EP1874741A1

EP1874741A1 - Azole derivatives in the form of lipase and phospholipase inhibitors

Info

Publication number: EP1874741A1
Application number: EP06761897A
Authority: EP
Inventors: Günter Müller; Stefan Petry; Gerhard Zoller; Norbert Tennagels; Hubert Heuer
Original assignee: Sanofi Aventis France
Current assignee: Sanofi SA
Priority date: 2005-04-20
Filing date: 2006-04-13
Publication date: 2008-01-09
Also published as: IL186635A0; MA29393B1; CA2606301A1; NO20075938L; KR20080004501A; CN101160293A; TW200722421A; ZA200707929B; JP2008536884A; NZ562694A; WO2006111321A1; DE102005018389A1; RU2007142657A; MY142441A; US8921404B2; RU2414458C2; US20080090867A1; AU2006237127A1; MX2007012732A; BRPI0608495A2

Abstract

The invention relates to azole derivatives of formula (I) whose meanings are given in a description and to salts thereof which can be pharmaceutically used in the form of drags.

Description

description

Azole derivatives as inhibitors of lipases and phospholipases

The present invention relates to azole derivatives of the general formula I, their pharmaceutically acceptable salts and their use as medicaments.

WO 2003/0051842 A2 describes compounds for inhibiting hormone-sensitive lipase. Among them are benzisoxazole derivatives and benzisothiazole derivatives. Benzisoxazole derivatives for the inhibition of glycogen synthase kinase-3 are described in WO 2004/058749.

The object of the present invention is to provide alternative compounds which cause an inhibition of hormone-sensitive lipase or endothelial lipase.

The invention relates to azole derivatives of the general formula I.

(I) where:

A S, O;

W - (C = O) -, - (S = O) -, - (SO ₂ ) -;

X is the same or different = C (-R) - or = N-;

Y is -O- or -NR1-; R is hydrogen, halogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₃ ) -alkyloxy- (C ₁ -C ₃ ) -alkylene,

Hydroxy, (C ₁ -C 6) -acylmercapto, amino, (C ₁ -C 6) -alkylamino, C ₁ -C 12 -alkylamino, C ₁ -C ₈ -alkylaminocarbonyl, C ₁ -C ₈ -alkylaminocarbonyl, COOR 4, Trifluoromethyl, (C _r C ₆ ) -alkylsulfonyl, (C ₁ -

C ₆₎ alkylsulfinyl, aminosulfonyl, nitro, pentafluorosulfanyl, (C ₆ -C o) aryl, CO-NR2R3, O-CO-NR2R3, O-CO- (C _r _C6) -alkylene-CO-O- ( C _r C ₆ ) -alkyl, O-CO- (C ₁ -C ₆ ) -alkylene-CO-OH, O-CO- (C ₁ -C ₆ ) -alkylene-CO-NR 2 R 3 or unsubstituted or monosubstituted or polysubstituted by F. (Ci-C ₆ ) - Alkyloxy;

R1 is hydrogen, (C _r _C6) alkyl, benzyl;

R2 (C ₅ -C ₁₆₎ alkyl, (Ci-C ₄₎ -alkyl- (C ₆ -Cio) aryl, wherein aryl is optionally substituted by halogen, (C _r _C6) alkyl, (C _r C ₃ ) -Alkyloxy, hydroxy, (C _r C ₆ ) -

Alkylmercapto, amino, (C ₁ -C ₆ ) -alkylamino, di (C ₂ -C ₁₂ ) -alkylamino, mono- (C ₁ -C ₆ ) -alkylaminocarbonyl, C ₁ -C ₈ -dialkylaminocarbonyl, (C ₁ -C ₆ ) - alkoxycarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (CrC ₆ ) - alkylsulfonyl, aminosulfonyl, nitro may be monosubstituted or polysubstituted;

R 3 is hydrogen, (C ₁ -C ₆ ) -alkyl; or

R 2 and R 3 together with the nitrogen atom carrying them can 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 whose individual members of the ring systems can be replaced by one to three atoms or Atom groups from the series -CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -C (= O) -, -O-, -S-, -SO-, -SO ₂ - replaced can be, with the proviso that two units from the

Series -O-, -S-, -SO-, -SO ₂ - may not be adjacent; R 4 is hydrogen, (C ₁ -C ₆ ) -alkyl, benzyl;

_R ₅ (C 1 -C ₆ ) -alkyl, halogen, trifluoromethyl, COOR 4, cyclopropyl,

Cyclopropylene;

the tautomeric forms of the compounds and their physiologically acceptable salts.

Preference is given to compounds of the formula I in which

W - (C = O) - means.

Preference is furthermore given to compounds of the formula I in which

W - (C = O) -;

X is the same or different = C (-R) - or = N-;

Y is -O-, -NR1-;

R is hydrogen, halogen, (C ₁ -C ₆ ) -alkyl, hydroxy, amino, COOR 4,

Trifluoromethyl, (C ₁ -C ₆ -alkylsulfonyl, nitro, pentafluorosulfanyl, (Ce-C ₁₀ ) -aryl, CO-NR 2 R 3, O-CO-NR 2 R 3 or O-CO- (C ₁ -C ₆ ) -alkylene-CO-O- (C ₁ -

C ₆ ) alkyl;

R1 is hydrogen, (C _r _C6) alkyl; R 2 (C ₆ -C ₁₀ ) -alkyl, (C ₁ -C ₃ ) -alkyl- (C ₆ -C 10) -aryl, where aryl may be replaced by

Halogen, (CrC ₆₎ alkyl, (C _r _C3) -alkyloxy, hydroxy, amino, (CrC ₆₎ - may be alkylamino, trifluoromethyl, nitro or polysubstituted;

R 3 is hydrogen, (C ₁ -C ₆ ) -alkyl; or

R 2 and R 3 together with the nitrogen atom carrying them can form a monocyclic, saturated 5- to 6-membered ring system or a bicyclic saturated or partially unsaturated 9- to 10-membered ring system, whose individual members of the ring systems are selected from one to three atoms or atomic groups of the series -CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -O-, -S-, with the proviso that two units from the series -O-, -S - may not be adjacent;

R 4 is hydrogen, (C ₁ -C ₆ ) -alkyl, benzyl;

R 5 is (C 1 -C ₆ ) -alkyl, halogen, trifluoromethyl, COOR 4, cyclopropyl,

Cyclopropylene mean.

