RU2395503C2 - Medicinal agents containing n-sulfamoyl-n'-arylpiperazines meant for preventing or treating obesity and related conditions - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to use of existing and novel N-sulfamoyl- N'-arylpiperazines and their physiologically compatible acid-addition salts of formula I

, where Ar denotes a monocyclic or bicyclic C₆-C₁₀aryl in which ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and/or where the C₆-C₁₀aryl ring system optionally contains 3-5 double bonds, and/or where the C₆-C₁₀aryl ring system is optionally substituted with 1 or 2 substitutes which can be identical or different and which can be selected from a group containing halogen, trifluoromethyl, cyano group, nitro group, C₁-C₄alkyl, C₁-C₄alkoxy group, C₁-C₄alkylsulfonyl; and two oxygen atoms which are bonded to two neighbouring carbon atoms of the C₆-C₁₀aryl ring system and are bonded by a C₁-C₂alkylene bridge; or where the C₆-C₁₀aryl ring system is substituted with phenyl which can optionally be substituted in the phenyl ring by one substitute which can be selected from a group containing halogen; for preventing or treating obesity and related diseases.

EFFECT: design of a method of obtaining the said compounds and a pharmaceutical composition based on the said compounds.

25 cl, 9 tbl, 5 ex

Description

The present invention relates to the known and new N-sulfamoyl-N'-arylpiperazines and their physiologically compatible acid additive salts and pharmaceutical compositions or drugs containing these compounds, which are intended for the prevention or treatment of obesity and related conditions.

Some N-sulfamoyl-N'-arylpiperazines and their use as herbicides are described in German patent application, such as DE-OS 1964441 (equivalent to US 3709677). Similar compounds and their use as insecticides and acaricides are also described in WO 95/09151.

WO 94/07867 describes substituted 4-pyrimidine derivatives as inhibitors of L-idiodehydrogenase, which can be used to treat or prevent diabetes-related complications in mammals.

In European patent application EP 0 470 616 A2, substituted 4-pyrimidine derivatives are described which can be used as reagents for screening aldehyde reductase inhibitors.

International patent application WO 03/075929 describes histone deacetylase inhibitors suitable for the treatment of, for example, cancer and psoriasis, which may be certain N-sulfamoyl-N'-aryl piperazines. Intermediates for the synthesis of these compounds are also described.

No. 2,748,125 describes 1-substituted 4-sulfamylpiperazines having anticonvulsant activity.

At J.M. McManus et al. (J Med Chem 8, 1965, c. 766-776) describe hypoglycemic agents based on sulfamylurea.

A method for identifying compounds that can be used to treat and / or prevent obesity by inhibiting lipogenesis by inhibiting carbonate dehydrogenases (carbonic anhydrase) in mammals and humans is described in WO 02/07821.

The object of the present invention are new drugs intended for the treatment and / or prevention of obesity and related and / or secondary diseases or conditions that are very effective and which can be obtained by a simple method.

When creating the invention, it was unexpectedly found that the new and known N-sulfamoyl-N'-arylpiperazines or their physiologically compatible acid addition salts can be used to treat and / or prevent obesity and related and / or secondary diseases or conditions.

According to the invention, N-sulfamoyl-N'-arylpiperazine of the general formula I

wherein

Ar is a monocyclic or bicyclic C ₆ -C ₁₀ aryl in which the ring carbon atoms are optionally substituted with 1-3 nitrogen, oxygen and / or sulfur atoms, and / or

wherein the C ₆ -C ₁₀ aryl ring system optionally contains from 3 to 5 double bonds, and / or

where the C ₆ -C ₁₀ aryl ring system is optionally substituted with 1, 2 or 3 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, pyrrolidinyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, C ₀ -C ₄ alkoxyphenyl, C ₁ -C ₄ alkylthio group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ alkyloxycarbonyl, C ₁ -C ₄ alkylsulfonyl; and two oxygen atoms that are bonded to two adjacent carbon atoms of the C ₆ -C ₁₀ aryl ring system and are connected by a C ₁ -C ₂ alkylene bridge; or

where the C ₆ -C ₁₀ aryl ring system is substituted with 1 or 2 substituents that may have the same or different meanings and which can be selected from the group consisting of halogen, carboxy group, hydroxy group, hydroxycarbamoyl, trifluoromethyl, cyano group, nitro group, C ₁ -C ₄ alkyl C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkylthio group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ alkyloxycarbonyl, C ₁ -C ₄ alkylsulfonyl; two oxygen atoms that are bonded to two adjacent carbon atoms of the C ₆ -C ₁₀ aryl ring system and are connected by a C ₁ -C ₂ alkylene bridge; or

where the C ₆ -C ₁₀ aryl ring system is substituted with thienyl, naphthyl, pyridyl, phenyl or benzyl, where each phenyl or benzyl may optionally be substituted on the phenyl ring with 1, 2 or 3 substituents that may have the same or different meanings and which can be chosen from the group consisting of halogen, trifluoromethyl, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, or C ₁ -C ₄ alkylsulfonyl;

or its physiologically compatible acid addition salts can be used to treat and / or prevent obesity and related and / or secondary diseases or conditions.

More specifically in the compounds of formula I

Ar is phenyl optionally substituted with 1, 2 or 3 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, carboxy group, hydroxy group, hydroxycarbamoyl, trifluoromethyl, cyano group, nitro group, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, C ₀ -C ₄ alkoxyphenyl, C ₁ -C ₄ alkylthio group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ alkyloxycarbonyl, C ₁ -C ₄ alkylsulfonyl and two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or

denotes phenyl substituted with phenyl or benzyl, each of which may optionally be substituted on the phenyl ring with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy group; or

denotes naphthyl; pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl; triazinyl; quinolinyl; isoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyl; isoindolinyl; thieno [3,2-d] pyrimidinyl or pyrazolo [1,5-a] pyrimidinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, hydroxycarbamoyl , trifluoromethyl, cyano, nitro, pyrrolidinyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkyloxycarbonyl.

If in the compounds of formula I, Ia and / or Ib or in other compounds indicated in the context of the present invention, the substituents are or contain C ₁ -C ₄ alkyl or C ₁ -C ₆ alkyl, then they can be straight or branched chain and preferably represent methyl. If the substituents in the compounds of formula I are halogen, fluorine, chlorine, bromine or iodine are acceptable. Fluorine and chlorine are preferred. If the substituents contain C ₂ -C ₄ alkanoyl, then it can be straight or branched chain. A preferred C ₂ -C ₄ alkanoyl is acetyl.

Ar preferably denotes optionally substituted phenyl; pyridyl, in particular 2-pyridyl or 4-pyridyl; pyrimidinyl, in particular 2-pyrimidinyl or 5-pyrimidinyl; naphthyl or quinolinyl. More preferred are phenyl, pyridyl and pyrimidinyl.

When Ar is optionally substituted phenyl, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, trifluoromethyl, cyano group, nitro group and C ₁ -C ₄ alkylsulfonyl are preferred substituents. Halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and trifluoromethyl are more preferred. Another preferred option is unsubstituted phenyl.

When Ar is optionally substituted pyridyl; pyrimidinyl; naphthyl; quinolinyl; isoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyl or isoindolinyl, the preferred substituents are halogen, trifluoromethyl, cyano, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy.

The most preferred compounds that can be used according to the invention and which are partially new are selected from the group consisting of 4-phenylpiperazin-1-sulfonic acid amide (synonym for N-sulfamoyl-N'-phenylpiperazine); 4- (2-chlorophenyl) piperazin-1-sulfonic acid amide; 4- (2-methoxyphenyl) piperazin-1-sulfonic acid amide; 4-pyridin-4-ylpiperazin-1-sulfonic acid amide; 4-pyrimidin-2-ylpiperazin-1-sulfonic acid amide; 4- (4-fluorophenyl) piperazin-1-sulfonic acid amide; 4- (4-chloro-3-trifluoromethylphenyl) piperazin-1-sulfonic acid amide; and 4- (3-chloro-5-trifluoromethylpyridin-2-yl) piperazin-1-sulfonic acid amide.

Physiologically compatible acid addition salts of the compounds of formula I are common salts with inorganic acids, such as, for example, sulfuric acid, phosphoric acids or hydrohalic acids, preferably hydrochloric acid, or with organic acids, such as, for example, lower aliphatic monocarboxylic, dicarboxylic or tricarboxylic acids, such as maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, or with sulfonic acids, such as, for example, sh.) alkanesulfonic acids, such as methanesulfonic acid or trifluoromethanesulfonic acid, or benzenesulfonic acids optionally substituted on the benzene ring with halogen or lower alkyl, such as para-toluenesulfonic acid. Preferred are hydrochloric acid salts of the compounds of formula I.

The next object of the invention are also compounds of General formula Ia

wherein

Ar ¹ is phenyl optionally substituted with 1, 2 or 3 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, C ₀ -C ₄ alkoxyphenyl, C ₁ -C ₄ alkylthio group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ alkyloxycarbonyl, C ₁ -C ₄ alkylsulfonyl and two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or

denotes phenyl substituted with phenyl or benzyl, each of which may optionally be substituted on the phenyl ring with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy and trifluoromethyl; or

denotes naphthyl; pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; pyrazinyl; pyridazinyl; triazinyl; quinolinyl; isoquinolinyl; 1,2,3,4-tetrahydroisoquinolinyl; indolyl; isoindolinyl; thieno [3,2-d] pyrimidinyl or pyrazolo [1,5-a] pyrimidinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, hydroxycarbamoyl , trifluoromethyl, cyano, nitro, pyrrolidinyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkyloxycarbonyl; and their physiologically compatible acid addition salts, intended for use as a medicine for mammals or humans; and / or pharmaceutical compositions containing a compound of Formula Ia or pharmaceutically compatible acid addition salts thereof in a pharmacologically effective amount and conventional pharmaceutically acceptable excipients and / or carriers.

