MXPA06008406A - Indazole derivatives as inhibitors of hormone-sensitive lipases - Google Patents

Abstract

The invention relates to indazole derivatives of general formula (I) or (II), with the meanings as given in the description, the pharmaceutically-acceptable salts and use thereof as medicaments.

Description

DERIVATIVES OF INDAZOL AS LIQUID INHIBITORS SENSITIVE TO HORMONES The present invention relates to derivadosdazole derivatives of the general formulas I or II, to the salts thereof which are useful from a pharmaceutical point of view and to the use thereof as drugs. Nandol derivatives for stimulating the cannabinoid receptor are described in WO 03/035005 and 3-amino-indazolecarboxylic acid derivatives are described in DE 24 58965. There are also descrins of phenylcarbamoyl indazoles in WO 2004/046090 and 3-amino-5 phenylindazo I-1-carboxamide in US 2004/0097485, these two documents having been published only after having presented the present priority application. The invention relates to indazole derivatives of the general formulas I or II, (I) (ll) in which the meanings are: W - (C = O) -, - (S = O) -, - (SO2) -; X = C (-R) - or = N-; Y -O- or -N (R1); R hydrogen, halogen, alkyl, (C? -C6), alkyloxy- (C? -C3) -alkyl- (C? -C3), hydroxy, alkyl- (C? -C6) -mercapto, amino, alkyl - (C? -C6) -amino, di-alkyl- (C2-C? 2) -amino, mono-alkyl- (C? -C6) -aminocar-bonyl, di-alkyl- (C2-C8) -aminocar - bonyl, COOR4, cyano, trifluoromethyl, alkyl- (C6-6) -sulfonyl, alkyl- (C6-6) -sulfinyl, aminosulfonyl, nitro, pentafluorosulfonyl, aryl- (C6-C6), heteroaryl- ( C5-C12), CO-NR2R3, O-CO-NR2R3, O-CO-alkylene-id-CeI-CO-O-alkyl-id-Ce), O-CO-alkylene- (C? -C6) -CO -OH, O-CO-alkylene-CrCei-CO-, NR2R3 or alkyloxy- (CrC6) unsubstituted or mono- or poly-substituted in F; R1 H, alkyl- (CrC6), benzyl; R2 H, alkyl-Id-Ce), alkyi- (C4) -phenyl; aryl- (C6-C10), where the phenyl or the aryl may be substituted, onally, with a halogen, (C? -C6) alkyl, (C? -C3) alkyloxy, hydroxy, alkyl- (C ? -C6) -mercapto, amino, alkyl- (C? -C6) -amino, di- (C2-C12) -alkylamino, mono-alkyl- (C? -C6) -aminocarbonyl, di-alqu L- (C2-C8) ~ aminocarbonyl, alkoxy- (C6C6) -carbonyl, cyano, trifluoromethyl, trifl uo ro m eti i oxy, alkyl- (C6C6) sulphonyl, aminosulfonyl, nitro; or tetramethyl-tetrahydronaphthalene; R3 H, alkyl-id-Ce); or R2 and R3 can form, together with the nitrogen atom carrying them, a saturated monocyclic or partially unsaturated 4 to 7 membered ring system or a saturated or partially unsaturated bicyclic 8 to 14 membered ring system, wherein the individual members of the ring systems can be replaced by one to two atoms or atomic groups of the series -CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -C (= O) -, - O-, -S-, -SO-, -SO2-, with the proviso that two units of the series -O-, -S-, -SO-, -SO2- may not be adjacent; R4 hydrogen, alkyl- (C? -C6), benzyl; R5 alkyl- (C? -C6), halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene; and the salts thereof physiologically tolerated as well as their tautomeric forms, with the proviso that in the compounds of the formula (I) with W = CO a) R2 and R3 form, together with the nitrogen atom that carries them, a system of monocyclic or bicyclic ring if Y = N (R1) with R1 = H or alkyl- (C? -C6) or b) Y-R1, R2 and R3 can not have, simultaneously, the following meanings: Y-R1 = OH, R2 = aryl- (C6-C? O) onally substituted and R3 = H. Preferred compounds of formulas I and II are those in which Y is -O-, or those in which W is - (C = OR)-. Preferred compounds of formulas I and II are further those in which NR2R3 is a saturated 5-6 membered monocyclic ring system comprising in the 4-position an atom or an atomic member of the series -CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -O-, -S-. Additional preferred compounds of formulas I and II are those in which X at positions 4, 5 and 7 is = C (-R) - with R = hydrogen. Particularly preferred compounds of formula I or II are those in which W is - (C = O) -; X is = C (-R) - or = N-; Cast-; R is hydrogen, halogen, alkyl- (C? -C6), hydroxy, amino, COOR4, trifluoromethyl, alkyI- (C? -C6) -sulfonyl, nitro, pentafluorosulfanyl, aryl- (C6-do) ), CO-NR2R3, O-CO- NR2R3 or O-CO-alkylene- (C1-C6) -CO-O-alkyl- (C? -C6); R1 is H, alkyl- (C? -C6), benzyl; R2 is alkyl- (C? -C6), benzyl, aryl- (C6-C? 0) or tetramethyl-tetrahydronaphthalene; R3 is H, alkyl- (C? -C6); or R2 and R3 can form, together with the nitrogen atom carrying them, a saturated 5-6 membered monocyclic ring system or a saturated or partially unsaturated bicyclic 9 to 10 membered ring system in which the individual members of the ring systems can be replaced by one to two atoms or atomic groups of the series -CHR5-, -CR5R5-, - (C = R5) -, - NR5-, -O-, -S-, with the proviso that two units of the series -O-, -S- may not be adjacent; R 4 is hydrogen, (C 6 -C 6) alkyl or benzyl; R5 is alkyl- (C? -C6), halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene. Particularly preferred compounds of the formula I are, in addition, those in which W is - (C = O) -; X is = C (-R) - or = N-; Cast-; R is hydrogen, halogen, nitro, hydroxy or alkyl- (C? -C6); R1 is H or alkyl- (C? -Ce); R2 is alkyl- (C6C6), benzyl or aryl- (C6-do); R3 is alkyl- (d-C6), or R2 and R3 can form, together with the nitrogen atom to which they are attached, a saturated 5-6 membered monocyclic ring system or a 9-10 membered bicyclic ring system saturated or partially unsaturated in which the individual members of the ring systems can be replaced by an atom or an atomic group of the series -CHR5-, -NR5-; and R5 is alkyl- (C? -C6), or cyclopropyl. Particularly preferred compounds of formula II also those in which W is - (C = O) -; X is = C (-R) - or = N-; Cast-; R is hydrogen, halogen, alkyi (C? -C6), hydroxy, amino, COOR4, trifluoromethyl, alkyl- (C? -C6) -sulfonyl, nitro, pentafluorosulfanyl, aryl- (C6-do), CO-NR2R3, O-CO- NR2R3 or O-CO-alkylene- (d-C6) -CO-O-alkyl- (C? -C6); R1 is H, alkyl- (C6C6) or benzyl; R2 is alkyl- (C? -C6), aryl- (C6-C? O) or tetramethyl-tetrahydronaphthalene; R3 is H, alkyl- (C? -C6); or R2 and R3 can form, together with the nitrogen atom carrying them, a saturated 5-6 membered monocyclic ring system or a saturated or partially unsaturated bicyclic 9 to 10 membered ring system in which the individual members of the ring systems can be replaced by one or two atoms or atomic groups of the series -CHR5-, -CR5R5-, - (C = R5) -, - NR5-, -O-, -S-, with the proviso that two units of the series -O-, -S- may not be adjacent; R 4 is hydrogen, (C 6 -C 6) alkyl, benzyl; and R5 is alkyl- (C? -C6), halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene. Very particularly preferred compounds of the formula I are those in which NR2R3 is piperidine comprising the atomic member CHR5 in the 4 position. The invention relates to compounds of the formulas I or II in the form of their salts, racemates, racemic mixtures and pure enantiomers, and their diastereomers and their mixtures. The alkyl radicals in the substituents R, R 1, R 2, R 3, R 4, R 5 can have straight or branched chain. Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine, Aryl means a monocyclic or bicyclic aromatic ring system with 6 to 10 ring or ring atoms which may be substituted, independently, with each other four substituents, preferably one or two substituents - as described herein. Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have an anion or cation acceptable from a pharmaceutical point of view. Salts of acid addition of the compounds of the invention suitable acceptable from pharmaceutical viewpoint are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acids, for example, acetic, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p- toluenesulfonic and tartaric acid. Suitable basic salts acceptable from pharmaceutical viewpoint are ammonium salts, alkali metal salts (such as sodium and potassium) and alkaline earth metal salts (such as magnesium salts and calcium) and salts trometamol (2-amino-2 -hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine. Salts with a non-acceptable anion from a pharmaceutical point of view are, within the scope of the invention, intermediates useful for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic applications., for example, in in vitro applications. The term "functional derivative from a physiological point of view" as used herein, refers to any derivative of a compound of the formula I or II of the invention that is tolerated from a physiological point of view, for example a ester, which when administered to a mammal, such as a human being, is capable of forming (directly or indirectly) a compound of formula I or II or an active metabolite thereof. Functional derivatives from a physiological point of view include prodrugs of the compounds of the invention as, for example, those described in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. These prodrugs can be metabolized in vivo to give a compound of the invention. These prodrugs can be active or not in themselves. The compounds of the invention can also exist in various polymorphic forms, for example, as amorphous or crystalline polymorphic forms. All polymorphic forms of the compounds of the invention fall within the scope of the invention and are a further aspect of the invention. All references to "compound (s) of formula I or II" hereinafter refer to compound (s) of formula I or 11 as described above, and to their salts, solvates and derivatives functional from a physiological point of view as described herein.