Also preferred compounds of formula I _1, wherein

W - (C = O) -;

X is the same or different = C (-R) - or = N-;

Y is -O-, -NR1-;

R is hydrogen, halogen, (C 1 -C 6) -alkyl, hydroxy, amino, COOR 4,

Trifluoromethyl, (C _r C ₆ ) -alkylsulfonyl, nitro, pentafluorosulfanyl, (C ₆ -C ₁₀ ) - Aryl, CO-NR2R3, O-CO-NR2R3 or O-CO- (C ₁ -C ₆₎ -alkylene-CO-O- (C ₁ - C ₆₎ alkyl, (C _r _C6) alkyloxy;

R1 is hydrogen, (C _r _C6) alkyl;

R 2 (C ₆ -C 10) -alkyl, where aryl is possibly through

Halogen, (CrC ₆₎ alkyl, _(Ci-C3) -alkyloxy, hydroxy, amino, (CrC ₆₎ - alkylamino, trifluoromethyl, nitro or polysubstituted may be substituted;

R3 is hydrogen, (C _r C ₆ ) -alkyl; or

R 2 and R 3 together with the nitrogen atom carrying them can form a monocyclic, saturated 5- to 6-membered ring system or a bicyclic saturated or partially unsaturated 9- to 10-membered ring system whose individual members of the ring systems can be replaced by one to three atoms or atomic groups from the Series -CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -O-, -S-, with the proviso that two units from the series -O-, -S- not be adjacent;

R 4 is hydrogen, (C 1 -C ₆ ) -alkyl, benzyl;

R 5 is (C ₁ -C ₆ ) -alkyl, halogen, trifluoromethyl, COOR 4, cyclopropyl,

Cyclopropylene mean.

Particular preference is given to compounds of the formula I in which

W - (C = O) -;

X is the same or different = C (-R) - or = N-; Y -O-;

R is hydrogen, halogen, nitro, hydroxy or (C ₁ -Ce) alkyl;

R 2 (C ₆ -C ₁₀ ) -alkyl or benzyl, where benzyl is optionally substituted by halogen, (C ₁ -C ₆ ) -

Alkyl or trifluoromethyl may be substituted;

R3 is hydrogen, (C _r C ₆ ) -alkyl; or

R 2 and R 3, together with the nitrogen atom bearing them, can form a monocyclic, saturated 5- to 6-membered ring system whose individual members of the ring systems can be replaced by one or two atoms or atom groups from the series -CHR 5 -, -NR 5 - ; and

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

Another particularly preferred embodiment are compounds of the formula I in which

W - (C = O) -;

X is the same or different = C (-R) - or = N-;

Y -O-;

R is hydrogen, halogen, nitro, hydroxy, (C _r C ₃ ) -alkyloxy or (C _r C ₆ ) -

alkyl; R 2 (C ₆ -C ₁₀ ) -alkyl or benzyl, where benzyl is optionally substituted by halogen, (C _r C ₆ ) -

Alkyl or trifluoromethyl may be substituted;

R3 is hydrogen; or

R 5 is (C 1 -C ₆ ) -alkyl, trifluoromethyl or cyclopropyl.

Another particularly preferred embodiment are compounds of formula I wherein

W - (C = O) -;

X is the same or different = C (-R) - or = N-;

Y -NR1-;

R is hydrogen, halogen, nitro, hydroxy or (CrCβJ-alkyl;

R1 is hydrogen, (C _r _C6) alkyl;

R 2 (C ₆ -C 10) -alkyl or benzyl, where benzyl is optionally substituted by halogen, (CrCe) -

Alkyl or trifluoromethyl may be substituted;

R3 is hydrogen, (C 1 -C ₆ ) -alkyl; or R 2 and R 3, together with the nitrogen atom bearing them, can form a monocyclic, saturated 5- to 6-membered ring system whose individual members of the ring systems can be replaced by one or two atoms or atom groups from the series -CHR 5 -, -NR 5 - ; and

R 5 is (C 1 -C ₆ ) -alkyl or cyclopropyl.

W - (C = O) -;

X is the same or different = C (-R) - or = N-;

Y -NR1-;

R is hydrogen, halogen, nitro, hydroxy, (C 1 -C ₃ ) -alkyloxy or (C ₁ -C ₆ ) -

alkyl;

R1 is hydrogen, (C _r _C6) alkyl;

R 2 (Ce-Cio) -alkyl or benzyl, where benzyl is optionally substituted by halogen, (C ₁ -C ₆ ) -

Alkyl or trifluoromethyl may be substituted;

R3 is hydrogen; or

R 2 and R 3, together with the nitrogen atom bearing them, can form a monocyclic, saturated 5- to 6-membered ring system whose individual members of the ring systems can be replaced by one or two atoms or atom groups from the series -CHR 5 -, -NR 5 - ; and R 5 is (C ₁ -C ₆ ) -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 a further embodiment of the invention, Y in the compounds of the formula I has the meaning O.

In a further embodiment of the invention, Y in the compounds of the formula I is NR 1, where R 1 may have the abovementioned meanings.

Very particular preference is given to the compounds of the formula I in which

NR2R3 is piperidine containing the atomic element CHR5 in the 4 position.

Preference is furthermore given to compounds of the formula I in which X is identical or different = C (-R) -.

Preference is furthermore given to compounds of the formula I in which

X is the same or different = C (-R) - or = N-, with the proviso that exactly one X equals = N-.

Preference is also given to the compounds of the formula I in which

X in position 4, 5 and 6 for the same or different = C (-R) -, in position 7 for = N-.

Further, preferred compounds of the formulas I ₁ wherein X in position 4, 5 and 7 for = C (-R) - where R = hydrogen, in position 6

R is not hydrogen.

Further preferred are compounds of the formula I in which

X in position 4 and 5 for = C (-R) - where R = hydrogen, in position 6 R is not hydrogen.

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

The alkyl radicals in the substituents R, R 1, R 2, R 3, R 4, R 5 can be both straight-chain and branched. Halogen is fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.

By aryl is meant an aromatic carbocyclic mono- or bicyclic ring system containing from 6 to 10 atoms in the ring or in the rings.

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 from the series N, O and S.

Pharmaceutically acceptable salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric acid. , Glucon, Glycol, Isethione, Milk, Lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts) and salts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine ,

Salts with a non-pharmaceutically acceptable anion, such as trifluoroacetate, are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.