The next object of the present invention are new N-sulfamoyl-N'-arylpiperazines of General formula Ib

wherein

Ar ² is phenyl which is substituted with one substituent selected from the group consisting of fluoro, 3-chloro, 4-chloro, bromo, iodo, hydroxy, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkoxy, C ₀ -C ₄ alkoxyphenyl, C ₁ -C ₄ alkylthio group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ hydroxycarbonyl, hydroxycarbamoyl, carboxy group, trifluoromethyl, cyano group, nitro group, two oxygen atoms that are linked to two adjacent carbon atoms that are connected by C ₁ - With ₂ alkylene bridge, and C ₁ -C ₄ alkylsulfonyl; or

denotes phenyl substituted with 2 or 3 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, carboxy, hydroxy, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, C ₁ -C ₄ alkylthio group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ hydroxycarbonyl, C ₁ -C ₄ alkylsulfonyl and two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by C ₁ -C ₂ alkylene a bridge; or

denotes phenyl substituted with one substituent representing phenyl or benzyl, each of which may optionally be substituted on the phenyl ring with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, C ₁ - C ₄ alkyl and C ₁ -C ₄ alkoxy; or

denotes naphthyl; pyridyl; 2-pyrimidinyl; 5-pyrimidinyl; pyrazinyl; pyridazinyl; triazinyl; quinolinyl; isoquinolinyl; indolyl; isoindolinyl; thieno [3,2-d] pyrimidinyl or pyrazolo [1,5-a] pyrimidinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, hydroxycarbamoyl , trifluoromethyl, cyano, nitro, pyrrolidinyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ hydroxycarbonyl; or

denotes 1,2,3,4-tetrahydroisoquinolinyl substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, hydroxycarbamoyl, trifluoromethyl, cyano, nitro, pyrrolidinyl, C ₁ -C ₄ alkyl C ₁ -C ₄ alkoxy and C ₁ -C ₄ hydroxycarbonyl;

and their physiologically compatible acid addition salts.

Some N-sulfamoyl-N'-arylpiperazines that fall within the scope of the general formula I of the present invention are already described, for example, in DE-OS 1964441 (US 3709677), WO 94/07867 and / or WO 95/09151, and they can be obtained using the processes proposed in the description of these documents, or using similar processes.

In General, compounds of formula I (including compounds of formulas Ia and Ib) can be obtained using a known method by either

a) the interaction of an arylpiperazine derivative of the general formula II,

in which Ar has the above meanings, with sulfamide, or

b) the interaction of an aryl piperazine of formula II with 4-dimethylaminopyridine (DMAP), a protected tert-butyloxycarbonyl (boc) group, of the formula III

and subsequent removal of the boc group under acidic conditions from the resulting intermediate, or

C) the interaction of an arylpiperazine of formula II with sulfamoyl chloride, preferably protected with a boc group, of formula IV

and subsequent removal of the boc group under acidic conditions from the resulting intermediate,

and, if necessary, converting the resulting free bases of formula I to their physiologically compatible salts or converting salts of the compounds of formula I to the free bases of formula I.

In option a) of the process, the reaction can be carried out in an organic solvent that is inert under the reaction conditions, in particular in an aprotic solvent such as toluene or xylene or a mixture of such solvents. Suitable reaction temperatures are from room temperature to the boiling point of the solvent or mixture of solvents, preferably from 60 to 100 ° C.

In process variant b), the reaction can be carried out in an organic solvent which is inert under the reaction conditions, in particular in a dipolar-aprotic solvent such as chloroform, dichloromethane or dioxane, or in a mixture of such solvents. Acceptable reaction temperatures are from 10 to 50 ° C, preferably represent room temperature. Then the protective boc group can be removed by a known method in acidic media, for example in an ethanolic hydrochloric acid solution.

In process variant c), the reaction can be carried out in an organic solvent which is inert under the reaction conditions, in particular in a dipolar-aprotic solvent such as chloroform or dichloromethane, or in a mixture of such solvents. Acceptable reaction temperatures are from 10 to 50 ° C, preferably represent room temperature. Then the protective boc group can be removed by a known method in acidic media, for example in an ethanolic hydrochloric acid solution. Preferred is the use of a boc protected sulfamoyl chloride. However, when using the appropriate reaction conditions known to those skilled in the art, unprotected sulfamoyl chloride in the presence of a base can also be used.

The compounds of formula II, as a rule, are known compounds or compounds that can easily be obtained by specialists in this field using known processes and from known starting products. For example, compounds of formula II in which Ar is an optionally substituted biaryl can be prepared by reacting a compound of general formula V

in which Ar ³ is a monocyclic or bicyclic C ₆ -C ₁₀ aryl, the carbon ring atoms of which are optionally substituted with 1-3 substituents selected from nitrogen, oxygen and / or sulfur, and / or in which the C ₆ -C ₁₀ aryl ring system is optional contains 3-5 double bonds; and X represents a leaving group of a halogen type, preferably bromo;

with a compound of general formula VI

in which Ar ⁴ is thienyl, naphthyl, pyridyl; phenyl or benzyl, each phenyl or benzyl may optionally be substituted on the phenyl ring with 1, 2 or 3 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, cyano, C ₁ -C ₆ alkyl, A C ₁ -C ₄ alkoxy group or a C ₁ -C ₄ alkylsulfonyl; in the presence of a palladium catalyst.

The reaction can be carried out according to the type of the known “Suzuki coupling reaction” in an organic solvent which is inert under the reaction conditions, especially in a dipolar-proton solvent, such as (lower) alkanol such as methanol or ethanol, or divalent (lower) ether alkanol, such as ethylene glycol dimethyl ether, or in a mixture of such solvents or in a mixture of such solvents with water. Suitable reaction temperatures are from 100 to 200 ° C., preferably from 120 to 180 ° C. It is also advisable to carry out the reaction using a microwave reactor. Typically, the reaction is carried out in the presence of a base such as an alkali metal carbonate, preferably potassium carbonate. Suitable palladium catalysts are palladium (II) salts, such as palladium (II) acetate.

The compounds of formulas III and IV, as a rule, are known compounds or compounds that can easily be obtained by specialists in this field using known processes and from known starting products. The compounds of formulas V and VI, as a rule, are known compounds or compounds that can easily be obtained by specialists in this field using known processes and from known starting products.

Another object of the present invention is also a method of treating or preventing obesity, metabolic syndrome and / or syndrome X and / or cardiovascular diseases in mammals and humans, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound formulas I or physiologically compatible acid addition salts thereof.

In the context of the present description, obesity is understood as any increase in the fat body that leads to an increase in body weight, including as a preferred option (but not limited to) the definition of obesity as it is understood in medicine. Thus, the invention also relates to non-medical related weight loss, for example weight loss for cosmetic purposes, and includes generally improving the appearance. In addition, obesity is also understood to mean drug-induced obesity and / or juvenile obesity.

Concomitant obesity diseases or secondary diseases, each of which can be treated with the compounds of the invention, are primarily metabolic syndrome and / or syndrome X and cardiovascular diseases.

The term "metabolic syndrome" in the context of the present description refers to a complex of clinical symptoms, which in addition to basic obesity includes mainly hypertension; primarily arterial hypertension; insulin resistance, especially type II diabetes mellitus; glucose intolerance; dyslipoproteinemia, primarily hypertriglyceridemia, accompanied by dyslipoproteinemia associated with low HDL cholesterol, as well as hyperuricemia, which can lead to gout. According to information from the American Heart Association, the metabolic syndrome is closely related to insulin resistance. Some people are genetically predisposed to insulin resistance. Acquired factors, such as excess body fat and low physical activity, can cause insulin resistance and metabolic syndrome in these people. Most people with insulin resistance are obese. At the molecular level, the biological mechanisms of the relationship between insulin resistance and metabolic risk factors have not yet been fully elucidated and are probably complex. One group of people at risk of developing metabolic syndrome are people with diabetes who have impaired insulin and cannot maintain their blood glucose levels. The other group includes people who have high blood pressure, who do not suffer from diabetes and insulin resistance, but who have a large amount of insulin secretion. This condition is called hyperinsulinemia. The third group includes people who survived after a heart attack, who, unlike hypertensive patients, suffer from hyperinsulinemia, but without abnormal glucose levels. Metabolic syndrome is becoming more common in highly developed countries such as the United States, and it is found in about 20-25% of adult Americans. While there are no acceptable criteria for the diagnosis of metabolic syndrome.

The criteria proposed by the Expert Group on the identification, assessment and treatment of high blood cholesterol in the third report of the National Cholesterol Education Program (NCEP) (Adult Treatment Panel III) are the most modern and widely used. According to the criteria of ATP III, metabolic syndrome is identified by the presence of three or more of the following indicators:

major obesity, estimated at the circumference of the waist (men - more than 40 inches; women - more than 35 inches);

fasting blood triglycerides above or equal to 150 mg / dl;

HDL cholesterol blood levels (men - less than 40 mg / dl; women - less than 50 mg / dl);

blood pressure is greater than or equal to 130/85 mm Hg. pillar;

fasting glucose is greater than or equal to 110 mg / dl.

