KR100679777B1 - Thiazole derivatives - Google Patents

Abstract

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used in the form of pharmaceutical compositions:

Formula I

Where

R ¹ to R ⁴ have the meaning given in claim 1.

Description

Thiazole derivatives {THIAZOLE DERIVATIVES}             

The present invention relates to novel thiazole derivatives useful as neuropeptide Y (NPY) receptor ligands, in particular neuropeptide Y (NPY) antagonists.

The present invention relates in particular to compounds of formula (I) or pharmaceutically acceptable salts or esters thereof:

R ¹ is aryl or heteroaryl, wherein at least one of the two meta positions of each aryl and heteroaryl group is substituted with R ⁵ ;

R ² is hydrogen, alkyl or cycloalkyl;

R ³ is cycloalkyl, aryl or heteroaryl, wherein at least one of the two ortho positions of each cycloalkyl, aryl and heteroaryl group is substituted with R ⁶ ;

R ⁴ is hydrogen, alkyl or cycloalkyl;

R ⁵ is hydrogen, cyano, trifluoromethyl, alkyl-SO _2- , amino-SO _2- , halogen, alkoxy, alkylcarbonyl or aminocarbonyl;

R ⁶ is hydrogen, halogen, cyano, nitro, trifluoromethyl, alkyl, alkoxy, hydroxy or alkoxycarbonyl;

Provided that one of R ⁵ and R ⁶ is not hydrogen.

Compounds of formula (I) and their pharmaceutically acceptable salts have novel and pharmaceutically useful properties. These are neuropeptide ligands such as neuropeptide receptor antagonists and in particular they are selective neuropeptide Y Y5 receptor antagonists.

Neuropeptide Y is a 36 amino acid peptide that is widely distributed in the central and peripheral nervous systems. This peptide mediates numerous physiological effects through its various receptor subtypes. Animal studies have demonstrated that neuropeptide Y is a potent stimulator of food intake, which leads to anorexia and reduced heat generation of neuropeptide Y Y5 receptor activity. Thus compounds that antagonize neuropeptide Y in the Y5 receptor subtype represent a method for the treatment of eating disorders such as obesity and anorexia.

Current research aims at clinical invention for inducing weight loss or for preventing weight gain. This is accomplished by disturbing appetite control and is mediated by the hypothalamus, an important brain region that has been demonstrated to regulate food intake. Neuropeptide Y (NPY) has been demonstrated herein as one of the most potent pivotal mediators of food intake in some animal species. Increased NPY levels result in severe food intake. Various receptors of neuropeptide Y (NPY) have been described to play a role in appetite control and weight gain. Interference of these receptors reduces appetite and consequently weight gain. Weight loss and long-term maintenance can also have beneficial consequences in correlated risk factors such as arthritis, cardiovascular disease, diabetes and kidney failure.

Thus, the compounds of formula (I) can be used for the prevention or treatment of arthritis, cardiovascular disease, diabetes, renal failure and especially eating disorders and obesity.

The object of the present invention is to provide a compound of formula (I) and its mentioned salts and their esters and their use as therapeutically active substances, the compounds, intermediates, pharmaceutical compositions, medicaments (including the compounds, their pharmaceutically acceptable salts and esters) Prevention and / or treatment of arthritis, cardiovascular disease, diabetes, renal failure and especially eating disorders such as anorexia and in particular obesity and arthritis, cardiovascular disease, diabetes, renal failure and especially eating disorders and obesity Use of said compounds, salts and esters for the manufacture of a medicament for treatment or prophylaxis.

As used herein, the term "alkyl", alone or in combination, is a straight or branched chain alkyl group of 1 to 8 carbon atoms, preferably a straight or branched chain alkyl group of 1 to 6 carbon atoms, particularly preferably 1 to 4 carbon atoms Means a straight or branched chain alkyl group. Examples of straight and branched C ₁ -C ₈ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric pentyl, isomeric hexyl, isomeric heptyl and isomeric octyl, preferably Are methyl and ethyl and most preferably methyl.