As used herein, the term "physiologically functional derivative" refers to any physiologically acceptable derivative of a compound of formula I, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.

The physiologically functional derivatives also include prodrugs of the compounds according to the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.

The compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention. Hereinafter, all references to "compound (s) according to formula I" refer to compound (s) of formula I as described above as well as their salts, solvates and physiologically functional derivatives as described herein.

use

The compounds of general formula I according to the invention have a surprising inhibitory effect on the hormone sensitive lipase, HSL, an allosteric enzyme in adipocytes, which is inhibited by insulin and for the

Degradation of fats into fat cells and thus responsible for the transfer of fat components into the bloodstream. An inhibition of this enzyme thus corresponds to an insulin-like action of the compounds of the invention, which ultimately leads to a reduction of free fatty acids in the blood and blood sugar. They can therefore be used in derangements of the metabolism such as non-insulin-dependent diabetes mellitus, the diabetic syndrome and direct damage to the pancreas.

In addition, the compounds of general formula I according to the invention may have an inhibitory effect on the endothelial lipase (EL). The antiatheroskleotically effective HDL is the preferred substrate for EL. A reduction in HDL levels leads to the progression of atherosclerosis and its sequelae, such as metabolic syndrome and coronary heart disease. An inhibition of EL should thus lead to the prevention of atherosclerotic diseases. The compounds of the formula I according to the invention can also have an inhibitory effect on the triglyceride lipase.

Furthermore, it has been found that the inhibitory effect of the compounds of general formula I according to the invention is selective over other lipases.

Particularly suitable are such compounds for the treatment and / or prevention of 1. - Disorders of fatty acid metabolism and glucose utilization disorders

2. Insulin sensitivity disorders of muscle, fat and liver cells (insulin resistance) - Metabolic syndrome

3. Diabetes mellitus, especially type 2 diabetes, including the prevention of associated sequelae.

Special aspects are the

- hyperglycemia,

- improvement of insulin resistance,

- Improvement of glucose tolerance, - Protection of the pancreatic beta cells

- Prevention of macrovascular and microvascular diseases

4. dyslipidemias and their consequences, e.g. Atherosclerosis, coronary heart disease, cerebrovascular diseases etc, especially those (but not limited to) characterized by one or more of the following factors:

high plasma triglyceride, high postprandial plasma triglyceride

concentrations

- low HDL-cholesterol concentration

- low apoA lipoprotein concentrations - high LDL cholesterol concentrations

- small dense LDL cholesterol particles

high ApoB lipoprotein concentrations

5. Various other conditions that may be associated with the metabolic syndrome include:

- obesity, including abdominal obesity

- thrombosis, stages of hypercoagulability and thrombosis (arterial and venous)

High blood pressure heart failure, e.g. (but not limited to) at state after

Myocardial infarction, hypertensive heart disease or cardiomyopathy 6. other diseases or conditions in which, for example, inflammatory reactions or cell differentiation play a role:

Atherosclerosis, e.g. (but not limited to) coronary sclerosis including angina pectoris or myocardial infarction, stroke - vascular restenosis or reocclusion

- Inflammatory bowel disease, e.g. Crohn's disease and ulcerative colitis

- pancreatitis

- Other inflammatory conditions - Retinopathy

- fatty cell tumors (adipose cell tumors)

- fatty cell carcinomas, e.g. liposarcoma

solid tumors and neoplasms, e.g. (but not limited to) carcinomas of the gastrointestinal tract, liver, biliary tract and pancreas, endocrine tumors, carcinomas of the lung, kidney and urinary tract

Organs, the genital tract, prostate carcinomas etc.

- acute and chronic myeloprolifeative diseases and lymphomas

- angiogenesis

- New rodegenerative diseases - Alzheimer's disease

- Multiple sclerosis

- Parkinson's disease

Erythemato-squamous dermatoses, e.g. Psoriasis (psoriasis)

- Acne vulgaris - Other skin diseases and dermatological conditions that are modulated by PPAR

- eczema and atopic dermatitis

Dermatitides, e.g. seborrheic dermatitis or light dermatitis

Keratitis and keratoses, e.g. seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or follicular keratosis

- keloids and keloid prophylaxis - Warts, including condylomata or condylomata acuminata

Human papilloma viral (HPV) infections, e.g. venereal papillomata, viral warts, e.g. Molluscum contagiosum, leukoplakia

- Papular dermatoses, e.g. Lichen planus - skin cancer, such as Basal cell carcinomas, melanomas or cutaneous T cells

lymphomas

- Localized, benign epidermal tumors, e.g. Keratoderma, epidermal nevi

- chilblains - high blood pressure

- Syndrome X

- polycystic ovarian syndrome (PCOS)

- Asthma

- osteoarthritis - lupus erythematosus (LE) or inflammatory rheumatic diseases, e.g. Rheumatoid arthritis

- Vasculitis

- wasting (cachexia)

- Gout - ischemia / reperfusion syndrome

- Acute Respiratory Distress Syndrome (ARDS) ("shock lung")

Galenik

The amount of compound of the invention required to achieve the desired biological effect is dependent upon a number of factors, eg, the specific compound chosen, the intended use, the mode of administration, and the clinical condition of the patient. In general, the daily dose ranges from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, eg, 3 -10 mg / kg / day. For example, an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, for example, from 1 mg to 100 mg, injectable ampoules, and orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, from 0.05 to 1000 mg, typically from 0.5 to 600 mg. For the therapy of the abovementioned conditions, the compounds according to formula I can themselves be used as compound, but they are preferably present with a compatible carrier in the form of a pharmaceutical composition. The carrier must of course be compatible in the sense that it is compatible with the other ingredients of the composition and is not harmful to 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 may also be present, including other compounds of the invention. The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in that the ingredients are mixed with pharmacologically acceptable carriers and / or excipients.

Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case is the nature and severity of the treatment State and on the nature of the particular compound used in accordance with formula I is dependent. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric-coated Coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients). In general, the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded, if necessary. For example, a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional ingredients. Pressed tablets may be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, and / or one or more surface active / dispersing agents in a suitable machine. Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for peroral (sublingual) administration include lozenges containing a compound of formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations may preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration are preferably as single dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil. Vaseline, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these substances can be used as the carrier. The active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.

Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may exist as single patches suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. As a special possibility For example, the drug may be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).

The compounds of the formula I are distinguished by favorable effects on metabolic disorders. They have a positive influence on the fat and sugar metabolism, they reduce in particular the triglyceride level and are suitable for the prevention and treatment of type II diabetes and atherosclerosis as well as their diverse secondary diseases.

Combinations with other medicines

The compounds according to the invention can be administered alone or in combination with one or more further pharmacologically active substances which, for example, have beneficial effects on metabolic disorders or diseases frequently associated therewith. Such medications are for example

1. Hypoglycaemic drugs, antidiabetics,

2. active ingredients for the treatment of dyslipidemias,

3. Antiatherosclerotic drugs,

4. Anti-obesity, 5. Anti-inflammatory agents

6. Active ingredients for the treatment of malignant tumors

7. Antithrombotic agents

8. agents for the treatment of hypertension

9. agents for the treatment of heart failure; and 10. active substances for the treatment and / or prevention of complications caused by

Diabetes are caused or associated with diabetes.

They can be combined with the compounds of the formula I according to the invention in particular for the synergistic effect improvement. The administration of the drug combination can either by separate administration of the active ingredients to the Patients or in the form of combination preparations, wherein several active ingredients are present in a pharmaceutical preparation carried out.

Examples include:

antidiabetics

Suitable antidiabetics are disclosed, for example, in the Red List 2001, Chapter 12 or the USP Dictionary of US and International Drug Names, US Pharmacopeia, Rockville 2003. Antidiabetics include all insulins and insulin derivatives such as, for example, Lantus ^® (see www.lantus.com) or Apidra ^®, and other insulins (see US 6,221, 633), GL P-1 receptor modulators fast acting as described in WO 01/04146 or such as those disclosed in WO 98/08871 by Novo Nordisk A / S. The orally active hypoglycemic agents preferably include the sulfonylureas acting on the ATP-dependent potassium channel of beta cells (eg, as disclosed in WO 97/26265 and WO 99/03861), biguanides, meglitinides, glucagon antagonists, oral GLP-1 agonists, DPP -IV inhibitors, insulin sensitizers, eg PPAR and PXR modulators and drugs such as oxadiazolidinediones, thiazolidinediones, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of the

Glucose uptake such as Glucosidase inhibitors, fat metabolism-altering compounds that alter the lipid composition of the blood, compounds that reduce food intake or food intake.

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 (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03 / 084922, WO 03/104188) In one embodiment, the compounds of formula I are administered in combination with an agent that acts on the ATP-dependent potassium channel of beta cells, such as sulfonylureas (eg, tolbutamide, glibenclamide, glipizide, glimepiride) or glinides (eg, repaglinide). In one embodiment, the compounds of formula I are administered in combination with a biguanide such as metformin.

In one embodiment, the compounds of formula I are used in combination with a PPARgamma agonist or thiazolidinedione, such as, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione the compounds of the formula I in combination with a DPPIV inhibitor, as described, for example, in WO98 / 19998, WO99 / 61431, WO99 / 67278, WO99 / 67279, WO01 / 72290, WO 02/38541, WO03 / 040174, in particular P 93/01 (1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98, LAF237 (1- [2- [3-hydroxyadamant-1-ylamino) acetyl] pyrrolidine-2- (S) carbonitrile), TSO21 ((2S, 4S) -4-fluoro-1 - [[(2-hydroxy-1,1-dimethylethyl) amino] acetyl] -pyrrolidine-2-carbonitrile monobenzene sulfonate)

In one embodiment, the compounds of formula I in combination with compounds having an inhibitory effect on SGLT-1 and / or 2, e.g. in WO2004 / 007517, WO2004 / 052902, WO2004 / 052903 and WO2005 / 121161 directly or indirectly disclosed.

In one embodiment, the compounds of formula I are administered in combination with an α-glucosidase inhibitor, such as miglitol or acarbose. In one embodiment, the compounds of the formula I are used in combination with more than one of the abovementioned compounds, for example in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, Repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

lipid modulators

In one embodiment of the invention, the compounds of formula I are 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 resorption inhibitor (see, e.g., U.S. 6,245,744, U.S. 6,221,897, U.S. 6,277,831, EP 0 683 773, EP 0 683 774).

In one embodiment of the invention, the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterol resorption inhibitor, e.g. in WO 02/50027, or Ezetimibe, Tiqueside, Pamaqueside administered.

In one embodiment of the invention, the compounds of formula I are administered in combination with an LDL receptor inducible (see, e.g., U.S. 6,342,512).

In one embodiment, the compounds of formula I in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob / Caromax ^® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct). 18 (5), 230-6)); Caromax is a carob-containing product from Nutrinova, Nutrition Speciales & Food Ingredients

GmbH, Industriepark Höchst, 65926 Frankfurt / Main). The combination with Caromax ^® can in a preparation carried out, or by separate administration of compounds of the formula I and Caromax ^®. Caromax ^® can also be administered in the form of food, such as in baked goods or muesli bars.

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

In one embodiment of the invention, the compounds of formula I in combination with a mixed PPAR alpha / gamma agonist, e.g. 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 as in WO 99/62872, WO 99/62871, WO 01/40171, WO 01/40169, WO 96/38428, WO 01/81327, WO 01/21602, WO 03/020269, WO 00/64888 or WO 00/64876.

In one embodiment of the invention, the compounds of formula I are used in combination with a fibrate, e.g. Fenofibrate, gemfibrozil, clofibrate, bezafibrate.

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

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

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

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

Antiobesity

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

In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. In yet another embodiment, the other active ingredient is sibutramine.