The concept of "Syndrome X" is close to the concept of "metabolic syndrome" and, as a rule, it is used to refer to an identical disease or condition. According to information received from the American Heart Association, the concept of “Syndrome X” also refers to a condition of the heart in which there is pain in the chest area and changes in the electrocardiogram that suggest the presence of coronary heart disease, but in which no angiographic analysis revealed coronary heart disease. Patients with heart syndrome X sometimes also suffer from lipid abnormalities.

The term "cardiovascular disease" in combination with obesity, as a rule, refers to coronary heart disease, which can lead to heart failure, cerebrovascular disease, which may be accompanied, for example, by an increased risk of "stroke", and peripheral occlusive arterial disease.

Given their inherent properties, it can be expected that the compounds of formula I or their physiologically compatible acid addition salts can also be used to treat diabetic conditions or diseases that are not associated with obesity. Such diabetic conditions or diseases are, for example, type II diabetes mellitus, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy and diabetic microangiopathy or diabetic macroangiopathy.

Other concomitant obesity and / or secondary diseases can be bladder diseases, such as bladder stones, sleep apnea, orthopedic complications, such as osteoarthritis, and psychosocial diseases.

The compounds of formula I can probably also be used as anticonvulsants for the prevention or treatment of epilepsy in mammals and humans.

The compounds of formula I of the invention are inhibitors of carbonate dehydrogenases in mammals, especially the isozymes of human carbonate dehydrogenases of subtypes II and / or V (hCA II and / or hCA V).

Pharmacological assessment methods

Below are examples of numerous accepted in pharmacology methods for evaluating drugs of this type.

1. In vitro Inhibition of Human Carbonate Dehydrogenase Isozyme II (hCA II)

Test compounds of formula I in 96-well titration plates were diluted with double-distilled water using an automatic pipettor (CyBiWell®). Aliquots of 20 μl from the plates with different dilutions were transferred for analysis using a pipetting device (Tecan Genesis®) into 96-well black plates. In the second stage, 148 μl of potassium phosphate buffer (20 mM, pH 7.4) was added, and in the third stage, 20 μl of an enzyme solution (1 μM isozyme II of human erythrocyte carbonate dehydrogenase (Sigma-Aldrich), dissolved in potassium phosphate buffer ), incubated for 60 min at room temperature, and a fluorescence signal (Tecan Ultra® fluorescence reader; excitation wavelength: 280 nm; emission wavelength: 465 nm) at the end of the pre-incubation period (FLU-1) was determined. After the pre-incubation period, 20 μl of an aqueous solution of dansilamide (1 mM dansilamide (Sigma-Aldrich), dissolved in hydrochloric acid) was added and the fluorescence signal was determined every 10 min for 60 min at 37 ° C. For the calculation, fluorescence data collected over 60 min (FLU-2) were used. The total volume of the mixture for analysis was adjusted to 208 μl. The final concentration of carbonate dehydrogenase II was 10 ^-7 M / L, dansilamide - 2.25 × 10 ^-6 and compounds from 10 ^-8 M / L to 10 ^-5 M / L. The final concentration of DMSO in which the compound was dissolved was 0.1 mM. Each microplate also contained control samples (“dummies”) that did not contain the compound and the enzyme, and controls containing the compound and ethoxolamide (final concentration 5 × 10 ^-8 M / L). All data was obtained based on the signal estimate. Data were expressed as% inhibition after calculation using the formula:

% inhibition = 100 ((1- (FLU-2 _compound -FLU-2 _“dummy” -FLU-1 _compound + FLU-1 _“dummy” ) / (FLU-2 _control -FLU-2 _“dummy” -FLU-1 _control -FLU-1 _"dummy" )

The% inhibition data for each compound and the corresponding final concentrations were used to calculate IC ₅₀ values using the Prism 4 program. The concentration dependence of activity curves was calculated using the Prism algorithm for nonlinear regression analysis (curve fitting): a sigmoid dose-response relationship was established with different slope and restrictions: upper limit: 100 and lower 0.

When using the specified test model in the studied compounds of formula I, presented below in table 1, the following IC ₅₀ values were found:

Table 1 The inhibitory effect of the studied compounds against hCA II in vitro Example No. IC ₅₀ [μm] 2 5.1 3 7.8 four 3,7 7 1.8 8 1.7 9 7.3 10 4.0 eleven 0.5 12 1,2 13 0.9 fourteen 0.2 fifteen 0.4 16 0.3 17 1.9 eighteen 1,6

Example No. IC ₅₀ [μm] 19 0.08 twenty 0.3 21 0.2

2. In vivo glucose tolerance test for oral administration to rats

The studies were carried out on male obese Zucker rats (n = 10 animals per group) weighing approximately 250-500 g. The rats were kept at a normal cycle of 12 h / 12 h light / dark (light was turned on at 07.00) and then gave food (laboratory food), while the animals had free access to water with the exception of the experiment, during which they fasted during the night before the introduction of glucose (sugar load).

The studied compounds of formula I were suspended in 2% polyethylene glycol (PEG) with the addition of 1% carboxymethyl cellulose and introduced by feeding through a gastric tube at a dose of 100 mg / kg / day; 1/3 of the dose (1 ml / kg, 33 mg / ml) was administered between 08.30 h and 09.30 h; the remaining 2/3 doses (2 ml / kg; 33 mg / ml) were administered between 16.00 and 17.00 hours and the last 1/3 dose was administered the next morning. Control animals were administered only vehicle. On the day of the experiment, 45 minutes after the last dose of the test compound / excipient was administered, blood samples (0 min) (tail vein) were taken, after which glucose (1.25 g / kg; 118 mg / ml) was orally administered to the rats. Additional blood samples were taken 30, 60, 90, 120 minutes after glucose administration. A second drop of blood from each sample was placed on the glucose test strip to determine the level of glucose in the blood (glucose meter like Life Scan One Touch Ultra Blood® and glucose test strips like Life Scan One Touch Ultra®; Life Scan Inc .; Milpitas , California, 95035). The remaining blood from each sample was centrifuged and the plasma was frozen at -80 ° C until an insulin test was performed (rat insulin assay kit 1-2-3 Rat Insulin ELISA, Alpco Diagnostics).

Based on the obtained data, curves were built and AUC was determined for the studied compounds and excipient (for glucose and insulin), after which the% AUC in the control,% of the control maximum value and% of the control initial level were evaluated to determine the effect of the studied compound on glucose tolerance.

Using the test model described above for the studied compounds, the following results were obtained (in% relative to the control):

table 2 The effect of the studied compounds on glucose and insulin levels Example No. Glucose Insulin Auc Maximum action Baseline Auc Maximum action Baseline 2 84 78 82 95 95 85 6 89 84 91 104 123 109 fourteen 102 94 88 107 92 97

3. Acute experience in vivo no assessment of feed intake by mice

The studies were carried out on male mice of C57B1 / 6 mice located in separate cells (n = 8 individuals in the group). The mice were kept in a reversed cycle of 12 h / 12 h light / dark (the light was turned on at 22:00). The animals were given food (a high-calorie diet) and they had free access to water. Feed intake and water absorption were estimated daily. The test compound of formula I was suspended in water containing 1% methyl cellulose and 2 vol% poloxamer 188 (Lutrol F68®) and was administered by feeding through a gastric tube at a dose of 100 mg / kg / day. Half the dose was administered between 7.00 and 9.00 hours; the remaining half of the dose was administered between 15.0-15.30 hours.

Using the test model described above, the studied compounds caused a decrease in feed intake by animals within 24 hours (when estimated as a percentage of feed intake) compared to the control, as can be seen from Table 3 below.

Table 3 The effect of the studied compounds on feed intake Example No. Feed Consumption [% Relative to Control] 2 68 7 78 12 53 fifteen 79 21 76

4. Chronic in vivo experiment to evaluate the effects on feed and water intake and body weight gain

Female Wistar rats (weighing 250-300 g; Charles River, Margit, Kent) each contained two individuals in polypropylene cages with a hard floor and litter of sawdust at a temperature of 21 ± 4 ° C and a humidity of 55 ± 20%. The animals were kept under an inverted light / dark cycle (the light was turned off for 8 hours from 10.00 to 18.00 hours), during this period the room was lit with a red lamp. Animals had free access to high-fat feed (VRF1 plus 20% lard), ground chocolate, ground peanuts, and tap water at any time. Three different feeds were placed in different glass jars with aluminum lids (Solmedia Laboratory Suppliers, Romford, Essex). A 3-4-cm hole was made in each lid, providing access to the feed. Animals were kept in 2 individuals for 12 weeks. At least 2 weeks before the start of the initial data acquisition, the animals were placed one in polypropylene cages with a floor from a wire lattice, which made it possible to estimate the feed intake of each rat. To fix any spillage of food, polypropylene trays with cell bedding were placed under each cage.