The term "cycloalkyl", alone or in combination, means a cycloalkyl ring having 3 to 8 carbon atoms, preferably a cycloalkyl ring having 3 to 6 carbon atoms. Examples of C ₃ -C ₈ cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethyl cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl- Cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.

The term "alkoxy", alone or in combination, refers to a group of the formula alkyl-O- and the term "alkyl" means the meaning already given, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso Butoxy, secondary-butoxy and tert-butoxy, 2-hydroxyethoxy, 2-methoxyethoxy, preferably methoxy and ethoxy and most preferably methoxy.

The term "aryl", alone or in combination, means a phenyl or naphthyl group, preferably a phenyl group, which is optionally each independently halogen, trifluoromethyl, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carba Moyl, alkoxycarbamoyl, methylenedioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO _2- , amino-SO ₂ -and cyclo One or more substituents selected from the group consisting of alkyl and the like. Phenyl or naphthyl is preferred, and in particular phenyl is optionally each independently cyano, trifluoromethyl, alkyl-SO _2- , amino-SO _2- , halogen, alkoxy, hydroxy, amino, cycloalkyl, alkylcarbo And a substituent selected from the group consisting of niyl, aminocarbonyl, nitro, alkyl and alkoxycarbonyl.

The term "aralkyl", alone or in combination, refers to an alkyl or cycloalkyl group as defined above and one hydrogen atom is replaced by an aryl group as defined above. Benzyl is preferred and benzyl is substituted with hydroxy, alkoxy or halogen, preferably fluorine. Especially benzyl is preferred.

The term "heteroaryl", alone or in combination, comprises an aromatic 5 to 10-membered heterocycle comprising one or more, preferably one or two, particularly preferably one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur Cycle, where nitrogen is preferred. Cyano, trifluoromethyl, alkyl-SO _2- , amino-SO _2- , halogen, alkoxy, hydroxy, amino, cycloalkyl, alkylcarbonyl, aminocarbonyl nitro, alkyl and / or alkoxycarbonyl One or more selected from the group consisting of may be substituted with carbon atoms. Preferred heteroaryl rings are pyridyl, pyrazinyl and thiophenyl, optionally cyano, trifluoromethyl, alkyl-SO _2- , amino-SO _2- , halogen, alkoxy, alkylcarbonyl, aminocarbonyl, Nitro, substituted by one or more, preferably one or two substituents selected from the group consisting of alkyl and alkoxycarbonyl.

The term "amino", alone or in combination, together with a secondary amino group having an alkyl or cycloalkyl substituent and two similar or different alkyl or cycloalkyl substituents or rings together with a tertiary amino group having two nitrogen substituents together with the formation of a nitrogen group; Primary, secondary or tertiary amino groups bonded by an atom, for example -NH ₂ , methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidine-1- Mono or piperidino and the like, preferably amino, dimethylamino and diethylamino and especially primary amino.

The term "halogen" means fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine.

The term "carbonyl", alone or in combination, means a -C (O)-group.

The term "nitro" alone or in combination means a -NO ₂ group.

The term "cyano" alone or in combination means a -CN group.

The term "meta position" as used in the definition of substituent R ¹ means that substituent R ⁵ is bonded to an aryl or heteroaryl group bonded to an -NR ₂ -group in a meta position to an atom of an aryl or heteroaryl group. For example in this case aryl means phenyl in the definition of R ¹ and substituent R ⁵ is bonded to a phenyl ring according to the formula:

According to the definition of substituent R ¹ , an aryl or heteroaryl ring is substituted by one or two R ⁵ substituents. In this case two R ⁵ substituents are bonded to an aryl or heteroaryl ring and the two R ⁵ substituents are the same or different. Preferably both R ⁵ substituents are the same. R ⁵ substituents are each selected from halogen, cyano, trifluoromethyl, alkyl-SO _2- , amino-SO _2- , halogen, alkoxy, alkylcarbonyl and aminocarbonyl groups.