In a further embodiment, the compounds of the formula I are used in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript-influenced transient influenza energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormones and Metabolism Research (2001), 33 (9), 554-558), NPY antagonists, eg, naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl} -amide; hydrochloride (CGP 71683A)), MC4 agonists (eg. Amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4 , 3-c] pyridin-5-yl) -1- (4-chloro-phenyl) -2-oxo-ethyl] -amide; (WO 01/91752)), orexin antagonists (eg 1- (2-methylbenzoxazol-6-yl) -3- [1,5] naphthyridin-4-ylurea; hydrochlorides (SB-334867-A) ), H3 agonist (3-cyclohexyl-1 - (4,4-dimethyl-1, 4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) -propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (eg, [2-methyl-9- (2,4,6-trimethyl-phenyl) -9 H -1,3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585)), CRF BP antagonists (eg, urocortin), urocortin agonists, α-3 agonists (eg, 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3- dimethyl-1H-indol-6-yloxy) -ethylamino] -ethanol; hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (eg, {2- [4- (4 Chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7-dimethyl-indole-1-yl} -acetic acid trifluoroacetic acid salt (WO 99/15525 )); Serotonin reuptake inhibitors (eg dexfenfluramine), mixed serotonin and noradrenergic compounds (eg WO 00/71549), 5HT agonists eg 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111) , Bombesin agonists, galanin antagonists, growth hormone (eg, human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tertiary butyl ester (WO 01/85695)), TRH agonists (see eg EP 0462 884), decoupling protein 2- or 3-modulators, leptin agonists (see eg Lee, Daniel W., Leinung, Matthew C; Rozhavskaya-Arena, Marina Grasso, Patricia, Leptin agonists as a potential approach to the treatment of obesity, Drugs of the Future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors ( eg WO 00/40569), PPAR modulators (eg WO 00/78312), RXR modulators or TR-E agonists.

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

In one embodiment, the other active ingredient is dexamphetamine, amphetamine, mazindol or phentermine. In one embodiment, the additional active ingredient is one or more antidiabetics, hypoglycemic agents, HMGCoA reductase inhibitors, cholesterol resorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha / gamma agonists, fibrates, MTP inhibitors, bile acid resorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers , LDL Receptor Inducer, ACAT Inhibitors, Antioxidants, Lipoprotein Lipase Inhibitors, ATP Citrate Lyase Inhibitors, Squalene Synthase Inhibitors, Lipoprotein (a) Antagonists, Lipase Inhibitors, Insulins, Sulphonylureas, Biguanides, Meglitinides, Thiazolidinediones, σ-Glucosidase- Inhibitors, beta-cell ATP-dependent potassium channel drugs, CART agonists, NPY agonists, MC4 agonists, orexin antagonists, H3 agonists, TNF agonists, CRF antagonists, CRF BP antagonists, urocortin agonists, 3-agonists, MSH (melanocyte stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors ibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, TRH agonists, decoupling protein 2- or 3-modulators, leptin agonists, DA agonists (bromocriptine, doprexin) , Lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR - / - agonists or amphetamines.

In one embodiment, the compounds of formula I are administered in combination with drugs having effects on the cardiovascular and blood vessel systems, e.g. ACE inhibitors (e.g., ramipril), drugs acting on the angiotensin-renin system, calcium antagonists, beta-blockers, etc.

In one embodiment, the compounds of formula I are administered in combination with anti-inflammatory drugs.

In one embodiment, the compounds of formula I are administered in combination with medicaments used for cancer therapy and cancer prevention. It is understood that any suitable combination of the compounds of the present invention with one or more of the foregoing compounds and optionally one or more other pharmacologically active substances is considered to fall within the scope of the present invention.

The activity of the compounds of the formula I according to the invention was tested on the following enzyme test systems:

1. Test for inhibition of HSL

1.1. Preparation of the partially purified HSL:

Isolated rat fat cells are obtained from epididymal adipose tissue from untreated male rats (Wistar, 220-250 g) by collagenase treatment according to published procedures (eg S. Nilsson et al., Anal. Biochem., 158, 1986, 399-407, G. Fredrikson et Chem. 256, 1981, 6311-6320, H. Tornquist et al., J. Biol. Chem. 251, 1976, 813-819). The fat cells from 10 rats are washed three times by flotation with in each case 50 ml of homogenization buffer (25 ml Tris / HCl, pH 7.4, 0.25 M sucrose, 1 mM EDTA, 1 mM DTT, 10 μg / ml leupeptin, 10 μg / ml antipain, 20 μg / ml pepstatin) and finally taken up in 10 ml homogenization buffer. The fat cells are homogenized in a Teflon-in-glass homogenizer (Braun-Melsungen) by 10 strokes at 1500 rpm and 15 ° C. The homogenate is centrifuged (Sorvall SM24 tube, 5000 rpm, 10 min, 4 ° C). The shelter between the fat layer above and the pellet is removed and the centrifugation repeated. The resulting shelter is centrifuged again (Sorvall

SM24 tubes, 20000 rpm, 45 min, 4 ⁰ C). The shelter is removed and treated with 1 g of heparin-Sepharose (Pharmacia Biotech, CL-6B, washed 5 times with 25 mM Tris / HCl, pH 7.4, 150 mM NaCl). (Shake at intervals of 15 min) after incubation for 60 min at 4 ° C, the batch is centrifuged (Sorvall SM24 tubes, 3000 rpm, 10 min, 4 ⁰ C). The supernatant is brought to pH 5.2 by addition of glacial acetic acid and incubated for 30 min at 4 ° C. The precipitates are through Centrifugation (Sorvall SS34, 12,000 rpm, 10 min, 4 ° C) and in 2.5 ml of 20 mM Tris / HCl, pH 7.0, 1 mM EDTA, 65 mM NaCl, 13% sucrose, 1 mM DTT, 10 μg / ml leupeptin / Pepstatin / antipain suspended. The suspension is dialyzed overnight at 4 ° C. against 25 mM Tris / HCl, pH 7.4, 50% glycerol, 1 mM DTT, 10 μg / ml leupeptin, pepstatin, antipain and then applied to a hydroxyapatite column (0.1 g per liter ml suspension, equilibrated with 10 mM potassium phosphate, pH 7.0, 30% glycerol, 1 mM DTT). The column is washed with four volumes of equilibration buffer at a flow rate of 20 to 30 ml / h. The HSL is eluted with a volume of equilibration buffer containing 0.5 M potassium phosphate, then dialyzed (see above) and concentrated 5-10 fold by ultrafiltration (Amicon Diaflo PM 10 filter) at 4 ° C. The partially purified HSL can be stored for 4 to 6 weeks at -70 ^0C.