At the beginning of the experiment, the animals were weighed (with an accuracy of about 0.1 g using electronic scales with upper cups) and combined into 6 experimental animals selected by weight of 10 animals each. After a 7-day baseline collection period, during which all animals were orally administered a vehicle once daily (1% Tylose MH50, 0.1% poloxamer 188), the vehicle or study compound of formula I was administered to rats for 28 days according to the schedule, below in table 4:

Table 4 The treatment scheme of rats with the compound of formula I, example 2 (pr 2) Group Processing 1 (0 h) Treatment 2 (4 h) n BUT Filler, ro Filler, ro 10 AT pr 2, 30 mg / kg, ro pr 2, 30 mg / kg, ro 10 FROM pr 2, 50 mg / kg, ro pr 2, 50 mg / kg, ro 10

The test compound from Example 2 was suspended in 1% Tylose MH50, 0.1% poloxamer 188 and administered via feeding through a gastric tube (2 ml / kg). In all cases, the treatment was carried out at the beginning of the 8-hour period of darkness (including the period immediately before and after the light was turned off). The second treatment was performed 4 hours after the first. During administration of the vehicle or test compound in rats, food cans and water bottles were weighed (with an accuracy of about 0.1 g) every day. At each data collection, the presence of feed spilled into the pan located under each cage was evaluated, which was returned to the appropriate jar before weighing. However, it was found that spillage of food from cans with food was negligible. The changes in body weight and energy levels were determined using various types of food, followed by expression of data on food intake in the form of kJ / kg of rat weight. Water consumption data were expressed in g / kg.

At the end of the experiment, on day 29, the animals were sacrificed (by CO ₂ treatment to minimize any fluid loss) and blood samples (5 ml whole blood / animal) were collected by cardiac puncture. Plasma was separated by centrifugation and stored at -75 ° C until analysis. After blood collection, the carcasses were weighed, frozen and stored at -75 ° C for analysis of body composition. In carcasses, the levels of the fat body, protein, water and ash were determined using standard chemical analyzes. Only the level of fat, protein, water and ash was determined, since other components (primarily carbohydrates) accounted for less than 2% of the composition of the whole organism.

The carcasses were milled separately at liquid nitrogen temperature, mixed and 2 representative samples were taken. The water content in the carcass was determined by freezing the samples to constant weight. The carcass fat content was determined in freeze-dried samples using a modified Soxhlet extraction protocol (petroleum ether at 40-60 ° C) using the Foss Soxtec ^® HT2 system (Foss UK Ltd, Veldrak, UK) according to the protocols recommended by the manufacturer. The protein content in the carcass was determined using the micro-Kjeldahl procedure on freeze-dried samples using a Foss 2012 ^® cleavage unit and a Foss 2200 ^® distillation apparatus (Foss UK Ltd). In the remaining carcass, the ash content was determined by burning freeze-dried samples at high temperature using a muffle ashing furnace. If necessary, the parameters of chemical analyzes were re-determined (for example, if the results obtained with duplication differed by more than 1%).

Table 5 The effect of the studied compounds of example 2 on the content of water, fat, protein and ash in the carcass: average weight per rat Group Water (g) Fat (g) Protein (g) Ash (g) Carcass (g) Filler 210.9 ± 2.7 144.5 ± 11.6 67.5 ± 1.2 12.52 ± 0.45 438.4 ± 12.1 Ex 2 (30 mg / kg) 205.8 ± 3.1 87.9 ± 3.8 ** 64.8 ± 1.2 12.13 ± 0.48 375.4 ± 4.8 ** Ex 2 (50 mg / kg) 202.2 ± 3.6 83.6 ± 6.9 ** 62.8 ± 1.3 11.38 ± 0.29 * 365.6 ± 3.8 **

The results were expressed as mean values for each experimental group (in all cases n = 9-10 and determined the differences between the experimental groups taking into account the initial differences in body weight between the groups) and the mean square error (standard deviation; calculated on the basis of the statistical model). Comparative statistical analysis was performed using ANCOVA (initial body weight as covariate) using the Williams test.

Significant differences regarding treatment with the filler were indicated with ** p <0.001, * ° p <0.1, * p <0.05.

Table 6 The effect of the studied compounds of example 2 on the content of water, fat, protein and ash in the carcass: average percentage, taking into account the final body weight Group Water(%) Fat (%) Protein (%) Ash (%) Total (%) Filler 48.8 ± 1.0 31.9 ± 1.4 15.7 ± 0.4 2.91 ± 0.12 99.3 Ex 2 (30 mg / kg) 55.2 ± 0.8 ** 22.8 ± 1.0 ** 17.4 ± 0.3 * ° 3.24 ± 0.12 98.6 Ex 2 (50 mg / kg) 55.7 ± 1.2 ** 22.3 ± 1.8 ** 17.3 ± 0.4 * ° 3.14 ± 0.1 98.4

Obtaining results and statistical processing was carried out according to the above method.

Table 7 The effect of the studied compounds of example 2 on the plasma parameters in female Wistar rats suffering from food-related obesity Group Glucose (mm) Insulin (ng / ml) Leptin (ng / ml) Filler 8.2 ± 0.7 2.33 ± 0.53 144.6 ± 22.7

Group Glucose (mm) Insulin (ng / ml) Leptin (ng / ml) Ex 2 (30 mg / kg) 8.6 ± 0.5 1.53 ± 0.33 68.8 ± 9.4 ** Ex 2 (50 mg / kg) 7.9 ± 0.5 1.40 ± 0.41 58.8 ± 11.6 **

Obtaining results and statistical processing was carried out according to the above method.

The present invention also relates to a pharmaceutical composition or medicament containing, in a pharmacologically effective amount, a compound of formula I or a physiologically compatible salt thereof, and preferably also containing conventional pharmaceutically acceptable excipients and / or carriers.

Suitable pharmaceutically acceptable excipients and / or carriers are well known in the art and are pharmaceutically pure starch, mannitol, lactose, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose (or other sugar), magnesium carbonate, gelatin, oil, alcohol, surfactants, emulsifiers or water (preferably sterile). The composition may be a mixed preparation or may be a combined preparation for simultaneous, separate or sequential use (including administration). The compounds of the invention, or their physiologically compatible acid addition salts, intended for the above indications, can be administered by any conventional method, for example, by oral (including by inhalation), parenteral administration, introduction into the mucous membrane (e.g., buccally, sublingual, nasal), rectal or transdermal administration and using appropriately adapted compositions. For oral administration, based on the compounds, it is possible to prepare, for example, liquid or solid forms, for example, solutions, syrups, suspensions or emulsions, tablets, capsules or lozenges. The liquid form is usually a suspension or solution of the compound or its physiologically compatible salt in an acceptable aqueous (s) or non-aqueous carrier (s), for example, water, ethanol, glycerol, polyethylene glycol or oil.

The formulation may also contain a suspending agent, preservative, flavoring or coloring agent. The composition in the form of a tablet can be obtained using any (s) pharmaceutical (s) carrier (s), which (s) are used, as a rule, for the preparation of solid formulations. Examples of such carriers are magnesium stearate, starch, lactose, sucrose and microcrystalline cellulose. The capsule composition can be prepared using standard encapsulation processes. For example, powders, granules or pills containing the active substance can be prepared using standard carriers and then filled into a hard gelatin capsule; in another embodiment, a dispersion or suspension can be prepared using any pharmaceutically acceptable carrier (s), for example, gums, celluloses, silicates or oils, and then filled into a soft gelatin capsule with a dispersion or suspension. In the composition for oral administration, it is possible to protect the active substance from degradation as it passes through the digestive tract, for example, by applying an external coating to a tablet or capsule. Typical parenteral compositions are a solution or suspension of a compound or its physiologically compatible acid addition salts in a sterile aqueous or non-aqueous vehicle, or an oil acceptable for parenteral administration, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with an acceptable solvent immediately prior to administration. Compositions for nasal or oral administration are conveniently formulated in the form of aerosols, drops, gels and powders.

Aerosol forms, as a rule, contain a finely divided suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solution and, as a rule, are in the form of one or more doses in sterile form in a sealed container, which may take the form of a cartridge or a replaceable can for use with a nebulizer. In another embodiment, the sealed container may be a device containing a single dose, such as a nasal inhaler containing a single dose, or an aerosol dispensing device equipped with a dispenser that is designed to simultaneously release the entire contents of the container. If the dosage form is an aerosol dispensing device, it should contain a pharmaceutically acceptable propellant. Aerosol forms of the drug may also be in the form of a nebulizer with a pump. Compositions intended for buccal or sublingual administration are tablets, lozenges and lozenges, for the preparation of which the active substance is combined with a carrier such as sugar and gum arabic, tragacanth or gelatin and glycerin. Compositions for rectal or vaginal administration are typically suppositories (containing the usual suppository base, such as cocoa butter), pessaries, vaginal pads, foams or enemas. Compositions suitable for transdermal use are ointments, gels, plaques, and injections, including powder injections. Typically, the composition is a unit dose of a drug, such as a tablet, capsule or ampoule. The pharmaceutical compositions of the invention can be used to prevent and / or treat obesity, concomitant and / or secondary diseases or conditions associated with obesity; other cases of weight loss related or unrelated to the medical condition; and / or diabetic conditions or diseases.

The compounds of the present invention and their physiologically compatible acid addition salts are generally administered in the form of pharmaceutical compositions, which are important and novel embodiments of the invention due to the presence of the compounds described herein. Embodiments of the invention are a pharmaceutical package or kit containing one or more containers filled with one or more ingredients of the pharmaceutical composition of the invention. Such container (s) may be accompanied by written materials, such as instructions for use, or a notice in the form required by a government agency that regulates the manufacture, use or sale of pharmaceutical products, where the notice reflects approval for medical or veterinary use, issued by the specified agency for the production, use or sale.