As used in the definition of substituent R ³ , the term “ortho position” refers to a cycloalkyl, aryl or heteroaryl ring in the ortho position at the atom of a cycloalkyl, aryl or heteroaryl group where substituent R ⁶ is bonded to a carbonyl group It means. For example in this case aryl means phenyl in the definition of R ³ and substituent R ⁶ is bonded to a phenyl ring according to the formula:

According to the definition of substituent R ³ , a cycloalkyl, aryl or heteroaryl ring may be substituted by one or two R ⁶ substituents. In this case two R ⁶ substituents are bonded to a cycloalkyl, aryl or heteroaryl ring and the two R ⁶ substituents can be the same or different. Preferably both R ⁶ substituents are identical.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological efficacy and properties of the free base or free acid, which are not biological or otherwise undesirable. Salts include inorganic acids (eg hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., preferably hydrochloric acid) and organic acids (eg acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid). , Tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. These salts can also be prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Acids derived from organic bases are primary, secondary and tertiary amines, naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine Salts of substituted amines including, but not limited to, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine, resins, and the like. The compounds of formula I may also exist in the form of zwitterions. In particular, preferred pharmaceutically acceptable salts of formula (I) are hydrochloric acid salts.

The compounds of formula (I) can also be solvated, for example hydrated. Solvents may be effective during the manufacturing process or may arise, for example, as a result of the hygroscopic properties of the anhydride compounds at the beginning of formula (I). The term pharmaceutically acceptable salts also includes physiologically acceptable solvates.

"Pharmaceutically acceptable esters" can be derived from functional groups that provide a possible derivative of reverse conversion of a compound of formula (I) to a source compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. In addition, any physiologically acceptable equivalent of a compound of formula (I) that is analogous to a metabolically labile ester capable of preparing a source compound of formula (I) in vivo is within the scope of the present invention.

The term “lipase inhibitor” refers to a compound capable of inhibiting the action of lipases, for example gastric and pancreatic lipases. For example, orlistat and lipstatin as described in US Pat. No. 4,598,089 are potent inhibitors of lipase. Lipstatin is a natural product of microbial origin, and orlistat is the result of hydrolysis of lipstatin. Other lipase inhibitors include a class of compounds commonly referred to as Panclicin. Panclicin is an analog of orlistat (Mutoh et al., 1994). The term "lipase inhibitor" also refers to a polymer bound to a lipase inhibitor as described in WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized by substitution with one or more groups that inhibit lipases. The term “lipase inhibitor” also includes pharmaceutically acceptable salts of these compounds. The term “lipase inhibitor” preferably refers to orlistat.

Orlistat is a compound that is usefully known for the control or prevention of obesity and hyperlipidemia. See also US Pat. No. 4,598,098, filed Jul. 1, 1986, which discloses a method for preparing orlistat, and US Pat. No. 6,004,996, which discloses a suitable pharmaceutical composition. Suitable pharmaceutical compositions are also described in WO 00/09122 and WO 00/09123. Further methods for preparing orlistat are disclosed in European Patent Publications 185,359, 185,577, 443,449 and 524,495.

Orlistat is preferably administered orally at 60 to 720 mg / day divided into two to three doses per day. Preferably from 180 to 360 mg / 1 day, most preferably 360 mg / 1 day, preferably in divided doses of the lipase inhibitor to the subject twice or in particular three times. The subject is preferably an obese or overweight human, ie a human having a body mass index of 25 or greater. In general, lipase inhibitors are preferably administered within about 1 or 2 hours of digestion of a meal containing fat. In general, for the administration of lipase inhibitors as defined above, it is preferred to administer to humans with a family history of strongly obesity and a body mass index obtained of at least 25.

Orlistat may be administered to humans in conventional oral compositions such as tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions. Examples of carriers that can be used in tablets, coated tablets, dragees, and hard gelatin capsules include lactose, other sugars, and sugar alcohols (sorbitol, mannitol, maltodextrin, or other fillers); Surfactants (sodium lauryl sulfate, Brij 96 or Tween 80); Disintegrants (sodium starch glycolate, corn starch or derivatives thereof); Polymers (povidone, crospovidone), talc, stearic acid or polymers thereof. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. In addition, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, anti-esthetics, salts of varying osmotic pressure, buffers, coatings and antioxidants. They may also contain other therapeutically important substances. Formulations may conventionally be present in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. Preferably, orlistat is administered according to the formulations set forth in the Examples and US Pat. No. 6,004,996, respectively.