Use The compounds of the invention of the general formulas I or II have a surprising inhibitory effect on hormone-sensitive lipase, HSL, an allosteric enzyme in adipocytes which is inhibited by insulin and which is responsible for the degradation of fats in fat cells and , therefore, to transfer the constituents of the fats to the bloodstream. Therefore, the inhibition of this enzyme is equivalent to an effect similar to that of the insulin of the compounds of the invention, which finally results in a reduction of free fatty acids in the blood and blood glucose. Therefore, they can be used in metabolic disorders such as, for example, in diabetes mellitus not dependent on insulin, in the diabetic syndrome and in direct damage of the pancreas. Compounds of this type are particularly suitable for the treatment and / or prevention of 1. - disorders of fatty acid metabolism and disorders of glucose utilization - disorders in which insulin resistance is involved 2. Diabetes mellitus, especially diabetes type 2, which includes the prevention of the sequelae associated with it. Particular aspects in this regard are - hyperglycemia, - improvement in insulin resistance, - improvement in glucose tolerance, - protection of pancreatic β cells - prevention of macro and microvascular disorders 3. Dyslipidemias and their sequelae, for example, atherosclerosis, coronary diseases, cerebrovascular disorders, etc., especially those (but not restricted to them) that are characterized by one or more of the following factors: plasma concentrations of high triglycerides, postprandial plasma concentrations of high triglycerides, of low HDL cholesterol - low ApoA lipoprotein concentrations - high LDL cholesterol concentrations - small dense LDL cholesterol particles - high ApoB lipoprotein concentrations 4. Other different states that may be associated with the metabolic syndrome, such as: - obesity (excessive weight ), which includes obesity centers l - thrombosis, hypercoagulation and prothrombotic states (arterial and venous) - high blood pressure - heart failure as, for example (but not restricted to), which follows myocardial infarction, heart disorder with hypertension or cardiomyopathy 5. Other disorders or states in which they may be involved, for example, inflammatory reactions or cell differentiation are: - atherosclerosis as, for example (but not restricted to), coronary sclerosis that includes angina pectoris or myocardial infarction, stroke - vascular restenosis or reocclusion - chronic inflammatory bowel disorders such as Crohn's disease and ulcerative colitis - pancreatitis - other inflammatory conditions - retinopathy - adipose cell tumors - lipomatous carcinomas, such as, for example, liposarcomas - solid tumors and neoplasms, for example (but not restricted a), carcinomas of the gastrointestinal tract, liver, biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, kidneys and urinary tract, genital tract, prostate carcinomas etc - acute and chronic myeloproliferative disorders and lymphomas - angiogenesis - neurodegenerative disorders - Alzheimer's disease - multiple sclerosis - Parkinson's disease - erythematous-squamous dermatoses such as, for example, psoriasis - acne vulgaris - other skin disorders and dermatological conditions that are modulated by PPAR - eczema and neurodermatitis - dermatitis such as, for example, seborrheic dermatitis or photodermatitis - keratitis and keratosis, such as seborrheic keratosis, senile keratosis, actinic keratosis, keratosis induced by light or follicular keratosis - keloids and keloids prophylaxis - warts that include condilomata or condilomata acuminata - human papillomavirus (HPV) infections such as, for example, venereal papillomata, viral warts such as molluscum contagiosum, leukoplakia - papular dermatosis such as, for example, lichen planus - skin cancer, such as, for example, basal cells, melanomas or cutaneous T-cell lymphomas - localized benign epidermal tumors such as, for example, keratoderma, epidermal naevi - chilblains - high blood pressure - syndrome X - polycystic ovary syndrome (PCOS) - asthma - osteoarthritis - lupus erythematosus (LE ) or rheumatic inflammatory disorders such as, for example, rheumatoid arthritis - vasculitis - cachexia - gout - ischemia / reperfusion syndrome -. acute respiratory distress (ARDS) - lipodystrophy and lipodystrophic states, also to treat adverse effects of medications (for example, after medications to treat HIV or tumors) Formulations The amount of a compound of the invention required to achieve the desired biological effect depends on several factors, for example, the specific compound chosen, the intended use, the route of administration and the clinical condition of the patient. The daily dose is generally in the range of 0.3 mg to 100 mg (typically 3 mg to 50 mg) per day and per kilogram of body weight, eg, 3-10 mg / kg / day. An intravenous dose can be, for example, in the range of 0.3 mg to 1.0 mg / kg, which can be administered, suitably, as an infusion of 10 ng to 100 ng per kilogram per minute. Infusion solutions suitable for these purposes may contain, for example, 0.1 ng to 10 mg, typically 1 ng to 10 mg, per milliliter. The individual doses may contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injections may contain, for example, 1 mg to 100 mg, and single dose formulations that can be administered orally, such as, for example, tablets or capsules, may contain, for example, 0.05. to 1,000 mg, typically from 0.5 to 600 mg. In the case of therapy of the conditions mentioned above, the compounds of formula I or II can be used as the compound itself, but preferably they are in the form of a pharmaceutical composition with an acceptable carrier. Of course, the vehicle must be acceptable in the sense that it is compatible with the other ingredients of the composition and that it is not detrimental to the patient's health. The carrier may be a solid or a liquid or both and preferably is 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 active substances can also be present from a pharmaceutical point of view, which include other compounds of the invention. The pharmaceutical compositions of the invention can be produced by one of the known pharmaceutical methods, consisting essentially of mixing the ingredients with vehicles and / or excipients acceptable from a pharmacological point of view. Pharmaceutical compositions of the invention are those, suitable for oral, rectal, topical, peroral for example, sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most appropriate administration route depends in each individual case of the nature and severity of the condition to be treated and the nature of the compound of formula I or II used in each case. Coated formulations and slow release coated formulations are also within the scope of the invention. Preference is given to formulations resistant to acids and gastric juices. Suitable coatings resistant to gastric juices comprise cellulose acetate phthalate, poly (vinyl acetate phthalate), hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. Pharmaceutical compounds suitable for oral administration may be in the form of individual units, such as, for example, capsules, tablets that are sucked or compressed, each of which contains a defined amount of the compound of formula I or II; as powders 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 mentioned above, these compositions can be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the vehicle (which can consist of one or more additional ingredients) are brought into contact. Generally, the compositions are produced by a uniform and homogeneous mixture of the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, when appropriate, with one or more additional ingredients. Pressed tablets can be produced by pressing the soft flowing compound, for example, from a powder or granules, where appropriate mixed with a binder, inert diluent and / or one or more surfactants / dispersants in a suitable machine . The molded tablets can be produced by molding the compound, which is in powder form and moistened with an inert liquid diluent, in a suitable machine. Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise sucking tablets containing a compound of formula I or II with a flavoring, usually sucrose and gum arabic or tragacanth, and lozenges comprising the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I or II, which are preferably isotonic with the blood of the recipient. These preparations are preferably administered intravenously, although they can also be administered by subcutaneous, intramuscular or intradermal injection. Preferably, these preparations can be produced by mixing the compound with water and sterilizing the resulting solution and making it isotonic with the blood. Generally, the injectable compositions of the invention contain from 0.1 to 5% by weight of the active compound. Pharmaceutical compositions suitable for rectal administration are preferably in the form of single dose suppositories. These can be produced by mixing a compound of the formula I or II with one or more conventional solid carriers, for example, cocoa butter, and by molding the resulting mixture. Pharmaceutical compositions suitable for topical use in the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Vehicles that can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. Generally, the active ingredient is present in a concentration of from 0.1 to 15% by weight of the composition, for example, from 0.5 to 2%. Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal uses may be in the form of individual patches that are suitable for close contact with the epidermis of the patient for a long period of time. Said patches suitably contain the active ingredient in an aqueous solution which is buffered when appropriate, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable concentration of the active ingredient is about 1% to 35%, preferably about 3% to 15%. A particular possibility is that the active ingredient is released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986). The compounds of formulas I and II are characterized by having favorable effects on metabolic disorders. They have a beneficial effect on the metabolism of lipids and sugars, in particular, they lower the level of triglycerides and are suitable for the prevention and treatment of type II diabetes and arteriosclerosis and the various sequelae of these.