The next object of the invention is a method of preparing the above pharmaceutical composition. The preparation can be carried out by standard methods well known in the art, which include combining the compound of the invention and pharmaceutically acceptable auxiliary agents and / or carriers. The composition may take any form, including a tablet, liquid, capsule or powder, or a food product, for example a functional food product. In the latter case, the food product itself may function as a pharmaceutically acceptable carrier.

The compound or composition is preferably administered to a patient who needs it in an amount sufficient to prevent and / or treat the symptoms of the condition, disorder or disease. In all objects of the invention, especially those related to medicine, the administration of the compound or composition is carried out according to the regimen, which is ultimately determined by the attending physician taking into account such factors as the compound used, type of animal, age, weight, severity of symptoms, route of administration, side effects reactions and / or other contraindications. The specific doses recommended for use can be determined using standard clinical trials, in which the patient's state of change and its recovery are fully monitored. In such experiments, increasing doses containing a small percentage of the maximum tolerated dose for animals can be used as an initial dose for humans. Physiologically acceptable compounds of the invention are typically administered according to a daily dosage regimen (for adult patients), for example, when administered orally using a dose of 1 to 2000 mg, preferably 30 to 1000 mg, for example 10 to 250 mg, or by intravenous, subcutaneous or intramuscular administration using a dose of from 0.1 to 100 mg, preferably from 0.1 to 50 mg, for example from 1 to 25 mg of a compound of formula I or a physiologically acceptable salt thereof, calculated on the free base, the compound can enter from 1 to 4 times in d hey. The compound of the invention can be administered to children or adolescents, the individual regimens in these cases being very carefully selected by the doctor and usually should be lower doses compared to the doses that are used for administration to adults.

The compounds can be used for continuous therapy, for example, for at least a week, but usually for a longer period of several weeks to several months. The invention also relates to a cosmetic method (non-therapeutic) for maintaining a given weight or for cosmetic weight loss, the method comprising administering a compound of the invention, preferably in combination with a pharmaceutically acceptable carrier or diluent.

The compound or composition is preferably administered to an individual who needs it in an amount sufficient to maintain a given weight or for cosmetic weight loss.

According to another aspect of the invention, the compounds of formula I and their physiologically compatible acid addition salts are preferably administered in combination with one or more active substances (in the form of a pharmaceutical composition comprising a combination) selected from antidiabetic agents; anti-obesity or appetite-controlling agents; cardiovascular active substances, in particular antihypertensive agents; diuretics; active substances that change the level of lipids, in particular agents that lower the level of lipids; and active substances for the treatment and / or prevention of complications caused by diabetes or related to diabetes.

Suitable antidiabetic agents are, for example, insulins, amylin, derivatives of GLP-1 and GLP-2 (glucagon-like peptides), such as, for example, the compounds described in WO 98/0887, and having hypoglycemic actives when administered orally. Hypoglycemic actives having oral administration are preferably sulfonylureas, for example tolbutamide, glibenclamide, glimepiride, glipizide, glycidone, glycoxepide, glibomuride or glyclazide; biaguanidides, for example metformin; meglitidines, e.g. repaglinide; beta 3 adrenergic receptor agonists; oxadiazolidinediones; glucosidase inhibitors, for example alpha glucosidase inhibitors such as miglitol or acarbose; glucagon receptor antagonists, GLP-1 agonists, diazoxide-type potassium channel openers or compounds described in WO 97/26265 or WO 99/03861; CB-1 antagonists / inverse agonists (cannabinoid-1 receptor); insulin sensitizers such as thiazolidinediones, for example troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds described in WO 97/41097, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy ] phenyl] methyl] -2,4-thiazolidinedione; activators of the kinase insulin receptor; inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, for example, glycogen phosphorylase inhibitors and modulators of glucose uptake and glucose excretion.

Suitable anti-obesity or appetite-regulating agents are one or more 5-HT transporter inhibitors (serotonin), NE transporter inhibitor (norepinephrine), CB-1 antagonists / inverse agonists (cannabinoid-1 receptor), ghrelin antibody, ghrelin antagonist, antagonist ghrelin / inverse agonist H3 (histamine H3), antagonist of MCH1R (receptor 1R of melanin-concentrating hormone), agonist / antagonist of MCH2R (receptor 2R of melanin-concentrating hormone), antagonist of NPY1 (neuropeptide Y, Y1), agonist of NPY2 (neuropeptide, Y2, neuropeptide, Y, Y, Y neuro peptide Y, Y5), leptin, leptin derivative, opioid antagonist, orexin antagonist, BRS3 agonist (bombesin subtype 3 receptor), CCK-A agonist (cholecystokinin-A), CNTF (ciliary neurotrophic factor), CNTF derivative, GHS potent agonist (agonist growth hormone secretion receptor), SHT2c agonist (serotonin receptor 2), Mc3r agonist (melanocortin 3 receptor), Mc4r agonist (melanocortin 4 receptor), monoamine reuptake inhibitor, serotonin reuptake inhibitor, GLP-1 agonist (peptide 1) , topiramate, derivative 57 phytopharma, ACC2 inhibitor (acetyl CoA carboxylase-2), beta3-adrenergic receptor agonist, DGAT1 inhibitor (diacetylglycerol acyltransferase 1), DGAT2 inhibitor (diacetylglycerol acyltransferase 2), PDE inhibitor, phosphodiesterase inhibitor thyroid hormone B agonist, UCP-1 activator (non-crosslinking protein 1), -2 or -3, acylestrogen, glucocorticoid antagonist, 11-HSD-1 inhibitor (11-beta-hydroxysteroid-dehydrogenase type 1), SCD-1 inhibitor (stearoyl -COA desaturase-1), dipeptidyl peptidase IV inhibitor (DP-IV), lipase inhibitor, tra inhibitor sportera fatty acids, dicarboxylate transporter inhibitor, a glucose transporter inhibitor, a phosphate transporter inhibitor, and pharmaceutically acceptable salts and esters.

Suitable appetite-regulating agents (appetite-reducing agents) are sibutramine or the mono- and bisdemethylated active metabolites of sibutramine; fenfluramine or dexfenfluramine; mazindole, diethylpropion or phentermine; leptin or modified leptin; dexamphetamine and amphetamine.

Suitable lipase inhibitors are orlistat, panclicins, lipase inhibitors isolated from microorganisms such as lipstatin (from Streptomyces toxytricini), ebelactone B (from Streptomyces aburaviensis), synthetic derivatives of these compounds; 2-hydroxy-4H-3,1-benzoxazin-4-one derivatives of the Alizyme's ATL-962 type or compounds similar in structure; 2-amino-4H-3,1-benzoxazin-4-one derivatives or plant extracts for which lipase inhibitory activity is known, for example, Alpinia officinarum extracts or compounds isolated from these extracts, such as 3-methylethergalanganine (from A.officinarum).

Suitable antagonists of CB ₁ -cannabinoid are rimonabant, SLV319, SR147778 and CP-945598.

Acceptable cardiovascular active agents are angiotensin II receptor antagonists, for example, abitesartan, benzillosartan, candesartan, elisartan, embusartan, enoltazosartan, eprosartan, fonsartan, forsartan, militsanosartan, milanosartanartart, milanosartanartart, milanosartanartart, milanosartanartart, milanosartanartart, Ripisartan, Saprisartan, Saralazine, Sarmezin, Tasosartan, Telmisaran, Valsartan, Zolasartan; Kissei KRH-94, Lusofarmaco LR-B / 057, Lusofarmaco LR-B / 081, Lusofarmaco LR B / 087, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, Uriach UR-7247, A-81282, A -81988, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE -3489, DMP-811, DuP-167, DuP-532, GA-0056, E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803 , EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KRI-1177, KT3-671, KW-3433, L-158809, L -158978, L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441, L-163007, L-163017, LY-235656, LY-285434, LY-301875 , LY-302289, LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U -96849, U-97018, UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510, YM-358, YM- 31472, ZD-6888, ZD-7155 and ZD-8731 or their physiologically compatible salts, solvates, prodrugs or esters; daglutrile; non-selective alpha adrenergic antagonists, for example tolazoline or phenoxybenzamine; selective alpha-adrenergic antagonists, for example, doxazosin, prazosin, terazosin or uraridil; beta-adrenoreceptor antagonists, for example, acetbutolol, alprenolol, atenolol, betaxolol, bisoprolol, bupranolol, karazolol, cartolol, celiprolol, mepindolol, metipranolol, metaprolol, nadolol, oxprenolol, penbutolol, pindolol, pindolol; mixed alpha and beta adrenoreceptor antagonists, for example carvedilol or labetolol; ganglionic blockers, for example reserpine or guanethidine; alpha2-adrenergic agonists (including central nervous system agonists alpha2-adrenergic receptors), for example, clonidine, guanfacin, guanbenzmethyldopa and moxonidine; renin inhibitors, e.g. alskiren; ACE inhibitors (angiotensin converting enzyme), for example benazepril, captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril, perindopril, ramipril, spirapril or trandolapril; mixed type antagonists or selective endothelin receptor antagonists, for example, atrasentan, bosentan, clazosentan, darusentan, sitaxssentan, tezosentan, BMS-193884 or J-104132; direct vasodilating factors, for example diazoxide, dihydralazine, hydralazine or minoxidil; mixed type ACE / NEP inhibitors, for example omapatrilate; ECE inhibitors, for example FR-901533; PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-30084; CGS-35066; SM-19712; Ro0677447; selective NEP inhibitors; vasopressin antagonists; aldosterone receptor antagonists, for example eplerenone or spironolactone; angiotensin vaccine; and urotensin II receptor antagonists.