Compounds of formula (I) may contain several asymmetric centers and optionally pure enantiomers, mixtures of enantiomers such as racemates, optionally pure mixtures of diastereomers, mixtures of diastereomers, diastereomeric racemates Or in the form of a mixture of diastereomeric racemates.

Preferred are the compounds of formula (I) and their pharmaceutically acceptable salts, in particular the compounds of formula (I).

In addition, preferred compounds of formula I and their pharmaceutically acceptable salts and esters are

R ¹ is aryl or heteroaryl, wherein at least one of the two meta positions of each aryl and heteroaryl group is substituted with R ⁵ ;

R ² is hydrogen, alkyl or cycloalkyl;

R ³ is cycloalkyl, aryl or heteroaryl, wherein at least one of the two ortho positions of each cycloalkyl, aryl and heteroaryl group is substituted with R ⁶ ;

R ⁴ is hydrogen, alkyl or cycloalkyl;

R ⁵ is cyano, trifluoromethyl, alkyl-SO _2- , amino-SO _2- , halogen, alkoxy, alkylcarbonyl or aminocarbonyl;

R ⁶ is halogen, cyano, nitro, trifluoromethyl, alkyl, alkoxy, hydroxy or alkoxycarbonyl.

In addition, the R ¹ aryl or heteroaryl, either of the two meta positions of each aryl or heteroaryl group is substituted with R ⁵ R ⁵ is a compound of formula I as defined above are preferred.

In addition, R ³ these two one ortho position is substituted with R ⁶ R ⁶ is a compound of formula I as defined above for cycloalkyl, aryl or heteroaryl, each of cycloalkyl, aryl or heteroaryl groups it is preferred .

Also preferred are compounds according to formula I, wherein R ⁴ is hydrogen or methyl. Particular preference is given to compounds of the formula I in which R ⁴ is hydrogen.

Another preferred compound of formula I is that R ² is hydrogen.

In addition, preferred compounds of formula I are those wherein R ³ is cyclohexyl, naphthyl, phenyl, pyridyl, pyrazinyl or thiophenyl and each of the cyclohexyl, naphthyl, phenyl, pyridyl, pyrazinyl and thiophenyl groups of one or more of the ortho positions is substituted with R ⁶ R ⁶ is as defined above.

Another preferred embodiment of the invention R ³ is phenyl or pyridyl and one or more of each of the two ortho positions of the phenyl and pyridyl group is substituted with R ^6, R ⁶ is a compound according to formula I as defined above .

In addition, R ¹ is phenyl or pyridyl and the compound according to formula I, such as the two least one of the meta-position is replaced by R ^5, R ⁵ has the definition of each phenyl or pyridyl group is preferred.

Another preferred embodiment of the invention is that R ¹ is phenyl or pyridyl and one of the two meta positions of each phenyl or pyridyl group is cyano, trifluoromethyl, alkyl-SO _2- , amino-SO _2- , Compound of formula (I) substituted with halogen, alkoxy, alkylcarbonyl or aminocarbonyl group.

Preference is also given to compounds of the formula (I) in which R ⁵ is cyano, trifluoromethyl, alkyl-SO _2- , amino-SO _2- , halogen, alkoxy, alkylcarbonyl or aminocarbonyl.

Another preferred embodiment of the invention is a compound of formula (I) wherein R ⁵ is cyano, trifluoromethyl, alkyl-SO _2- , amino-SO ₂ -or alkylcarbonyl.

Preferred are compounds of formula I, wherein R ⁵ is cyano, trifluoromethyl, methyl-SO _2- , NH ₂ -SO ₂ -or methylcarbonyl.

Preference is also given to compounds of the formula (I) in which R ⁶ is a halogen, cyano, nitro, trifluoromethyl, alkyl, alkoxy, hydroxy or alkoxycarbonyl group.