1.2. Assay for HSL activity:

For the preparation of the substrate, 25-50 μCi [3H] trioleoylglycerol (in toluene), 6.8 μmol unlabelled trioloylglycerol and 0.6 mg phospholipids (phosphatidylcholine / phosphatidylinositol 3: 1 w / v) are mixed, dried over N ₂ and then dissolved in 2 ml 0.1 M KPi (pH 7.0) by sonication (Branson 250, microtip, setting 1-2, 2 x 1 min at 1-min interval). After adding 1 ml of KPi and re-sonication (4 x 30 sec on ice at 30-sec intervals), 1 ml of 20% BSA (in KPi) is added (final concentration of trioleoyl glycerol 1.7 mM). For the reaction, 100 μl substrate solution are prepared to 100 μl HSL solution (HSL as above, diluted in 20 mM KPi, pH 7.0, 1 mM EDTA, 1 mM DTT, 0.02% BSA, 20 μg / ml pepstatin, 10 μg / ml Leupeptin) and incubated for 30 min at 37 ° C. After addition of 3.25 ml of methanol / chloroform / heptane (10: 9: 7) and 1.05 ml of 0.1 MK ₂ CO ₃ , 0.1 M boric acid (pH 10.5) is mixed well and finally centrifuged (800 xg, 20 min). After phase separation, one equivalent of the upper phase (1 ml) is taken and the radioactivity determined by liquid scintillation measurement. 1.3. Evaluation of HSL inhibitory activity:

Substances are usually tested in four independent approaches. The inhibition of the enzymatic activity of HSL by a test substance is determined by comparison with a non-inhibited control reaction. The calculation of IC _ö o value from an inhibition plot with min. 10 concentrations of the test substance. For the analysis of the data the software package GRAPHIT, Elsevier BIOSOFT, is used.

2nd test for inhibition of EL:

2.1. Preparation of EL

EL is released as a secretory protein from recombinant cell lines (CHO, HEK293) in high concentration in cell culture medium (conditioned medium). This is used after concentration as an enzyme solution.

2.2. Assay for EL activity

To characterize the enzymatic activity of endothelial lipase and the action of inhibitors, the phospholipase-specific substrate becomes 1,2-bis- (4,4-difluoro-δ.Z-dimethyl-bora- Sa -a-diaza-s-indacene By hydrolysis of the A1 ester bond of this phospholipid by the enzyme, the fluorescent dye Bodipy is released which, after separation by thin layer chromatography on an HPTLC plate (Kieselgel 60, Chromatography, Vol. Merck) or directly in the reaction vessel by measuring the fluorescence.For the preparation of the substrate solution are 100 ug 1, 2-bis (4,4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza- s-indacene-3-undecanoyl) -sn-glycero-3-phospho-choline (manufacturer Molecular Probes), 2.4 mg tripalmitin (Sigma) and 7.9 mg DOP choline (1, 2-dioleoyl) sn-glycero-3-phosphocholine) in 393 .mu.l of chloroform and then transferred 157 .mu.l in a fresh reaction vessel. After evaporation of the solvent, the lipid mixture is dissolved in 4 ml of 200 mM TRIS-HCl, 150 mM sodium chloride, pH = 7.4 by sonicating twice. The subsequent enzyme reaction takes place at 37 ^° C. for 60 minutes. To this end, 45 μl of the substrate solution are incubated with 1 μl inhibitor of appropriate concentration (dissolved in DMSO, pure DMSO solution is used for the control) and 5 μl of enzyme solution (conditioned medium). Subsequently, 3 .mu.l of the test mixture are applied to an HPTLC plate (Kieselgel 60, Merck) and the liberated fluorescent dye for detection with a flow agent (diethyl ether: petroleum benzine: acetic acid [78: 22: 1]) separated. After evaporation of the solvent, the plate is read into a fluorescence scanner. As a measure of the enzyme activity, an increased release of the fluorescent dye in the uninhibited reaction can be observed.

2.3. Evaluation of the EL inhibitory effect:

Depending on the inhibitor concentration used, there is a reduction in the enzymatic activity, the inhibitor concentration at which a half-maximal enzyme activity is observed is referred to as ICs ₀ .

In these tests, the compounds of the examples showed the following of IC ₅₀ values:

Process for the preparation

The preparation of the compounds of general formula I according to the invention is carried out according to methods known per se, e.g. by acylation of substituted or unsubstituted azoles II with carbamoyl chlorides III (method A), or in two stages by reacting azoles II with phosgene or equivalents such as trichloromethyl chloroformate, carboxylic acid nitrilotiormethyl or 4-nitrophenyl chloroformate and further reacting the obtained Azolcarbonsäurederivats with amines IV (Method B). For compounds in which R3 is hydrogen (formula Ia), the azoles II can also be reacted with the corresponding isocyanates V R2-N = C = O (method C).

IV

Ia

Since acids are generally released in these reactions, it is advisable to add bases such as pyridine, triethylamine, sodium hydroxide solution or alkali metal carbonates to accelerate them. The reactions can be carried out in wide temperature ranges. In general, it has been found to be advantageous to work at 0 ⁰ C to the boiling point of the solvent used. The solvents used are, for example, methylene chloride, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, diethyl ether or pyridine. When working under anhydrous conditions, strong bases such as lithium hydride, sodium hydride or potassium tert-butoxide have also proven useful in aprotic solvents such as THF or DMF. The azoles or corresponding azabased derivatives used as starting compounds II are commercially available or can be prepared by literature methods (eg 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, MA Khan, FK Rafla, J. Chem. Soc., 1975, 693-694).

The following examples serve to illustrate the invention, but without limiting it. Examples

Example 1:

4-Methyl-piperidine-1-carboxylic acid 6-chloro-benzo [d] isoxazol-3-yl ester

200 mg (1.18 mmol) of 6-chloro-benzo [d] isoxazol-3-ol, 228.7 mg (1.41 mmol) of 4-methylpiperidine-1-carbonyl chloride and 164 μl (2.36 mmol) of triethylamine were dissolved in 10 ml of pyridine and Stirred for 24 h at room temperature. The reaction mixture was concentrated, the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18,

Acetonitrile / water O.1% TFA). Yield: 147 mg (42%), M + H +: 295.2.

Example 2: 4-Methyl-piperidine-1-carboxylic acid isoxazolo [5,4-b] pyridin-3-yl ester

125 mg (0.918 mmol) of isoxazolo [5,4-b] pyridin-3-ol, 178 mg (1.1 mmol) of 4-methylpiperidine-1-carbonyl chloride and 255 μl (1.84 mmol) of triethylamine were dissolved in 10 ml of pyridine and stirred for 4 h at room temperature. A further 89 mg (0.55 mmol) of 4-methyl-piperidine-1-carbonyl chloride and 128 μl (0.92 mmol) of triethylamine were added and the mixture was stirred at room temperature for a further 6 h. The reaction mixture was concentrated, 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: 101 mg (42%), M + H +: 262.1.