Acceptable diuretics are thiazide diuretics, for example, altiazide, bemetizide, bendroflumethiazide, benzyl hydrochlorothiazide, benzthiazide, butiazide, chlortiazide, cyclothiazide, hydrochlorothiazide, hydroflumethiazide, polychlorothiazide, triphlaziazide, triphlaziazide; diuretics that are thiazide analogues, for example, chloraminophenamide, chlortalidone, clofenamide, clopamide, clorexolone, fenchizone, indapamide, mefruside, metolazone, quinetazone, tripamide, xipamide; diuretics affecting loops (Gende), for example, azosemide, bumetanide, furosemide, pyrethanide, torsemide; calcium-saving diuretics, for example, amiloride, potassium canrenoate, spironolactone, triamteren or any physiologically compatible tautomers, salts, solvates, prodrugs or esters of any of the above diuretics.

Suitable active ingredients that alter lipid levels are lipid metabolism modifying compounds, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, such as HMG-CoA reductase inhibitors, for example, atorvastatin, berivastatin, cerivastatin, crilvastatin, clovvastatin, clovvastatin, clovvastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, flovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin or any physiologically compatible salts, solvates, prodrugs or esters thereof; cholesterol transport / cholesterol absorption inhibitors; bile acid reabsorption inhibitors or microsomal triglyceride transporter protein (MTP) inhibitors; compounds that reduce food absorption, PPAR (proliferator-activated peroxisome receptors) and RXR agonists and active substances that affect the ATP-dependent potassium channel of beta cells; fibric acids, for example bezafibrate, ciprofibrate, clofibrate, fenofibrate or demfibrozil; cholestyramine, colestipol, probucol, ezetimibe and dextrotyroxine; HMG-CoA synthase inhibitor, cholesterol absorption inhibitor, acyl-CoA cholesterol acyltransferase (ACAT) inhibitor, cholesteryl ester transfer protein inhibitor (CETP), squalene synthetase inhibitor, antioxidant, PPARα agonist, L receptor agonist, FXR receptor modulator lipoprotein synthesis inhibitor, reninangiotensin system inhibitor, triglyceride transport inhibitor in the microsome, bile acid reabsorption inhibitor, PEAR8 agonist, triglyceride synthesis inhibitor, transcription modulator, squalene epoxidase inhibitor, inducer a low density lipoprotein receptor receptor, a platelet aggregation inhibitor, a 5-LO or FLAP inhibitor, a partial PPAR8 agonist, and a niacin or niacin receptor agonist and their pharmaceutically acceptable salts and esters.

Other active substances that can be used in combination with the compound of the formula I of the present invention can be selected from the group consisting of CART agonists, H3 antagonists, TNF agonists, CRF agonists, BP CRF antagonists, urocortin agonists, beta3 agonists, MSH agonists (melanocyte-stimulating hormone), serotonin reuptake inhibitors, mixed-type serotonin and norepinephrine reuptake inhibitors, 5HT modulators, MAO inhibitors, galanin antagonists, growth hormone, growth hormone releasing factors, agony you TRH, modulators non-crosslinkable proteins 2 or 3, leptin agonists, dopamine agonists (bromocriptine, doprexin) modulators, RXR, hCNTF agonists and TR-beta agonists.

Preferred pharmaceutical combination compositions of the invention are combinations comprising at least one compound of formula I and at least one biguanide; at least one compound of formula I and at least one fibric acid; at least one compound of formula I and at least one HMG-CoA reductase inhibitor; and at least one compound of formula I and at least one insulin sensitizer.

Preferred compounds of the formula I which are intended to be combined with the aforementioned active substances are 4-phenylpiperazin-1-sulfonic acid amide; 4- (2-chlorophenyl) piperazin-1-sulfonic acid amide; 4- (2-methoxyphenyl) piperazin-1-sulfonic acid amide; 4-pyridin-4-ylpiperazin-1-sulfonic acid amide; 4-pyrimidin-2-ylpiperazin-1-sulfonic acid amide; 4- (4-fluorophenyl) piperazin-1-sulfonic acid amide; 4- (4-chloro-3-trifluoromethylphenyl) piperazin-1-sulfonic acid amide; and / or 4- (3-chloro-5-trifluoromethylpyridin-2-yl) piperazin-1-sulfonic acid amide.

A preferred biguanide to be combined with at least one compound of formula I is metformin.

Preferred fibric acids to be combined with at least one compound of formula I are bezafibrate, ciprofibrate, clofibrate, fenofibrate and / or gemfibrozil. Most preferred is fenofibrate.

Preferred HMG-CoA reductase inhibitors for combining with at least one compound of Formula I are atorvastatin, berivastatin, cerivastatin, krillvastatin, fluvastatin, glenvastatin, lovastatin, mevastatin, pitavastatin, pravastatin or fistiva or anyva compatible salts, solvates, prodrugs or esters. Most preferred are simvastatin, lovastatin and / or pravastatin.

Preferred insulin sensitizers intended to be combined with at least one compound of formula I are thiazolidinediones, in particular troglitazone, ciglitazone, pioglitazone and / or rosiglitazone. Most preferred are rosiglitazone and pioglitazone.

The most preferred combinations of the invention are combinations of 4-phenylpiperazin-1-sulfonic acid amide with metformin; 4-phenylpiperazin-1-sulfonic acid amide with fenofibrate; 4-phenylpiperazin-1-sulfonic acid amide with simvastatin; and 4-phenylpiperazin-1-sulfonic acid amide with rosiglitazone.

In one embodiment of the above pharmaceutical combination compositions of the invention, the compounds of formula I can be prepared and administered in combination with other active ingredients, for example, in the form of a combined unit dose such as one tablet or capsule, i.e. in the form of a physical combination. In such a combined unit dose, the compound of formula I and other active substances can be separated from each other, for example, by using various layers in a tablet, for example by using inert intermediate layers known in the art; or using different departments in a capsule. The corresponding active substances or their pharmaceutically acceptable salts can be used in the form of hydrates or they can include other solvents used for crystallization. The unit dose may be a fixed combination. A preferred alternative is a unit dose, especially a fixed combination of a compound of formula I and one or more other active ingredients.

In another embodiment, the compounds of formula I and other active substances can be prepared and administered in two or more different unit doses, for example, two or more tablets or capsules, the tablets or capsules being physically separated from each other. Two or more different individual standard doses can be administered simultaneously or in stages (separately), for example sequentially one after the other in any order. So, the compounds of formula I and other active substances can be administered in any order at the same time or at different points in time during the day; the optimal dosage regimen is usually determined by the attending physician.

The following examples are given only for the purpose of further explaining the invention and are not intended to limit its scope.

Example 1:

N-sulfamoyl N'-phenylpiperazine (4-phenylpiperazine-1-sulfonic acid amide)

A mixture containing 25.0 g of phenylpiperazine in 77.0 ml of toluene and 17.8 g of sulfamide was allowed to warm to reflux for 8 hours. The mixture was kept at room temperature from Saturday to Monday. The resulting solid particles were suspended in 200 ml of methanol and kept at 90 ° C for 60 minutes. The suspension was concentrated (removing 140 ml of methanol) by evaporation under reduced pressure, cooled and filtered, washed with diethyl ether and finally dried. The crude product was recovered and recrystallized from 200 ml of methanol (the procedure described above without concentration).

Example 2:

N-sulfamoyl-N'-phenylpiperazine hydrochloride

The crystalline fraction obtained by the method described in Example 1 above was treated with an ethanolic hydrochloric acid solution, evaporated and finally dissolved in 100 ml of methanol at 65 ° C. To this resulting solution was added 150 ml of isopropyl alcohol and methanol was removed under reduced pressure. After crystallization overnight, filtration, washing with diethyl ether and drying under reduced pressure (oil pump), 29.1 g of the title compound are obtained, _mp. = 184 ° C.

Table 8 Elemental analysis of the compounds of example 2 (MM 277.77): Calculated Detected C% 43.24 43.32 H% 5.81 5.86 N% 15.13 15.31 Cl ^- % 12.76 12.77

Example 3:

4- (2-Methoxyphenyl) piperazine-1-sulfonic acid amide hydrochloride

A) 12 ml of chlorosulfonyl isocyanate was added dropwise to an ice-cooled solution containing 13 ml of tert-butyl alcohol in 100 ml of dichloromethane. After 30 minutes, 4-dimethylaminopyridine (34.5 g) was added. The resulting mixture was stirred for 1 h at room temperature and diluted with dichloromethane until a clear solution was obtained. It was washed several times with water, the organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated strongly. The residue was recrystallized from acetonitrile to obtain 30.4 g of a BOC-protected DMAP reagent, _mp 156 ° C.

B) 2-Methoxyphenylpiperazine (152 mg) was dissolved in 10 ml of dichloromethane. The BOC-protected DMAP reagent (238 mg) obtained above was added to the resulting solution, and the resulting mixture was kept overnight at room temperature. The mixture was then evaporated and the residue was purified by flash chromatography (stationary phase: silica gel; mobile phase: tetrahydrofuran + 5% methanol) to obtain 192 mg of a BOC-protected intermediate.