Combinations with other medications The compounds of the invention can be administered alone or in combination with one or more additional substances active from a pharmacological point of view which have, for example, favorable effects on alterations or metabolic disorders which are frequently associated with them. Examples of these medications are 1. drugs that lower blood glucose, antidiabetics, 2. active ingredients for the treatment of dyslipidemias, 3. anti-atherosclerotic drugs, 4. anti-obesity agents, 5. anti-inflammatory active ingredients 6. active ingredients for the treatment of malignant tumors 7. active ingredients antithrombotic 8. active ingredients for the treatment of high blood pressure 9. active ingredients for the treatment of heart failure and 10. active ingredients for the treatment and / or prevention of complications caused by diabetes or associated with diabetes. They can be combined with the compounds of the invention of the formula I or II, in particular, in order to achieve a synergistic improvement in the effect. Administration of the active ingredient combination can take place by separate administration to the patient of the active ingredients or in the form of combination products in which a plurality of active ingredients are present in a pharmaceutical preparation.

Examples that may be mentioned are: Suitable Antidiabetic Antidiabetics are described, for example, in Rote 2001, Chapter 12 or in the USP Dictionary of USAN and International Drug Yams, US Pharmacopeia, Rockville 2001. Antidiabetics include all insulins and insulin derivatives such as, for example, Lantus® (see www.lantus.com) or Apidra®, and other fast-acting insulins (see US 6,221,633), GLP-1 receptor modulators as described in WO 01/04146 or also, for example, those described in WO 98/08871 of Novo Nordisk A / S. Oral active ingredients that are effective hypoglycemic agents include, preferably, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, DPP-IV inhibitors, compounds that open the potassium channels , for example, those described in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes that are involved in the stimulation of gluconeogenesis and / or glucogenolysis, modulators of glucose uptake , compounds that alter the lipid metabolism and that give rise to a change in the lipid composition of the blood, compounds that reduce food intake, PPAR and PXR modulators and active ingredients that act on the ATP-dependent potassium channel of the cells beta. In one embodiment of the invention, the compounds of the formula I or II are administered in combination with insulin. In one embodiment of the invention, the compounds of the formula I or II are administered in combination with substances that influence the hepatic production of glucose such as, for example, inhibitors of glycogen phosphorylase (see: WO 01/94300, WO 02/096864, WO 03/084923, WO 03/084922, WO 03/104188). In one embodiment, the compounds of formula I or II are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride. In one embodiment, the compounds of formula I or II are administered in combination with an active ingredient that acts on the ATP-dependent potassium channel of beta cells such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment, the compounds of formula I or 11 are administered in combination with a biguanide, such as, for example, metformin. In a further embodiment, the compounds of the formula I or II are administered in combination with a meglitinide as, for example, repaglinida. In one embodiment, the compounds of formula I or 11 are administered in combination with a thiazolidinedione such as, for example, ciglitazone, pioglitazone, rosiglitazone or the compounds described in WO 97/41097 of the Research Foundation of Dr. Reddy, in particular - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] -phenyl] etl] -2,4-thiazolidinedione In one embodiment, the compounds of the formula 1 or II are administered in combination with a DPPIV inhibitor as described, for example, in WO 98/19998, WO 99/61431, WO 99/67278, WO 99/67279, WO 01/72290, WO 02/38541, WO 03 / 040174, in particular, P 93/01 (chloride of 1-cyclopentyl-3-methyl-1-oxo-2-pentanamine), P-31/98, LAF237 (1- [2- [3-hydroxiadamant-1-ylamino) acetyl] pyrroidine-2- (S) -carbonitrile ), TS021 ((2S, 4S) -4-fluoro-1 - [[(2-hydroxy-1,1-dimethylethyl) amino] -acetyl-pyrrolidine-2-carbonitrile mono-benzenesulfonate). In one embodiment of the invention, the compounds of the formula I or II are administered in combination with a PPARgama agonist such as, for example, rosiglitazone, pioglitazone. In one embodiment, the compounds of the formula I or II are administered in combination with compounds having an inhibitory effect on SGLT-1 and / or 2, as described directly or indirectly, for example, in PCT / EP03 / 06841, PCT / EP03 / 13454 and PCT / EP03 / 13455. In one embodiment, the compounds of formula I or II are administered in combination with an α-glucosidase inhibitor such as, for example, miglitol or acarbose. In one embodiment, the compounds of the formula I or II are administered in combination with more than one of the aforementioned compounds, for example, in combination with a sulphonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea , insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

Lipid modulators In one embodiment of the invention, the compounds of formula I or II 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 the formula I or II are administered in combination with an inhibitor of bile acid reabsorption (see, for example, US 6,245,744, US 6,221,897, US 6,277,831, EP 0683 773, EP 0683 774). In one embodiment of the invention, the compounds of formula I or II are administered in combination with a polymeric adsorbent of bile acids such as, for example, cholestyramine, colesevelam. In one embodiment of the invention, the compounds of formula I or II are administered in combination with a cholesterol absorption inhibitor as described, for example, in WO 0250027, or ezetimibe, tiqueside, pamaqueside. In one embodiment of the invention, the compounds of formula I or II are administered in combination with an inducer of LDL receptors (see, for example, US 6,342,512).