Example 3: 4-Trifluoromethyl-piperidine-1-carboxylic acid 6-chloro-benzo [d] isoxazol-3-yl ester

200 mg (1.18 mmol) of 6-chloro-benzo [d] isoxazol-3-ol with 305. Were analogously to Example 1 mg (1.41 mmol) of 4-trifluoromethyl-piperidine-1-carbonyl chloride. Yield: 229 mg (56%), M + H +: 349.05.

Example 4:

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

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

Example 5:

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

45 mg (0.3 mmol) of benzo [d] isothiazol-3-one were reacted analogously to Example 1 with 58 mg (0.36 mmol) of 4-methyl-piperidine-1-carbonyl chloride. Yield: 26 mg (32%), M + H +: 277.14.

Example 6: 1-Hexyl-3- (5-nitrobenzo [d] isothiazol-3-yl) urea

100 mg (0.513 mmol) of 5-nitrobenzo [d] isothiazol-3-ylamine were suspended in 5 ml of THF. After addition of 78.1 mg (0.61 mmol) of 1-isocyanato-hexane was 2 h at RT and stirred for 2 h at 70 ⁰ C. Then another 0.3 mmol of 1-isocyanato-hexane was added and the mixture was stirred at 7O ⁰ C for a further 6 h. The reaction mixture was concentrated, 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: 18 mg (11%), M + H +: 323.15. Example 7:

1- (2-methyl-benzyl) -3- (5-nitro-benzo [d] isothiazol-3-yl) -urea

100 mg (0.51 mmol) of 5-nitrobenzo [d] isothiazol-3-ylamine were used as in Example 6

90.4 mg (0.61 mmol) of i-isocyanatomethyl-2-methyl-benzene reacted. Yield: 11 mg (6%), M + H +: 343.16.

Example 8:

1-Benzo [d] isoxazol-3-yl-3-hexyl-urea

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

Example 9:

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

2.99 g (9.82 mmol) of isothiazoio [5,4-b] pyridin-3-ol were reacted with 2.33 g (10.81 mmol) of 4-trifluoromethyl-piperidine-1-carbonyl chloride analogously to Example 1. Yield: 1.3 g (40%), M + H +: 332.09.

Example 10:

4-Methyl-piperidine-1-carboxylic acid 6-Chloro-isoxazolo [5,4-b] pyridin-3-yl ester

55 mg (0.32 mmol) of 6-chloro-isoxazolo [5,4-b] pyridin-3-ol were reacted with 62.7 mg (0.39 mmol) of 4-methylpiperidine-1-carbonyl chloride analogously to Example 1. Yield: 22 mg (24%), M + H +: 296.04. Example 11:

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

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

Claims

claims

1. Compound of general formula I.

7

(I) wherein: AS ₁ O;

W - (C = O) -, - (S = O) -, - (SO ₂ ) -;

X is the same or different = C (-R) - or = N-;

Y is -O- or -NR1-;

R is hydrogen, halogen, (C _r _C6) alkyl, (dC ^ alkyloxy-fd-C ^ alkylene,

Hydroxy, (C ₁ -C ₆ ) -alkylmercapto, amino, (C ₁ -C ₆ ) -alkylamino, C ₁ -C ₁₂ -alkylamino, mono- (C ₁ -C ₆ ) -alkylaminocarbonyl, C ₁ -C 4 -dichloromethane, C ₁ -C 4 -alkylamino, C ₁ -C 4 -alkylamino ₈₎ - alkylaminocarbonyl, COOR4, trifluoromethyl, (Ci-C ₆₎ alkylsulfonyl, (C _r _C6) -Alkylsulfιnyl, aminosulfonyl, nitro, pentafluorosulfanyl, (C ₆ -C ₁₀₎ aryl, CO-NR2R3, O-CO -NR2R3, O-CO- (CrC ₆₎ -alkylene-CO-O- (C ₁ -C ₆₎ alkyl,

O-CO- (C 1 -C ₆ ) -alkylene-CO-OH, O-CO- (C 1 -C ₆ ) -alkylene-CO-NR 2 R 3 or (C 1 -C ₆ ) -alkyloxy which is unsubstituted or mono- or polysubstituted by F;

R1 is hydrogen, (C 1 -C ₆ ) alkyl, benzyl; R 2 (C ₅ -C ₁₆ ) -alkyl, (C 1 -C ₄ -alkyC-Cene-D-y-aryl, where aryl may be replaced by

Halogen, (C ₁ -Ce) -alkyl, (CrC ^ -alkyloxy, hydroxy, (C ₁ -C ₆₎ - alkylmercapto, amino, (CiC _δ J-alkylamino, di- (C ₂ -C ₂₎ alkylamino, mono- (CrC ₆₎ -alkylaminocarbonyl, di- _(C2-C8) -alkylaminocarbonyl, (C ₁ -Ce) - alkoxycarbonyl, cyano, trifluoromethyl, trifluoromethyloxy, (Ci-Ce) -

Alkylsulfonyl, aminosulfonyl, nitro may be monosubstituted or polysubstituted;

R 3 is hydrogen, (C 1 -C ₆ ) -alkyl; or

R 2 and R 3, together with the nitrogen atom bearing them, can 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 whose individual members of the ring systems can be substituted by one to three atoms Atomic groups from the series

-CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -C (= O) -, -O-, -S-, -SO-, -SO ₂ -, may be replaced with with the proviso that two units from the series -O-, -S-, -SO-, -SO ₂ - must not be adjacent;

_R _{4 is} hydrogen, (C 1 -C ₆ ) -alkyl, benzyl;

R 5 (C 1 -C ₆ ) -alkyl, halogen, trifluoromethyl, COOR 4, cyclopropyl,

Cyclopropylene; mean the tautomeric forms of the compounds and their physiologically acceptable salts.

2. Compounds of formula I according to claim 1, wherein

W - (C = O) - means.