C) 100 ml of absolute ethanol was cooled to 0 ° C in an ice bath, and then 20 ml of acetyl chloride was added dropwise and the resulting mixture was stirred for 20 minutes. From the ethanol solution of hydrochloric acid thus obtained, 5 ml of the BOC-protected compound obtained above (192 mg) dissolved in it was taken and stirred at room temperature for 3 hours. The mixture was then evaporated several times with ethanol and finally evaporated to dryness to obtain 225 mg specified in the connection header, t _pl. 191 ° C.

Example 4:

4-Pyridin-2-ylpiperazin-1-sulfonic acid amide

A) Tert-butyl alcohol (6.5 ml) was dissolved in 30 ml of dichloromethane. The resulting solution was added dropwise to an ice-cooled solution of chlorosulfonyl isocyanate (6.0 ml) in 40 ml of dichloromethane. After the reaction was carried out for 30 minutes, the resulting mixture was diluted with dichloromethane to 100 ml to obtain 0.854 molar mother liquor, which was used in the next step without further purification.

B) A freshly prepared mother liquor of tert-butyl sulfamoyl chloride (1.67 ml; 0.854 molar in dichloromethane obtained according to the above method) was added to a solution of 2-pyridylpiperazine (232 mg) in 4 ml of dichloromethane and the resulting mixture was stirred at room temperature for 24 hours Then, 3 ml of an ethanolic HCl solution (prepared according to the method described above in Example 3B) was added, after which the resulting mixture was kept overnight at room temperature. After evaporation of the solvents under reduced pressure, a crude solid was isolated. After flash chromatography of a solid (stationary phase: silica gel; mobile phase: tetrahydrofuran / methanol / ammonia 70: 30: 1 v / v / v) and drying product fractions, 200 mg of the title compound were obtained; liquid chromatography / mass spectroscopy (LC-MS): M + H 243 (99% ELSD).

Example 5:

4- (4'-Fluorobiphenyl-4-yl) piperazin-1-sulfonic acid amide

A) 1- (4-Bromophenyl) piperazine (250 mg), 4-fluorobenzeneboronic acid (254 mg), potassium carbonate (372 mg, dried and ground) and palladium (II) acetate (23.3 mg) were dissolved in 20 ml ethylene glycol dimethyl ether / water / ethanol mixtures (7: 3: 2 v / v / v) and placed in a microwave reactor (Emrys Optimizer®). After the reaction was carried out for 5 min at 150 ° C, methyl tert-butyl ether was added to the resulting clear solution, the organic phase was washed successively with water and brine, and dried over Na ₂ SO ₄ . The organic phase was strongly evaporated under reduced pressure. Another similar batch was obtained and the crude products from both parties were dissolved together in dichloromethane. The organic phase was diluted with soda solution, dried over Na ₂ SO ₄ , the solvent was evaporated strongly under reduced pressure, and the residue was purified by flash chromatography (stationary phase: silica gel, mobile phase: dichloromethane / methanol, 9: 1 v / v), giving 0 6 g of 1- (4'-fluorobiphenyl-4-yl) piperazine.

¹ H-NMR (500 MHz), δ [ppm]: 7.62 d (1H), 7.61 d (1H), 7.22 t (2 H), 7.49 d (2H), 6.98 d (2H), 3.17 m (4H), 3.09 m (4H).

B) The 1- (4'-fluorobiphenyl-4-yl) piperazine (0.6 g) and sulfamide (0.3 g) obtained according to the method described above were dissolved in 30 ml of dioxane and then heated under reflux for 3 h. After cooling to room temperature, most of the solvent was removed under reduced pressure. The resulting solid was crystallized from methyl tert-butyl ether to give 0.4 g of the title compound, _mp . 243.5-245.2 ° C.

The compounds of formula I below in table 9 can also be obtained using the methods described above in the examples or using methods analogous to them:

Table 9 Other compounds of formula I Etc. No. Ar Salt t _square 6 4-pyridinyl Hcl 243 ° C 7 2-pyrimidinyl 8 2,3-dimethylphenyl Hcl 202 ° C 9 4-fluorophenyl Hcl 125 ° C 10 3-chlorophenyl eleven 2-methyl-5-chlorophenyl Hcl 190 ° C 12 3-trifluoromethyl-4-chlorophenyl Hcl 180 ° C 13 3-cyan-2-pyridinyl Hcl 190 ° C fourteen 3-chloro-5-trifluoromethyl-2-pyridinyl Hcl 159 ° C fifteen 4-acetylphenyl Hcl 156 ° C 16 3,5-dichloro-4-pyridinyl Hcl 206 ° C 17 2-trifluoromethyl-4-quinolyl Hcl 191 ° C eighteen 4-trifluoromethyl-2-pyrimidinyl Hcl 156 ° C 19 5-trifluoromethyl-2-pyridinyl Hcl 169 ° C twenty 2-nitro-4-trifluoromethylphenyl Hcl 134 ° C 21 2-fluoro-4-methylsulfonylphenyl Hcl 184 ° C 22 benzo [1,3] dioxol-5-ylmethyl Hcl 233 ° C 23 1-naphthalenyl Hcl 193 ° C 24 4-ethoxyphenyl 25 5,6-dimethylthieno [2,3-D] -4-pyrimidinyl 26 2-methyl mercaptophenyl 27 2- (tert-butyl) -5- (trifluoromethyl) pyrazolo [1,5-A] -7-pyrimidinyl 28 benzyloxyphenyl 29th 5-cyano-6-methyl-2-nicotinic acid ethyl ester thirty 3,5-dichlorophenyl Hcl 185 ° C 31 3,4-dichlorophenyl Hcl 176 ° C 32 2,4-difluorophenyl Hcl 165 ° C 33 4-trifluoromethylphenyl Hcl 159 ° C

Example I:

Capsules containing N-sulfamoyl-N'-phenylpiperazine hydrochloride:

Capsules were prepared having the following composition per capsule:

N-sulfamoyl-N'-phenylpiperazine hydrochloride 70 mg corn starch 60 mg lactose 250 mg ethyl acetate (EA) q.s.

The active substance, corn starch and lactose were treated to obtain a homogeneous pasty mixture using EA. The paste was ground and the resulting granules were placed in an acceptable tray and dried at 45 ° C. to remove the solvent. The dried granules were passed through a crusher and mixed in a mixer with the following excipients:

talc 5 mg magnesium stearate 5 mg corn starch 10 mg

and then 400 mg were added to capsules (capsule size 0).

Claims (25)

1. The use of the compounds of formula I,

where Ar is a monocyclic or bicyclic C ₆ -C ₁₀ aryl, in which the ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and / or
wherein the C ₆ -C ₁₀ aryl ring system optionally contains from 3 to 5 double bonds, and / or
where the C ₆ -C ₁₀ aryl ring system is optionally substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy; C ₁ -C ₄ alkylsulfonyl; and two oxygen atoms that are bonded to two adjacent carbon atoms of the C ₆ -C ₁₀ aryl ring system and are connected by a C ₁ -C ₂ alkylene bridge; or
wherein the C ₆ -C ₁₀ aryl ring system is substituted with phenyl, which optionally can be substituted on the phenyl ring 1 with a substituent that can be selected from the group consisting of halogen;
and its physiologically compatible acid addition salts for the preparation of a medicament for the prevention or treatment of obesity in mammals and humans. 2. The use of a compound of formula I and its physiologically compatible acid addition salts according to claim 1, wherein Ar is phenyl optionally substituted with 1 or 2 substituents which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, a cyano group, a nitro group, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ alkylsulfonyl group and two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or
denotes phenyl substituted with phenyl, which optionally may be substituted with 1 substituent, which can be selected from the group including halogen; or
denotes pyridyl; pyrimidinyl or quinolinyl; each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 3. The use of a compound of formula I and its physiologically compatible acid addition salts according to claim 1, wherein Ar is phenyl optionally substituted with one or two substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, a cyano group, a nitro group, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ alkylsulfonyl group and two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or
denotes pyridyl; pyrimidinyl or quinolinyl; each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 4. The use of a compound of formula I and its physiologically compatible acid addition salts according to claim 2, wherein Ar is phenyl optionally substituted with one or two substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, a cyano group, a nitro group, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ alkylsulfonyl group and two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or
denotes pyridyl; pyrimidinyl or quinolinyl; each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 5. The use of the compounds of formula I and its physiologically compatible acid additive salts according to claim 1, where
Ar is phenyl substituted with 1 or 2 substituents which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ - C ₄ alkylsulfonyl and two oxygen atoms which are bonded to two adjacent carbon atoms which are connected by a C ₁ -C ₂ alkylene bridge; or is pyridyl; pyrimidinyl or quinolinyl, each of which is optionally substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 6. The use of the compounds of formula I and its physiologically compatible acid additive salts according to claim 2, where
Ar is phenyl substituted with 1 or 2 substituents which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ - C ₄ alkylsulfonyl and two oxygen atoms which are bonded to two adjacent carbon atoms which are connected by a C ₁ -C ₂ alkylene bridge; or is pyridyl; pyrimidinyl or quinolinyl, each of which is optionally substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 7. The use of the compounds of formula I