In one embodiment, the compounds of formula I or II are administered 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 product that contains algarrobo from Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Hoechst, 65926 Frankfurt / Main) ). The combination with Caromax® is possible in a preparation or by separate administration of the compounds of formula I and Caromax®. In this regard, Caromax® can also be administered in the form of food products such as, for example, bread products or muesli bars. In one embodiment of the invention, the compounds of formula I or II are administered in combination with a PPARalpha agonist. In one embodiment of the invention, the compounds of the formula I or II are administered in combination with a mixed PPAR alpha / gamma agonist such as, for example, AZ 242 (Tesaglitazar, (S) -3- (4- [2- (4-methanesulfonyloxyphenyl) ethoxy] -phenyl) -2 ~ ethoxypropionic), BMS 298585 (N - [(4-methoxyphenoxy) carbon]] - N - [[4- (2- (5-methyl-2-phenyI-4-oxazolyl) ethoxy] phen I] methyl] gli-ciña) or as described 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 or II are administered in combination with a fibrate such as, for example, fenofibrate, gemfibrozil, clofibrate, bezafibrate. embodiment of the invention, the compounds of the formula 1 or II are administered in combination with nicotinic acid or niacin In one embodiment of the invention, the compounds of the formula I or II are administered in combination with a CETP inhibitor, for example, CP-529,414 (torcetrapib). In one embodiment of the invention, the compounds of formula I or II are administered in combination with an ACAT inhibitor. In one embodiment of the invention, the compounds of the formula I or II 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 or II are administered in combination with an antioxidant. In one embodiment of the invention, the compounds of the formula I or II are administered in combination with a lipoprotein lipase inhibitor. In one embodiment of the invention, the compounds of formula I or II are administered in combination with an inhibitor of ATP citrate lyase. In one embodiment of the invention, the compounds of the formula I or II are administered in combination with an inhibitor of squalene synthetase. In one embodiment of the invention, the compounds of formula I or II are administered in combination with a lipoprotein (a) antagonist.

Anti-obesity agents In one embodiment of the invention, the compounds of formula I or II are administered in combination with a lipase inhibitor, such as, for example, orlistat. In one embodiment, the additional active ingredient is fenfluramine or dexfenfluramine. In another embodiment, the additional active ingredient is sibutramine. In a further embodiment, the compounds of formula I or II are administered in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormone and Metabolic Research (2001), 33 (9), 554-558), with NPY antagonists, for example, hydrochloride. { 4 - [(4-aminoquinazolin-2-ylamino) methyl] -cyclohexylmethyl} amide of naphthalene-1-sulfonic acid (CGP 71683A)), with MC4 agonists (for example, [2- (3a-benzyl-2-methyl-3-oxo-2,3,3a, 4, 6,7-hexahydropyrazolo [4,3-c] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoetyl] -amide of 1-amino-1,2,3,4-tetrahydro acid -naphthalene-2-carboxylic acid (WO 01/91752), with orexin antagonists (for example, 1- (2-methylbenzoxazol-6-yl) -3- [1,5] naphthyridin-4-iiurea hydrochloride (SB -334867-A)), with H3 agonists (3-cyclohexyI-1- (4,4-dimethyl-1, 4,6,7-tetrahydroimidazo [4,5-c] pyridin-5-yl) salt) oxalic propan-1-one (WO 00/63208)); with TNF agonists, with CRF antagonists (for example, [2- methylene-9- (2,4,6-trimethylphenyl) -9H-1,3I9-triazafluoren-4-yl] dipropylamine (WO 00/66585)), with CRF BP antagonists (eg, urocortin), with urocortin agonists, with β3 agonists (eg, 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- ( 2,3-dimethyl-1H-indoI-6-yloxy) ethylamino] -ethanol (WO 01/83451)), with MSH agonists (melanocyte-stimulating hormone), with CCK-A agonists (eg, acid { 2- [4- (4-Chloro-2,5-d¡methoxyphenyl) -5- (2-cyclohexy-ethyl) thiazol-2-ylcarbamoyl] -5,7-dimethyl-indol-1-yl} -acetic acid trifluoroacetic acid salt (WO 99/15525)), with serotonin reuptake inhibitors (e.g., dexfefluramine), with mixed serotonergic and noradrenergic compounds (e.g., WO 00/71549), with 5HT agonists e.g. of 1- (3-ethylbenzofuran-7-yl) piperazine oxalic acid (WO 01/09111), with bombesin agonists, with galanin antagonists, with growth hormone (e.g., human growth hormone), with compounds that release growth hormone (t-butyl ester or of 6-benzyloxy-1- (2-diisopropylaminoethyl-carbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid (WO 01/85695)), with TRH agonists (see, for example, EP 0 462 884), with modulators 2 or 3 protein uncouplers, with leptin agonists (see, for example, Lee, Daniel W .; Leinung, Mattew 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), with DA agonists (bromocriptine, Doprexin), with lipase / amylase inhibitors (eg, WO 00/40569), with PPAR modulators (eg, WO 00/78312), with RXR modulators or with TR-β agonists. In one embodiment of the invention, the additional active ingredient is leptin. In one embodiment, the additional active ingredient is dexamfetamine, amphetamine, mazindol or phentermine. In one embodiment, the compounds of formula I or II are administered in combination with drugs that have effects on the coronary circulation and the vascular system such as, for example, ACE inhibitors (e.g., ramipril), with drugs that act on the angiotensin-renin system, with calcium antagonists, with beta-blockers etc. In one embodiment, the compounds of formula I or II are administered in combination with drugs that have an anti-inflammatory effect. In one embodiment, the compounds of formula I or II are administered in combination with drugs that are used in cancer therapy and in the prevention of cancer. It should be appreciated that each suitable combination of the compounds of the invention with one or more of the compounds mentioned above and, optionally, with one or more other pharmaceutically active substances, is considered to be in the protection conferred by the present invention. The activity of the compounds of the invention of formulas I or II was tested in the following enzyme assay system: Substrate preparation: Preparation of the substrate NAG (NBD monoacyl glyceride): 6 mg of phosphatidylcholine and 6 mg of phosphatidylinositol were dissolved in 1 ml of chloroform, each. 10 mg of NAG was dissolved in 1 ml of chloroform. Two parts of the phosphatidylinositol solution (eg, 83.5 μl) and a portion of the phosphatidylcholine solution (eg, 41.5 μl) and 100 μl of the NAG solution in plastic scintillation containers were co-pipetted. (final concentration in the assay: 0.0375 mg phospholipid / ml, 0.05 mg / NAG / ml). Chloroform (total volume 225 μl) was completely removed by passing a stream of N2 over it. The dried substrate can be stored at 4 ° C for up to 3 days. To prepare the phospholipid vesicles / micelles with NAG intercalated (on the day of the assay), the dried substrate was dissolved in 20 ml of the assay buffer (25 mM Tris / HCl, pH 7.4, 150 mM NaCl) and with two ultrasound treatments with an ultrasonic probe (Branson Sonifier Type II, standard microtip): 1st treatment adjustment 2, 2 x 1 min, in between 1 min on ice every time; 2nd treatment adjustment 4, 2 x 1 min, in between 1 min on ice every time. During this procedure, the color of the substrate solution changes from yellow (maximum extinction 481 nm) to red (maximum extinction 550 nm) allowing the intercalation of NAG between the phospholipid molecules in the vesicles / micelles. Before being used as a substrate (in the next 2 h), the solution is incubated on ice for 15 min.

Indirect NAG test: The assay was carried out in 1.5 ml Eppendorf containers or in 96-well plates at 30 ° C for 60 min. In order to find inhibitors of HSL, 10 μl of the substance to be tested was introduced into the assay buffer (25 mM Tris / HCl, pH 7.4, 150 mM NaCl) in the presence of 16.6% DMSO. 180 μl of the substrate solution (20 μg / ml phosphatidylcholine, 10 μg / ml phosphatidylinositol, 50 μg / ml NAG in the assay buffer) was added. After preincubation at 30 ° C for 15 min, 20 μl of the enzyme solution was pipetted into the assay buffer (diluted 1 to 4 times), and the extinction was immediately measured at 480 nm in a photometer cuvette (cuvette). 0.5 ml) or in a microplate reader. After incubation at 30 ° C for 60 min, the extinction was measured again. The increase in the extinction at 480 nm is a measure of the enzymatic activity. Under standard conditions, 20 μg of partially purified HSL results in a change of 0.4 = 4,000 arb units. in the extinction.