Preference is also given to compounds of the formula (I) in which R ⁶ is a halogen, trifluoromethyl or alkyl group.

Preferred examples of compounds of formula I are as follows:

1. 3- [5- (naphthalene-2-carbonyl) -thiazol-2-ylamino] -benzonitrile;

2. 3- (5-benzoyl-thiazol-2-ylamino) -benzonitrile;

3. 3- [5- (4-Methyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

4. [2- (3-Methanesulfonyl-phenylamino) -thiazol-5-yl] -phenyl-methanone;

5. [2- (3-methoxy-phenylamino) -thiazol-5-yl] -phenyl-methanone;

6. Phenyl- [2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

7. 3- [5- (3-methoxy-benzoyl) -thiazol-2-ylamino] -benzonitrile;

8. 3- [5- (4-Fluoro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

9. 3- [5- (4-chloro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

10. [2- (3,5-Dichloro-phenylamino) -thiazol-5-yl]-(2-fluoro-phenyl) -methanone;

11. (2-Chloro-phenyl)-[2- (3,5-dichloro-phenylamino) -thiazol-5-yl] -methanone;

12. 3- [5- (4-Bromo-benzoyl) -thiazol-2-ylamino] -benzonitrile;

13. 3- [5- (3-chloro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

14. 3- [5- (2-fluoro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

15. 3- [5- (3-fluoro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

16. 3- [5- (2-methoxy-benzoyl) -thiazol-2-ylamino] -benzonitrile;

17. 3- [5- (3-trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

18. 3- [5- (2-chloro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

19. 3- [5- (3-Bromo-benzoyl) -thiazol-2-ylamino] -benzonitrile;

20. [2- (4-Chloro-phenylamino) -thiazol-5-yl]-(2-fluoro-phenyl) -methanone;

21. (2-Chloro-phenyl)-[2- (4-chloro-phenylamino) -thiazol-5-yl] -methanone;

22. p-tolyl- [2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

23. (4-Fluoro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

24. (3-methoxy-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

25. (3-Chloro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

26. (2-Fluoro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

27. (3-Fluoro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

28. (2-methoxy-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

29. (2-Chloro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

30. (3-Bromo-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

31. [2- (pyridin-4-ylamino) -thiazol-5-yl] -o-tolyl-methanone;

32. (2,4-Dichloro-phenyl)-[2- (pyridin-4-ylamino) -thiazol-5-yl] -methanone;

33. (2,4-Dimethyl-phenyl)-[2- (pyridin-4-ylamino) -thiazol-5-yl] -methanone;

34. (2-nitro-phenyl)-[2- (pyridin-4-ylamino) -thiazol-5-yl] -methanone;

35. 3- [5- (pyridine-2-carbonyl) -thiazol-2-ylamino] -benzonitrile;

36. 3- [5- (pyridine-3-carbonyl) -thiazol-2-ylamino] -benzonitrile;

37. 3- [5- (pyridine-4-carbonyl) -thiazol-2-ylamino] -benzonitrile;

38. 3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

39. 3- (5-cyclohexanecarbonyl-thiazol-2-ylamino) -benzonitrile;

40. 3- [5- (2,4-Dichloro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

41. 3- [5- (2,4-Dimethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

42. 3- [5- (2-nitro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

43. (2-Fluoro-phenyl)-[2- (3-methoxy-phenylamino) -thiazol-5-yl] -methanone;

44. [2- (3-methoxy-phenylamino) -thiazol-5-yl] -o-tolyl-methanone;

45. (2,4-Dimethyl-phenyl)-[2- (3-methoxy-phenylamino) -thiazol-5-yl] -methanone;

46. [2- (3-methoxy-phenylamino) -thiazol-5-yl]-(2-nitro-phenyl) -methanone;

47. Pyridin-4-yl- [2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

48. o-tolyl- [2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

49. cyclohexyl- [2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

50. (2,4-Dichloro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

51. (2,4-Dimethyl-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

52. (2-nitro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

53. (2-Fluoro-phenyl)-[2- (3-fluoro-phenylamino) -thiazol-5-yl] -methanone;