where Ar is a monocyclic or bicyclic C ₆ -C ₁₀ aryl, in which the ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and / or
wherein the C ₆ -C ₁₀ aryl ring system optionally contains from 3 to 5 double bonds, and / or
where the C ₆ -C ₁₀ aryl ring system is optionally substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy; C ₁ -C ₄ alkylsulfonyl; and two oxygen atoms that are bonded to two adjacent carbon atoms of the C ₆ -C ₁₀ aryl ring system and are connected by a C ₁ -C ₂ alkylene bridge; or
where the C ₆ -C ₁₀ aryl ring system is substituted with phenyl, which is substituted on the phenyl ring 1 with a substituent that can be selected from the group consisting of halogen;
and its physiologically compatible acid addition salts for the preparation of a medicament for the prophylaxis or treatment of metabolic syndrome and / or syndrome X in mammals and humans. 8. The use of the compounds of formula I according to claim 7, where the disorders or diseases associated with metabolic syndrome and / or syndrome X, are disorders or diseases selected from the group comprising hypertension, especially arterial hypertension; insulin resistance, especially type II diabetes mellitus; glucose intolerance; dyslipoproteinemia, primarily hypertriglyceridemia, accompanied by dyslipoproteinemia associated with low HDL cholesterol, and hyperuricemia. 9. The compound of formula Ia,

where Ar ¹ is phenyl substituted with 1 or 2 substituents which may have the same or different meanings and which can be selected from the group consisting of a nitro group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ alkylsulfonyl and two oxygen atoms which are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or
denotes phenyl substituted with phenyl which is substituted on the phenyl ring 1 with a substituent which can be selected from the group consisting of halogen; or
denotes naphthyl; pyridyl or quinolinyl; each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, cyano;
and its physiologically compatible acid addition salts. 10. The compound of formula Ia and its physiologically compatible acid additive salts according to claim 9, intended for use as medicines for the treatment of obesity, metabolic syndrome and / or syndrome X in mammals and humans, where
Ar ¹ is phenyl substituted with 1 or 2 substituents which may have the same or different meanings and which can be selected from the group consisting of nitro group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ alkylsulfonyl and two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or is naphthyl; pyridyl or quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 11. The compound of formula Ia and its physiologically compatible acid additive salts according to claim 9, intended for use as medicines for the treatment of obesity, metabolic syndrome and / or syndrome X in mammals and humans, where Ar ¹ is phenyl substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of a nitro group, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ alkylsulfonyl and two oxygen atoms that are bonded to two adjacent carbon atoms that are are single C ₁ -C ₂ alkylene bridge; or
denotes pyridyl; or quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 12. The compound of formula Ia and its physiologically compatible acid additive salts according to claim 11, intended for use as medicines for the treatment of obesity, metabolic syndrome and / or syndrome X in mammals and humans, where Ar ¹ is phenyl substituted with 1 or 2 substituents, which may be the same or different and which may be selected from the group consisting of nitro, C ₂ -C ₄ alkanoyl, C ₁ -C ₄ alkylsulfonyl and two oxygen atoms which are bonded to two adjacent carbon atoms to which Uniform C ₁ -C ₂ alkylene bridge; or denotes pyridyl or quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 13. The compound of formula Ia and its physiologically compatible acid addition salts according to claim 9, intended for use as medicines for the treatment of obesity, metabolic syndrome and / or syndrome X in mammals and humans, where Ar ¹ is phenyl substituted with 1 or 2 substituents which may have the same or different meanings and which can be selected from the group consisting of C ₁ -C ₄ alkylsulfonyl; or denotes pyridyl or quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 14. The compound of formula Ia and its physiologically compatible acid addition salts according to claim 11, intended for use as medicines for the treatment of obesity, metabolic syndrome and / or syndrome X in mammals and humans, where Ar ¹ is phenyl substituted with 1 or 2 substituents which may have the same or different meanings and which can be selected from the group consisting of C ₁ -C ₄ alkylsulfonyl; or
denotes pyridyl or quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 15. A pharmaceutical composition intended for the treatment of obesity, metabolic syndrome and / or syndrome X, containing a compound of formula Ia according to claim 9 or its physiologically compatible acid addition salts in a physiologically effective amount and conventional pharmaceutically acceptable excipients and / or carriers. 16. The compound of formula Ib,

where Ar ² is phenyl which is substituted with one substituent selected from the group consisting of 3-chloro, C ₂ -C ₄ alkoxy, two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or
denotes phenyl substituted with 2 or 3 substituents, which may have the same or different meanings and which can be selected from the group consisting of trifluoromethyl, nitro, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkylsulfonyl; or
denotes phenyl substituted with one substituent selected from phenyl, which is substituted on the phenyl ring 1 with a substituent which can be selected from the group consisting of halogen; or
denotes naphthyl; pyridyl or quinolinyl; each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano; or
its physiologically compatible acid addition salts. 17. The compound of formula Ib and its physiologically compatible acid addition salts according to clause 16, wherein Ar ² is phenyl substituted with 1 substituent selected from the group consisting of 3-chloro, C ₂ -C ₄ alkoxy, and two oxygen atoms, which bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or
denotes phenyl substituted with 2 substituents which may have the same or different meanings and which can be selected from the group consisting of trifluoromethyl, nitro group, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkylsulfonyl;
or
denotes pyridyl; naphthyl; quinolinyl; each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 18. The compound of formula Ib and its physiologically compatible acid additive salts according to clause 16, where
Ar ² is phenyl substituted with 1 substituent selected from the group consisting of 3-chloro, C ₂ -C ₄ alkoxy and two oxygen atoms that are bonded to two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or
denotes phenyl substituted with 2 substituents which may have the same or different meanings and which can be selected from the group consisting of trifluoromethyl, nitro group, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkylsulfonyl;
or
denotes pyridyl; quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same
or various values and which may be selected from the group consisting of halogen, trifluoromethyl and cyano. 19. The compound of formula Ib and its physiologically compatible acid addition salts according to claim 17, wherein Ar ² is phenyl substituted with 1 substituent selected from the group consisting of 3-chloro, a C ₂ -C ₄ alkoxy group and two oxygen atoms that are linked with two adjacent carbon atoms that are connected by a C ₁ -C ₂ alkylene bridge; or
denotes phenyl substituted with 2 substituents which may have the same or different meanings and which may be selected from the group consisting of trifluoromethyl, nitro group, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkylsulfonyl;
or
denotes pyridyl; quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 20. The compound of formula Ib and its physiologically compatible acid additive salts according to clause 16, where
Ar ² is phenyl substituted with 1 substituent selected from the group consisting of 3-chloro, C ₂ -C ₄ alkoxy; or is phenyl substituted with 2 substituents which may have the same or different meanings and which can be selected from the group consisting of trifluoromethyl, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkylsulfonyl;
or
denotes pyridyl; or quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 21. The compound of formula Ib and its physiologically compatible acid addition salts according to claim 17, wherein Ar ² is phenyl substituted with 1 substituent selected from the group consisting of 3-chloro, C ₂ -C ₄ alkoxy, or
denotes phenyl substituted with 2 substituents which may have the same or different meanings and which can be selected from the group consisting of trifluoromethyl, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkylsulfonyl; or
denotes pyridyl or quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 22. The compound of formula Ib and its physiologically compatible acid addition salts according to claim 18, where
Ar ² is phenyl substituted with 1 substituent selected from the group consisting of 3-chloro, C ₂ -C ₄ alkoxy; or is phenyl substituted with 2 substituents which may have the same or different meanings and which can be selected from the group consisting of trifluoromethyl, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkylsulfonyl;
or
denotes pyridyl or quinolinyl, each of which may optionally be substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl and cyano. 23. The compound of formula Ib and its physiologically compatible acid addition salts according to claim 16, selected from the group consisting of 4-pyridin-4-yl-piperazine-1-sulfonic acid amide; and 4- (3-chloro-5-trifluoromethylpyridin-2-yl) piperazin-1-sulfonic acid amide. 24. A method for treating or preventing obesity, metabolic syndrome and / or syndrome X in mammals and humans, the method comprising administering to a subject in need of a therapeutically effective amount a compound of formula I according to claim 1 or physiologically compatible acid- additive salts. 25. A method of obtaining a compound of formula I,

where Ar is a monocyclic or bicyclic C ₆ -C ₁₀ aryl, in which the ring carbon atoms are optionally substituted with 1-3 nitrogen or oxygen atoms, and / or
wherein the C ₆ -C ₁₀ aryl ring system optionally contains from 3 to 5 double bonds, and / or
where the C ₆ -C ₁₀ aryl ring system is optionally substituted with 1 or 2 substituents, which may have the same or different meanings and which can be selected from the group consisting of halogen, trifluoromethyl, cyano, nitro, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy; C ₁ -C ₄ alkylsulfonyl; and two oxygen atoms that are bonded to two adjacent carbon atoms of the C ₆ -C ₁₀ aryl ring system and are connected by a C ₁ -C ₂ alkylene bridge; or where the C ₆ -C ₁₀ aryl ring system is substituted with phenyl, which optionally can be substituted on the phenyl ring 1 with a substituent that can be selected from the group consisting of halogen;
and its physiologically compatible acid addition salts, by
a) interaction arylpiperazine formula II

in which Ar has the above meanings,
with 4-dimethylaminopyridine (DMAP) protected by a tert-butyloxycarbonyl (boc) group, of formula III,

and subsequent removal of the boc group under acidic conditions from the resulting intermediate, or by
b) reacting an arylpiperazine of formula II with sulfamoyl chloride, preferably protected with a boc group, of formula IV,

and subsequent removal of the boc group under acidic conditions from the resulting intermediate,
and, if necessary, converting the resulting free bases of formula I to their physiologically compatible salts or converting salts of the compounds of formula I to the free bases of formula I.