Direct NAG test: As an alternative to the measurement of the change in the extinction of the substrate solution, the products of the HSL reaction were investigated by phase separation / thin layer chromatography. For this purpose, 1.3 ml of methanol / chloroform / heptane (10: 9: 7) and then 0.4 ml of 0.1 M NaOH were added to the incubation mixture (total volume 200 μl, see the Indirect NAG) in 2 ml Eppendorf containers. After mixing vigorously (10 s), phase separation was initiated by centrifugation (800 x g, 20 min, room temperature). Equivalent volumes (e.g., 0.4 ml) of the upper aqueous phase were taken, and the extinction was determined at 481 nm in a photometer. In the case of thin layer chromatography, the aqueous phase was dried (SpeedVac) and dissolved in 50 μl of tetrahydrofuran. 5 μl samples were loaded onto Si-60 silica gel plates (Merck). Chromatography was carried out with 78 ml of diethyl ether / 22 ml of petroleum ether / 1 ml of glacial acetic acid as the mobile phase. The amount of NBD-fluorescent fatty acid released was determined by Phosphorimaging (Molecular Dynamics, Storm 840 and ImageQuant Software) at an excitation wavelength of 460 nm and at an emission wavelength of 540-560 nm.

Preparation of the enzyme: Preparation of partially purified HSL: Rat adipose cells are obtained from epidimal adipose tissue of untreated male rats (Wistar, 220-250 g) by treatment with collagenase according to published methods (for example, S. Nilsson et al. , Anal, Biochem, 158, 1986, 399-407; G. Fredrikson et al., J. Biol. Chem. 256, 1981, 6311-6320; H. Tornquist et al., J. Biol. Chem. 251, 1976, 813-819). The fat cells of 10 rats are washed three times by flotation with 50 ml of homogenization buffer (25 ml Tris / HCl, pH 7.4, 0.25 M sucrose, 1 mM ETDA, 1 mM DTT, 10 μg / ml leupeptin , 10 μg / ml antipain, 20 μg / ml pepstatin) each time and finally resuspend in 10 ml of homogenization buffer. The fat cells are homogenized in a Teflon and glass homogenizer (Braun-Melsungen) by 10 strokes at 1,500 rpm at 15 ° C. The homogenate is centrifuged (SM24 Sorvall tubes, 5,000 rpm, 10 min, 4 ° C). The subnatant between the fat layer in the upper part and the sediment is collected and the centrifugation is repeated. The resulting subnatant is centrifuged again (SM24 Sorvall tubes, 20,000 rpm, 45 min, 4 ° C). The subnatant is collected and 1 g of Sepharose-heparin is added (Pharmacia-Biotech, CL-6B, washed 5x with 25 mM Tris / HCl, pH 7.4, 150 mM NaCl). After incubating at 4 ° C for 60 min (with shaking at 15 min intervals), the mixture is centrifuged (SM24 Sorvall tubes, 3,000 rpm, 10 min, 4 ° C). The supernatant is adjusted to pH 5.2 by the addition of glacial acetic acid and incubated at 4 ° C for 30 min. The precipitates are collected by centrifugation (Sorvall SS34, 12,000 rpm, 10 min, 4 ° C) and resuspended 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. The suspension is dialyzed against 25 M Tris / HCl, pH 7.4, 50% glycerol, 1 mM DTT, 10 μg / ml leupeptin, pepstatin, antipain at 4 ° C overnight and then loaded onto a column of hydroxyapatite (0.1 g per 1 ml of 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 and then dialyzed (see above) and concentrated 5 to 10 times by ultrafiltration (Amicon Diaflo PM 10 Filter) at 4 ° C. Partially purified HSL can be stored at -70 ° C for 4 to 6 weeks.

Test: In order to prepare the substrate, 25-50 μCi of [3H] trioleoylglycerol (in toluene), 6.8 μmol of unlabeled trioleoylglycerol and 0.6 mg of phospholipids (phosphatidylcholine / phosphatidylinositol 3: 1 w / v) are mixed. , they are dried with N2 and then resuspended in 2 ml of 0.1 M KPi (pH 7.0) by means of ultrasonic treatment (Branson 250, microtip, adjustment 1-2, 2 x 1 min with an interval of 1 min) . After adding 1 ml of KPi and a new ultrasound treatment (4 x 30 sec on ice at 30 s intervals), 1 ml of 20% BSA is added > (in KPi) (final concentration of 1.7 mM trileoylglycerol). For this reaction, 100 μl of the substrate solution is pipetted into 100 μl of the HSL solution (HSL prepared as described 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 at 37 ° C for 30 min. After the addition of 3.25 ml of methanol / chloroform / heptane (10: 9: 7) and 1.05 ml of 0.1 M K2CO3, 0.1 M boric acid (pH 10.5) is mixed thoroughly and centrifuged (800 xg, 20 min). After separation of the phases, an equivalent of the upper phase (1 ml) is collected and the radioactivity is determined by liquid scintillation determination.

Evaluation: Normally, the substances are tested in four independent mixtures. The inhibition of the enzymatic activity of HSL by a test substance is determined by comparison with a control reaction without inhibition. The IC50 is calculated from a representation of the inhibition with min. 10 concentrations of the substance to be tested. The GRAPHIT, Elsevier-BIOSOFT software package is used to analyze the data. The compounds of Examples 1 to 103 show inhibitions in the IC50 range of 1 nM-1 μM in this assay. The compounds of the invention of the general formulas I or II are prepared by methods known per se, for example by acylation of III indazoles substituted or unsubstituted with carbamoyl chlorides (method A), or in two steps by the reaction of indazoles III with phosphogen or equivalents such as trichloromethyl chlorocarbonate or dithrichloromethyl carbonate and further reaction of the resulting indazolecarbonyl chloride with amines or anilines (method B). In the case of the compounds in which R3 is hydrogen, the indazoles III can also be reacted with the appropriate isocyanates R2-N = C = O.

III IV As acids are normally 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. It has been found that it is usually advantageous to operate at 0 ° C to the boiling point of the solvent used. Examples of solvents used are methylene chloride, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, diethyl ether or pyridine. If anhydrous conditions are used, it has been shown that strong bases such as lithium hydride, sodium hydride or potassium t-butoxide in aprotic solvents such as THF or DMF are also suitable. The indazoles used as starting compounds III, or the corresponding aza-substituted derivatives, are commercially available or can be prepared by processes known from the literature (for example, L. Baiocchi, G. Corsi Syntesis (1978), 633-648, I. Sekikawa et al., J. Het. Chem. (1973), 931-932). The compounds of the general formulas I and II are separated and purified by chromatographic methods known per se. The examples detailed below serve to illustrate the invention, however, they do not restrict it.

Examples Example 1: 1 H-ldazol-3-yl 4-methylpiperidine-1-carboxylate 300 mg (2.24 mmol) of 1 H-indazol-3-ol were dissolved in 25 ml of THF and cooled to -20 ° C. : 1.3 ml (2.46 mmol) of phosgene in toluene (20 percent) was added dropwise and the reaction mixture was stirred for 90 min, during which it was warmed up to room temperature. The reaction mixture was concentrated and washed once more with a few ml of toluene. The residue was dissolved in 15 ml of THF, 265 μl (2.2 mmol) of 4-methylpiperidine was added dropwise and the mixture was stirred at room temperature for 3 h, concentrated and purified by Preparative HPLC (PR18, acetonitrile / water 0.1% TFA). Yield: 347 mg (60%), M + H +: 260.4.

Example 2: 4-Methylpiperidine-1-carbonyl chloride 9 g (90.75 mmol) of 4-methylpiperidine and 13.9 ml (100 mol) of triethylamine in 100 ml of THC were dissolved at -30 ° C. they added 54.9 ml (100 mmol) of phosgene in toluene (20 percent), and the mixture was stirred for 2.5 h, during which time it was warmed to room temperature. The reaction mixture was concentrated, the residue was mixed with methylene chloride and filtered, and the filtrate was concentrated. The crude product (12.7 g) was reacted without further purification.