3. A compound of formula I according to claim 1 or 2, characterized in that

W - (C = O) -;

X is the same or different = C (-R) - or = N-;

Y is -O-, -NR1-;

R is hydrogen, halogen, (C 1 -C ₆ ) -alkyl, hydroxy, amino, COOR 4,

Trifluoromethyl, (Ci-C ₆₎ alkylsulfonyl, nitro, pentafluorosulfanyl, (C ₆ -C ₁₀₎ - aryl, CO-NR2R3, O-CO-NR2R3 or O-CO- (C _r _C6) -alkylene-CO- O- (C _r _C6) alkyl, (CrC ₆₎ alkyloxy;

R1 is hydrogen, (C 1 -C ₆ ) -alkyl;

R2 (C ₆ -C ₁₀₎ alkyl, (Ci-C ₃₎ -alkyl- (C ₆ -C ₁₀₎ -aryl, wherein aryl is optionally by

Halogen, (CrC ₆₎ alkyl, (C _r _C3) -alkyloxy, hydroxy, amino, (C ₁ -C ₆₎ - alkylamino, trifluoromethyl, nitro or polysubstituted may be substituted;

R3 is hydrogen, (C _r C ₆ ) -alkyl; or

R 2 and R 3, together with the nitrogen atom bearing them, can form a monocyclic, saturated 5- to 6-membered ring system or a bicyclic saturated or partially unsaturated 9- to 10-membered ring system whose individual members of the ring systems can be replaced by a - three atoms or groups of atoms from the series -CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -O-, -S- may be replaced, with the proviso that two units from the series - O-, -S- may not be adjacent;

_R _{4 is} hydrogen, (C 1 -C ₆ ) -alkyl, benzyl;

R 5 (C ₁ -C ₆ ) -alkyl, halogen, trifluoromethyl, COOR 4, cyclopropyl,

Cyclopropylene mean.

4. A compound of formula I according to claims 1, 2 or 3, characterized in that

W - (C = O) -;

X is the same or different = C (-R) - or = N-;

Y -O-;

R is hydrogen, halogen, nitro, hydroxy, (C ₁ -C ₃ ) -alkyloxy or (C ₁ -C ₆ ) -

alkyl;

R 2 is (C ₆ -C 10) -alkyl or benzyl, where benzyl may optionally be substituted by halogen, (C ₁ -C ₆ ) -alkyl or trifluoromethyl;

R3 is hydrogen; or

R2 and R3 together with the nitrogen atom carrying them can form a monocyclic, saturated 5- to 6-membered ring system, the individual thereof Members of the ring systems may be replaced by one to two atoms or atomic groups from the series -CHR5-, -NR5-; and

R5 is (CrCβ) alkyl, trifluoromethyl or cyclopropyl.

5. A compound of formula I according to claims 1, 2 or 3, characterized in that

W - (C = O) -;

X is the same or different = C (-R) - or = N-;

Y -NR1-;

R is hydrogen, halogen, nitro, hydroxy, (C ₁ -C ₃ ) -alkyloxy or (C ₁ -C ₈ ) -

alkyl;

R1 is hydrogen, (C _r _C6) alkyl;

R2 (C ₆ -C ₁₀₎ -A! Ky! or benzyl, where benzyl is optionally substituted by halogen, (CrCβ) -

Alkyl or trifluoromethyl may be substituted;

R3 is hydrogen; or

R 5 is (C 1 -C ₆ ) -alkyl, trifluoromethyl or cyclopropyl.

6. A compound of formula I according to claims 1 to 5, characterized in that

NR2R3 is piperidine containing the atomic element CHR5 in the 4 position.

7. Compounds of formula I according to claims 1 to 6, characterized in that

8. A compound of formula I according to claims 1 to 7, characterized in that

9. A compound of formula I according to claims 1 to 6, characterized in that

X is the same or different = C (-R) -.

10. A compound of formula I according to claims 8 or 9, characterized in that

11. Medicaments containing one or more compounds of the formula I according to claims 1 to 10.

12. Medicament, according to claim 11, characterized in that it contains as further active ingredient one or more

Antidiabetics, hypoglycemic agents, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists,

PPAR alpha agonists, PPAR alpha / gamma agonists, fibrates, MTP inhibitors, bile acid resorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists,

Lipase inhibitors, insulins, sulphonylureas, biguanides, meglitinides, thiazolidinediones, σ-glucosidase inhibitors, beta-cell ATP-dependent potassium channel drugs, CART agonists, NPY agonists, MC4 agonists, orexin antagonists, H3 agonists, TNF agonists, CRF antagonists, CRF BP antagonists, urocortin

Agonists, / 3-agonists, MSH (melanocyte stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, TRH agonists, decoupling protein 2- or 3-modulators, leptin agonists, DA agonists (bromocriptine, doprexine), lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR - /? agonists or amphetamines ,

13. Use of the compounds of the formula I according to claims 1 to 10 for the treatment and / or prevention of disorders of the fatty acid metabolism and glucose utilization disorders.

14. Use of the compounds of the formula I according to claims 1 to 10 for the treatment and / or prevention of disorders in which insulin resistance plays a role.

15. Use of the compounds of the formula I according to claims 1 to 10 for the treatment and / or prevention of diabetes mellitus and the associated secondary diseases.

16. Use of the compounds of the formula I according to claims 1 to 10 for the treatment and / or prevention of dyslipidemias and their consequences.

17. Use of the compounds of the formula I according to claims 1 to 10 for the treatment and / or prevention of conditions associated with the metabolic syndrome.

18. Use of the compounds of the formula I according to claims 1 to 10 in combination with at least one further active ingredient for the treatment and / or prevention of disorders in which insulin resistance plays a role.

19. A process for the preparation of a medicament comprising one or more of the compounds of the formula I according to claims 1 to 10, characterized characterized in that it is mixed with a pharmaceutically suitable carrier and this mixture is brought into a suitable form for administration.

20. A process for the preparation of compounds of the general formula I according to claims 1 to 10, characterized in that azoles of the formula II

a) be acylated with carbamoyl chlorides of the formula III; or b) are reacted in two stages, first with phosgene or equivalents such as trichloromethyl chloroformate, carboxylic acid or Nitrethyl chloroformate and a second step with amines of the formula IV, wherein the substituents have the meanings given above.

III

IV

21. A process for the preparation of compounds of general formula I with R3 hydrogen (formula Ia) according to claims 1 to 10, characterized in that azoles of the formula II are reacted with isocyanates of the formula V: O = C = N-R2.

Ia