

w is- (C ═ O) -, - (S ═ O) -, - (SO)₂)-；

X is, identically or differently, ═ C (-R) -or ═ N-;

y is-O-or-NR 1-;

r1 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

r3 is hydrogen, (C)₁-C₆) -an alkyl group; or

R2 and R3 together with the nitrogen atom carrying them may form a monocyclic, saturated or partially unsaturated 4-to 7-membered ring system or a bicyclic, saturated or partially unsaturated 8-to 14-membered ring system, each of said ring systemsThe members may be substituted with 1 to 3 groups selected from-CHR 5-, -CR5R5-, - (C ═ R5) -, -NR5-, -C (═ O) -, -O-, -S-, -SO₂-is replaced by an atom or group provided that two are selected from-O-, -S-, -SO₂-the units may not be contiguous;

r4 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

r5 is (C)₁-C₆) -alkyl, halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene; tautomeric forms of the compounds and their physiologically tolerated salts.

2. A compound of formula I according to claim 1, wherein

W is- (C ═ O) -.

3. A compound of formula I according to claim 1 or 2, wherein

W is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-O-, -NR 1-;

r is hydrogen, halogen, (C)₁-C₆) -alkyl, hydroxy, amino, COOR4, trifluoromethyl, (C)₁-C₆) Alkylsulfonyl, nitro, pentafluorothio, (C)₆-C₁₀) Aryl, CO-NR2R3, O-CO-NR2R3 or O-CO- (C)₁-C₆) alkylene-CO-O- (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -an alkoxy group;

r1 is hydrogen, (C)₁-C₆) -an alkyl group;

r2 is (C)₆-C₁₀) Alkyl radicals, (C)₁-C₃) -alkyl- (C)₆-C₁₀) -aryl, wherein aryl may optionally be substituted

Substituted one or more times with: halogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₃) -alkoxy, hydroxy, amino, (C)₁-C₆) -alkylamino, trifluoromethyl, nitro;

r3 is hydrogen, (C)₁-C₆) -an alkyl group; or

r4 is hydrogen, (C)₁-C₆) -alkyl, benzyl;

4. A compound of formula I according to claim 1, 2 or 3, wherein

W is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-O-;

r3 is hydrogen; or

R5 is (C)₁-C₆) -alkyl, trifluoromethyl or cyclopropyl.

5. A compound of formula I according to claim 1, 2 or 3, wherein

W is- (C ═ O) -;

x is, identically or differently, ═ C (-R) -or ═ N-;

y is-NR 1-;

r1 is hydrogen, (C)₁-C₆) -an alkyl group;

r3 is hydrogen; or

R5 is (C)₁-C₆) -alkyl, trifluoromethyl or cyclopropyl.

6. Compounds of formula I as claimed in claims 1 to 5, wherein

NR2R3 is a piperidine containing the atom member CHR5 at the 4-position.

7. The compound of formula I according to claims 1 to 6, wherein:

8. Compounds of formula I according to claims 1 to 7, wherein

9. Compounds of formula I as claimed in claims 1 to 6, wherein

X is, identically or differently, ═ C (-R) -.

10. A compound of formula I according to claim 8 or 9, wherein

11. A medicament comprising one or more compounds of the formula I as claimed in claims 1 to 10.

12. The medicament of claim 11, which comprises as further active ingredients one or more antidiabetic agents, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR γ agonists, PPAR α/γ agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid absorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthase inhibitors, lipoprotein (a) antagonists, lipase inhibitors, insulin series, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α -glucosidase inhibitors, active ingredients acting on ATP-dependent potassium channels of β cells, CART agonists, NPY agonists, MC4 agonists, a, Orexin antagonists, H3 agonists, TNF agonists, CRF antagonists, CRF BP antagonists, urocortin agonists, β 3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, dopexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR- β agonists or amphetamines.

13. The use of compounds of the formula I as claimed in claims 1 to 10 for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders.

14. The use of compounds of the formula I as claimed in claims 1 to 10 for the treatment and/or prophylaxis of disorders in which insulin resistance is involved.

15. The use of the compounds of the formula I as claimed in claims 1 to 10 for the treatment and/or prophylaxis of diabetes mellitus and the sequelae associated therewith.

16. The use of compounds of the formula I as claimed in claims 1 to 10 for the treatment and/or prophylaxis of dyslipidemias and their sequelae.

17. The use of compounds of the formula I as claimed in claims 1 to 10 for the treatment and/or prevention of disorders which are associated with the metabolic syndrome.

18. The use of compounds of the formula I as claimed in claims 1 to 10 in combination with at least one further active ingredient for the treatment and/or prophylaxis of disorders in which insulin resistance is involved.

19. A process for the preparation of a medicament comprising one or more compounds of the formula I as claimed in claims 1 to 10, which comprises mixing the latter with a pharmaceutically suitable carrier and converting the mixture into a form suitable for administration.

20. A process for the preparation of compounds of the general formula I according to claims 1 to 10, which comprises reacting a pyrrole of the formula II

a) Acylation with a carbamoyl chloride of formula III; or

b) The reaction is carried out in two stages, first with phosgene or an equivalent such as trichloromethyl chlorocarbonate, bis (trichloromethyl) carbonate or 4-nitrophenyl chloroformate, and in a second step with an amine of the formula IV,

wherein the substituents have the above-mentioned meanings,

21. a process for the preparation of compounds of the general formula I (formula Ia) according to claims 1 to 10, wherein R3 is hydrogen, which process comprises reacting a pyrrole of formula II with formula V: reacting O-C-N-R2 isocyanate,