Example 3: 4-Fluoro-1 H-indazol-3-yl 4-methylpiperidine-1-carboxylate 100 mg (0.66 mmol) of 4-fluoro-1 H-indazol-3-ol and 116 were heated to reflux. 8 mg (0.72 mmol) of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 10 ml of piperidine for 4 h and was left overnight. After the addition of 24 mg of 4-methylpiperidine-1-carbonyl chloride, it was heated to reflux for an additional 2 h while the pyridine was distilled in vacuo, 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: 56 mg (31%), M + H +: 278.1.

Example 4: 1-Met l-1 H-indazolyl-3-yl-4-methylpiperidine-1-carboxylate 80.1 mg (0.31 mmol) of 1 H-indazol-3-yl-4-methylpiperidine- were stirred. 1-carboxylate (Example 1), 38.1 mg (0.34 mmol) of potassium t-butoxide and 48.2 mg (0.34 mmol) of iodomethane at room temperature for 48 h. The solvent was removed by distillation in vacuo, 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: 7 mg (8%), M + H +: 274.1.

Example 5: 100 mg (0.56 mmol) of 6-nitro-1 H-indazoI-3-ol and 135.3 mg (0.83 mmol) of 4-methylpiperidine-1-carbonyl chloride were heated to reflux ( Example 2) in 10 ml of pyridine for 5 h and left overnight. The pyridine was removed by distillation in vacuo, 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: 5 mg (3%) of A: (3-hydroxy-6-nitroindazol-1-yl) - (4-methylpiperidin-1-yl) methanone, M + H +: 305.1 and 64 mg (38%) of B: 6-nitro-1H-indazol-3-yl-4-methylpiperidine-1-carboxylate, M + H +: 305.1.

Example 6: 5-Nitro-1 H-indazol-3-yl 4-methylpiperidine-1-carboxylate. 200 mg (1.12 mmol) of 5-nitro-1H-indazol-3-ol and 180.4 were heated to reflux. mg (1.67 mmol) of 4-methylpiperidine-1-carbonyl chloride (Example 2) in 20 ml of pyridine for 5 h and left overnight. The pyridine was removed by distillation in vacuo, 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: 48 mg (14%), M + H +: 304.99.

Example 7: 6-Amino-1 H-indazol-3-yl 4-methylpiperidine-1-carboxylate 30 mg (0.1 mmol) of 6-nitro-1 H-indazol-3-yl 4-methylpiperidine-1 was hydrogenated -carboxylate (Example 5B) in 15 ml of ethanol in the presence of % > palladium / carbon under a hydrogen pressure of 2 bar at room temperature for 2.5 h. The catalyst was removed by suction filtration, and the filtrate was concentrated. Yield: 21 mg (76%), M + H +: 275.2.

Example 8: Example 1 was repeated with 2 g (14.9 mmol) of 1H-indazol-3-ol.

In this case, it was possible to isolate A: 1 H-indazol-3-yl 4-methylpiperidine-1-carboxylate and the isomeric products B: (3-hydroxyninzol-1-yl) - (4-methylpiperidin-1-yl) methanone and C: 2- (4-methylpiperidine-1-carbonyl) -1,2-dihydroin-dazol-3-one.

Example 9: 1 H-Pyrazolo [3,4-b] pyridin-3-yl 4-methylpiperidine-1-carboxylate a) 1 H-pyrazolo [3,4-b] pyridin-3-ol was heated to reflux: g (26.94 mmol) of ethyl 2-chloronicotinate and 47, 6 g (80.82 mmol) of hydrazine hydrate (85 percent) in 10 ml of ethanol for 6 h. The reaction mixture was concentrated. Yield: 3.5 g (96%), M + H +: 135.9. b) 300 mg (2.2 mmol) of 1H-pyrazolo [3,4-b] pyridin-3-ol and 538.2 mg (3.3 mmol) of 4-methylene chloride were heated to reflux. peridin-1-carbonyl (Example 2) in 25 ml of pyridine for 4 h and left overnight. After adding 24 mg of 4-methylpiperidin-1-carbonyl chloride, it was heated to reflux for an additional 2 h, the pyridine was removed by distillation in vacuo, 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: 99 mg (17%), M + H +: 261.28.

Example 10: 500 mg (2.16 mmol) of 1 H-indazol-3-ylamine were heated to reflux; compound with sulfuric acid and 419.3 mg (2.59 mmol) of 4-methylpiperidine-1-carbonyl chloride (Example 2) and 300 μl (4.32 mmol) of triethylamine in 30 ml of pyridine for 5 hrs. all night. After adding 302 μl of triethylamine and 390 mg of 4-methylpiperidine-1-carbonyl chloride, the mixture was heated for an additional 2.5 h. The pyridine was distilled off in vacuo and the residue 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: 55 mg (10%) of A: 4-methylpiperidine-1-carboxylic acid (1H-indazol-3-yl) amide, M + H +: 259.1 and 36.4 mg (7%) of B: (3-aminoindazol-1-yl) - (4-methylpiperidin-1-yl) methanone, M + H +: 259.1.

Example 11: 4-Trifluoromethylpiperidine-1-carbonyl chloride Ditrichloromethyl carbonic acid ester (840 mg, 2.83 mmol) in 30 ml of methylene chloride and, in an ice bath, 2.06 ml (25.24 mmol) of pyridine were added slowly. After 30 min, 4-trifluoromethylpiperidine hydrochloride (1.45 g, 7.65 mmol) was slowly added in portions. After removing it from the ice bath, stirring was continued for 90 min, the precipitate was collected by filtration and washed with n-heptane, and the filtrate was concentrated. The resulting product (1.9 g) still contained some salt and was reacted directly.

Example 12: 4- Hydroxy-4-methyl-1 H-pyrazolo- [3,4-b] pyridin-3-yl 4-trifluoromethyl-1-pyridin-1-carboxylic acid ester 4-methyl-1 was stirred H-pyrazolo [3,4-b] pyridine-3,6-diol (1 g, 6.05 mmol), 4-trifluoromethyl-piperidnan-1-carbonyl chloride (1.436 g, 6.6 mmol ) and triethylamine (1.68 ml, 12.11 mmol) in 25 ml of pyridine at room temperature for 1 h. After the addition of 0.5 ml of triethylamine it was stirred for 2 h, concentrated and ethyl acetate and water were added. The resulting precipitate was filtered with suction and dried. Yield: 765 mg (37%) of 6-hydroxy-4-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl ester of 4-trifluoromethylpiperidine-1-carboxylic acid ester. The organic phase was separated, concentrated and purified by preparative HPLC (PR18, acetonitrile / water 0.1% TFA). Yield: 96 mg (5%) of 6-hydroxy-4-methyl-1H- ester pyrazolo [3,4-b] pyridin-3-yl of 4-trifluoromethylpiperidin-1-carboxylic acid. M + H +: 345.13; 102 mg (3%) of 4-methyl-3- (4-trifluoromethylpiperidine-1-carbonyloxy) -1H-pyrazolo [3,4-b] pyridin-6-yl ester of 4-trifluoromethylpiperidine-1 - carboxylic, M + H +: 524.20; 106 mg (3%) of 6-hydroxy-4-methyl-1- (4-trifluoromethylpperidine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl ester of 4- acid trifluoromethylpiperidine-1-carboxylic acid, M + H +: 524.52; 54 mg (1.3%) of ester 4-methyl-3- (4-trifluoromethylpiperidine-1-carbonyloxy) -1- (4-trifluoromethylpiperidine-1-carbonyl) -1H-pyrazolo [3,4-b] 4-trifluoromethylpiperidine-1-carboxylic acid pyridin-6-yl, M + H +: 703.36.

Example 13: 4-Methyl-3- (4-trifluoromethylpiperidine-1-carbonyloxy) -1H-pyrazolo [3,4-b] pyridin-6-yl ester of 4-methylpiperazine-1-carboxylic acid; compound with trifluoroacetic acid 4-Trifluoropiperidine-1-carboxylic acid 6-hydroxy-4-methyl-1H-pyrazolo [3,4-b] pyridin-3-yl ester (300 mg, 0.87 mmol), hydrochloride, was stirred. 4-methylpiperazine-1-carbonyl chloride (191 mg, 0.96 mmol) and triethylamine (0.48 mL, 3.48 mmol) in 10 mL of pyridine at room temperature for 5 h. After adding 0.4 ml of triethylamine and 100 mg of 4-methyl-piperazine-1-carbonyl hydrochloride chloride, it was stirred for 1 h, concentrated and ethyl acetate and water were added and adjusted to pH 8. The organic phase it was separated (multiple extraction), concentrated and purified by preparative HPLC (PR18, acetonitrile / water 0.1% TFA). Yield: 125 mg (25%) of 4-methyl-3- (4-trifluoromethylpiperidine-1-carbonyloxy) -1H-pyrazolo [3,4-b] pyridin-6-yl ester of 4-methylpiperazine-1 -carboxylic; compound with trifluoroacetic acid, M + H +: 471, 24; 82 mg (13%) of 6-hydroxy-4-methyl-1- (4-methylpiperazine-1-carbonyl) -1H-pyrazolo [3,4-b] pyridin-3-yl ester of 4-methyl-4-methyl FIuoromethylpiperidine-1-carboxylic acid; compound with trifluoroacetic acid, M + H +: 471.27.

Example 14: 6-Nitro-1 H-indazol-3-ol 2-Fluoro-4-nitrobenzoic acid methyl ester (5g, 25.11 mmol) and hydrazine hydrate (1.34 mL, 27.62 mmol) were dissolved. ) in 250 ml of ethanol and heated to reflux for 11 h. An additional 0.26 ml of hydrazine hydrate was added and heated to reflux for a further 6 h, and the mixture was concentrated and ethyl acetate and water were added. The precipitated residue was filtered with suction and dried. Purification by preparative HPLC (PR18, acetonitrile / water 0.1% TFA) resulted in 1.39 g of product, M + H +: 180.05.

Example 15: 6-Fluoro-1 H-indazol-3-ol 2-Amino-4-fluorobenzoic acid (25 g, 161.2 mmol) was resuspended in 250 ml of water and 39 ml of concentrated hydrochloric acid. At 0 ° C, sodium nitrite (11.2 g, 161.2 mmol) was added dropwise in 30 ml of water below 10 ° C. After 30 min at room temperature, sodium sulfite (69 g, 400 mmol) in 250 mL of water was added. After stirring for 2 h, 30 ml of concentrated hydrochloric acid was added, and the mixture was left overnight. It was then heated to reflux for 9 h, cooled and adjusted to pH 5.5 with sodium bicarbonate. The precipitate was filtered with suction and dried. Yield: 19.8 g, (81%), M + H +: 152.94.

Example 16: 3-Hydroxy-1 H-indazole-6-carboxylic acid 2-aminoterephthalic acid dimethyl ester (5 g, 23.9 mmol) was dissolved in 40 ml of water and 6 ml of concentrated hydrochloric acid. At 0 ° C, sodium nitrite (1.65 g, 23.9 mmol) was added dropwise in 5 ml of water below 10 ° C. After 30 min at room temperature, sodium sulfite (11.02 g, 87.42 mmol) in 40 ml of water was added. After stirring for 1 h, 10 ml of concentrated hydrochloric acid was added, and the mixture was left overnight. Then it was heated at 80 ° C for 24 h, cooled and adjusted to pH 5.5 with a sodium hydroxide solution. The precipitate was filtered with suction and dried. Yield: 2.29 g, (54%), M + H +: 179.04.

Example 17: 3-Hydroxy-4-methyl-1 H -pyrazolo [3,4-b] pyridine-6-carboxylic acid 5-amino-2H-pyrazol-3-ol was resuspended (3.1 g, 31.6 mmol) in 100 ml of methanol. Then sodium methoxide (5.1 g, 95 mmol) and 2,4-dioxopentanoic acid ethyl ester (5 g, 31.6 mmol) were added, and the mixture was refluxed for 12 h. The solvent was removed on a rotary evaporator, water was added to the residue, the precipitate was filtered off with suction, and the filtrate was adjusted to pH 6 with dilute hydrochloric acid. The precipitated product (both precipitates) was filtered with suction and dried. Yield: 4.9 g (70%), M + H +: 194.09. The following compounds were prepared analogously to the described examples: 15 20 56 (6-Fluoro-3-methoxy-indazol-1-yl) - (4-methyl-piperidin-1, 292, 20 yl) -methanone 57 5,6-difluoro-1H-indazol-3 ester -4- 296.25 methyl-piperidine-1-carboxylic acid (3-4-hydroxy-313.15-indazole-2-yl) -1-lyl) -methanone 59 (6-chloro-3-hydroxy-4-methyl-pyrazoium [3,4-b] pyridin-1-yl) -343,12 (3,4-dihydro-1H- Soquinolin-2-yl) -methanone 60-1-benzyl-6-hydroxy-4-methyl-1H-pyrazolo [3,4-381,27 b] pyridin-3-yl acid ester of 4-methyl-piperidine- 1-carboxylic acid 6-methanesulfonyl-1H-indazol-3-yl ester of 338,17 4-methyl-piperidine-1-carboxylic acid 10 62 6- Idroxy-1H-pyrazolo [3,4-b] pyridine ester -3-yl of 277.15 4-methyl-piperidine-1-carboxylic acid 63 (3,6-Dihydroxy-pyrazolo [3,4-b] pyridin-1-yl) - (4-methyl) - 277.15 pyridin-1-yl) -methanone 64 (6-chloro-3-hydroxy-4-methyl-pyrazolo [3,4-b] pyridin-1-yl) - 309.13 (4-methyl-piperidin -1-yl) -metanone 65 Ester of 4-methyl-3- (4-methyl-piperidine-1- 405.26 carbonyloxy) - 1 H-pyrazolo [3,4-b] pyridin-6-yl 15 methyl ester of succinic acid 66 6-fluoro-1 H-indazol-3-yl ester of 4-methyl-279,15 piperazine-1 -carboxylic; compound with trifluoroacetic acid 67 1 H-pyrazolo [3,4-b] pyridin-3-yl ester of 295,18 3,4-dihydro-1 H -soquinoline-2-carboxylic acid ester 6-Fluoro-1 H ester -indazol-3-yl of 4,4- 300,25 difluoro-piperidine-1-carboxylic acid 69 69 4-methyl-3- (4-methyl-piperidine-1, 438, 31 carbonyloxy) -1 Hp ester razolo [3,4-b] pyridin-6-yl of 4,4-difluoro-piperidine-1-carboxylic acid 70 6-Fluoro-1H-indazol-3-yl ester of acid 6,7- 318, 11 dihydro-4H-thieno [3,2-c] pyridine-5-carboxylic acid

Claims (21)

1. - An indazole derivative of the formulas I or II (l) (II) in which the meanings are: w - (C = O) -, - (S = O) -, - (SO2) -; x = C (-R) - or = N-; I-; R hydrogen, halogen, alkyl- (d-C6), alkyloxy- (d-C3) -alkyl- (d-C3), hydroxy, alkyl- (C? -C6) -mercapto, amino, alkyl- (CrC6) - amino, di-alkyl- (C2-C? 2) -amino, mono-alkyl- (C? -C6) -aminocarbonyl, di-alkyl- (C2-C8) -aminocarbonyl, COOR4, cyano, trifluoromethyl, alkyl - (d-C6) -sulfonyl, (C? -C6) -sulphinyl-alkyl, aminosulfonyl, nitro, pentafluorosulfonyl, aryl- (C6-C? 0), heteroaryl- (C5-Ci2), CO-NR2R3, O- CO-NR2R3, O-CO-alkylene- (d-C6) -CO-O-alkyl- (d-C6), O-CO-alkylene- (d-C6) -CO-OH, O-CO-alkylene- (C? -C6) -CO-, NR2R3 or a -cyloxy- (d-C6) unsubstituted or mono- or poly-substituted in F; R1 H, alkyl- (C? -C6), benzyl; R2 H, alkyl- (d-C6), alkyl- (d-C4) -phenyl, aryl- (C6-do), wherein the phenyl or the aryl may be substituted, optionally, with a halogen, Io- (C? -C6), alkyloxy- (C? -C3), hydroxy, alkyl- (C-? C6) -mercapto, amine, alkyl- (C? -C6) -amino, di-alkyl- (C2-C? 2) -amino, mono-alkyl- (C -? - C6) -aminocarbonyl, di-alkyl- (C2-Cs) -aminocarbonyl, alkoxy- (C? -C6) -carbon cyano, trifluoromethyl, trifluoromethyloxy, alkyl- (C6C6) sulfonyl, aminosulfonyl, nitro; or tetramethyl-tetrahydronaphthalene; R3 H, alkyl- (C? -C6); or R2 and R3 can form, together with the nitrogen atom carrying them, a saturated or partially unsaturated monocyclic 4 to 7 membered ring system or a saturated or partially unsaturated bicyclic 8 to 14 membered ring system, that the individual members of the ring systems can be replaced by one to three atoms or atomic groups of the series -CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -C (= O) -, -O-, -S-, -SO-, -SO2-, with the proviso that two units of the series -OR-, -S-, -SO-, -SO2- may not be adjacent; R4 hydrogen, alkyl- (C? -C6), benzyl; R5 alkyl- (C? -C6), halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene; and the salts thereof physiologically tolerated as well as their tautomeric forms, with the proviso that in the compounds of the formula (!) with W = CO a) R2 and R3 form, together with the nitrogen atom that carries them, a system of monocyclic or bicyclic ring if Y = N (R1) with R1 = H or a- Q- (C? -C6) or b) Y-R1, R2 and R3 do not have, simultaneously, the following meanings: Y-R1 = OH, R2 = aryl- (C6-C? O) optionally substituted and R3 = H.

2. - An indazole derivative of the formula I or II according to claim 1, wherein W is - (C = O) -.

3. An indazole derivative of the formulas I and II, in which NR2R3 is a saturated 5-6 membered monocyclic ring system comprising in the 4-position an atom or an atomic member of the series -CHR5-, -CR5R5- , - (C = R5) -, -NR5-, -O-, -S-.

4. An indazole derivative of the formula I or II according to claims 1 to 3, wherein X at positions 4, 5 and 7 is = C (-R) -, with R = hydrogen.

5. - An indazole derivative of the formula I or II according to claims 1 to 4, wherein W is - (C = O) -; X is = C (-R) - or = N-; Cast-; R is hydrogen, halogen, (C 1 -C 6) alkyl, hydroxy, amine, COOR 4, trifluoromethyl, (C 6 -C 6) alkylsulfonyl, nitro, pentafluorosulfanyl, aryl (C 6 -C 6), CO- NR2R3, O-CO- NR2R3 or O-CO-alkylene- (d-C6) -CO-O-alkyl- (d-C6); R1 is H, alkyl- (C? -C6), benzyl; R2 is alkyl- (C? -C6), benzyl, aryl ~ (C6-C? O) or tetramethyl-tetrahydronaphthalene; R3 is H, alkyl- (C? -C6); or R2 and R3 can form, together with the nitrogen atom carrying them, a saturated 5-6 membered monocyclic ring system or a saturated or partially unsaturated bicyclic 9 to 10 membered ring system in which the individual members of the Ring systems can be replaced by one to two atoms or atomic groups of the series -CHR5-, -CR5R5-, - (C = R5) -, - NR5-, -O-, -S-, with the proviso that two units of the series -O-, -S- may not be adjacent; R 4 is hydrogen, (C 6) alkyl or benzyl; R5 is alkyl-id-Cß), halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene.

6. - An indazole derivative of the formula I according to claims 1 to 5, wherein W is - (C = O) -; X is = C (-R) - or = N-; Cast-; R is hydrogen, halogen, nitro, hydroxy or alkyl- (C? -C6); R1 is H or alkyl- (C? -C6); R2 is alkyl- (C? -C6), benzyl or aryl- (C6-C? O); R3 is alkyl- (C? -C6); or R2 and R3 can form, together with the nitrogen atom carrying them, a saturated monocyclic 5 to 6 membered ring system or a saturated or partially unsaturated bicyclic 9 to 10 membered ring system in which the individual members of the ring systems can be replaced by an atom or an atomic group of the series -CHR5-, -NR5-; and R5 is alkyl- (C? -C6), or cyclopropyl.

7. - A ndazole derivative of the formula II according to claims 1 to 5, wherein W is - (C = O) -; X is = C (-R) - or = N-; Cast-; R is hydrogen, halogen, (d-C6) alkyl, hydroxy, amino, COOR4, trifluoromethyl, alkyl- (C? -C6) -sulfonyl, nitro, pentafluorosulfanyl, aryl- (C6-C? O) , CO-NR2R3, O-CO-NR2R3 or O-CO-alkylene- (C? -C6) -CO-O-alkyl- (C? -C6); R1 is H, alkyl-id-Cß) or benzyl; R2 is alkyl- (C? -C6), aryl- (C6-C? O) or tetramethyl-tetrahydronaphthalene; R3 is H, alkyl- (C? -C6); or R2 and R3 can form, together with the nitrogen atom carrying them, a saturated 5-6 membered monocyclic ring system or a saturated or partially unsaturated bicyclic 9 to 10 membered ring system in which the individual members of the Ring systems can be replaced by one to two atoms or atomic groups of the series -CHR5-, -CR5R5-, - (C = R5) -, -NR5-, -O-, -S-, with the proviso that two units of the series -O-, -S- may not be adjacent; R 4 is hydrogen, (C 6 -C 6) alkyl, benzyl; and R5 is alkyl- (C? -C6), halogen, trifluoromethyl, COOR4, cyclopropyl, cyclopropylene.

8. - An indazole derivative of the formula II according to claims 1 to 5 and 8, wherein NR2R3 is piperidine comprising the atomic member CHR5 in the 4-position.

9. - A medicament comprising one or more of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8.

10. - A medicament with an inhibitory effect on hormone-sensitive lipase, comprising one or more of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8.

11. - A medicament with an inhibitory effect on hormone-sensitive lipase, comprising one or more of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 and one or more active ingredients having favorable effects in alterations or metabolic disorders associated with them.

12. - A medicament with an inhibitory effect on hormone-sensitive lipase, comprising one or more of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 and one or more antidiabetics.

13. - A medicament with an inhibitory effect on hormone-sensitive lipase, comprising one or more of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 and one or more lipid modulators.

14. Use of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 for the treatment and / or prevention of disorders of the metabolism of fatty acids and disorders of the use of glucose.

15. Use of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 for the treatment and / or prevention of disorders in which insulin resistance is involved.

16. Use of the ndazole derivatives of the formula I or II according to one or more of claims 1 to 8 for the treatment and / or prevention of diabetes mellitus and the sequelae associated therewith.

17. Use of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 for the treatment and / or prevention of dyslipidemias and their sequelae.

18. Use of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 for the treatment and / or prevention of conditions associated with the metabolic syndrome.

19. The use of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 in combination with at least one additional active ingredient for the treatment and / or prevention of disorders of the metabolism of fatty acids and of disorders of glucose utilization.

20. The use of the indazole derivatives of the formula I or II according to one or more of claims 1 to 8 in combination with at least one additional active ingredient for the treatment and / or prevention of disorders in which resistance to insulin.

21. A process for producing a medicament comprising one or more of the indazole derivatives of the formula I or ll according to one or more of claims 1 to 8, which comprises mixing the active ingredient with a suitable vehicle from a pharmaceutical point of view , and convert this mixture into a suitable form to be administered.