54. [2- (3-Fluoro-phenylamino) -thiazol-5-yl] -o-tolyl-methanone;

55. (2-Chloro-phenyl)-[2- (3-fluoro-phenylamino) -thiazol-5-yl] -methanone;

56. [2- (3-Bromo-phenylamino) -thiazol-5-yl] -phenyl-methanone;

57. [2- (3-Bromo-phenylamino) -thiazol-5-yl] -o-tolyl-methanone;

58. [2- (3-Bromo-phenylamino) -thiazol-5-yl]-(2-chloro-phenyl) -methanone;

59. [2- (3-Bromo-phenylamino) -thiazol-5-yl]-(2,4-dimethyl-phenyl) -methanone;

60. 1- {3- [5- (2-Fluoro-benzoyl) -thiazol-2-ylamino] -phenyl} -ethanone;

61. 1- {3- [5- (2-Methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -ethanone;

62. 1- {3- [5- (2-Chloro-benzoyl) -thiazol-2-ylamino] -phenyl} -ethanone;

63. 1- {3- [5- (2,4-Dimethyl-benzoyl) -thiazol-2-ylamino] -phenyl} -ethanone;

64. (2-Fluoro-phenyl)-[2- (pyridin-3-ylamino) -thiazol-5-yl] -methanone;

65. [2- (pyridin-3-ylamino) -thiazol-5-yl] -o-tolyl-methanone;

66. (2-Chloro-phenyl)-[2- (pyridin-3-ylamino) -thiazol-5-yl] -methanone;

67. 3- [5- (3-methyl-pyrazin-2-carbonyl) -thiazol-2-ylamino] -benzonitrile;

68. 3- [5- (3-ethyl-pyrazin-2-carbonyl) -thiazol-2-ylamino] -benzonitrile;

69. 3- [5- (3-methyl-thiophen-2-carbonyl) -thiazol-2-ylamino] -benzonitrile;

70. 3- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

71. 3- [5- (2-trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

72. 3- [5- (3-methyl-pyridine-2-carbonyl) -thiazol-2-ylamino] -benzonitrile;

73. 3- [5- (2-methyl-pyridine-3-carbonyl) -thiazol-2-ylamino] -benzonitrile;

74. 3- [5- (2,5-dimethyl-thiophen-3-carbonyl) -thiazol-2-ylamino] -benzonitrile;

75. (3-Methyl-thiophen-2-yl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

76. (2-Ethyl-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methaneone;

77. (2-Trifluoromethyl-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

78. (3-Methyl-pyridin-2-yl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

79. (2,5-Dimethyl-thiophen-3-yl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

80. o-tolyl- (2-m-tolylamino-thiazol-5-yl) -methanone;

81. (2-ethyl-phenyl)-(2-m-tolylamino-thiazol-5-yl) -methanone;

82. (2-m-tolylamino-thiazol-5-yl)-(2-trifluoromethyl-phenyl) -methanone;

83. (2-Fluoro-phenyl)-(2-m-tolylamino-thiazol-5-yl) -methanone;

84. (2-Chloro-phenyl)-(2-m-tolylamino-thiazol-5-yl) -methanone;

85. (2-methoxy-phenyl)-(2-m-tolylamino-thiazol-5-yl) -methanone;

86. (2,5-dimethyl-thiophen-3-yl)-(2-m-tolylamino-thiazol-5-yl) -methanone;

87. [2- (3-Methanesulfonyl-phenylamino) -thiazol-5-yl] -o-tolyl-methanone;

88. (2-ethyl-phenyl)-[2- (3-methanesulfonyl-phenylamino) -thiazol-5-yl] -methanone;

89. [2- (3-Methanesulfonyl-phenylamino) -thiazol-5-yl]-(2-trifluoromethyl-phenyl) -methanone;

90. (2-Chloro-phenyl)-[2- (3-methanesulfonyl-phenylamino) -thiazol-5-yl] -methanone;

91. [2- (3-Methanesulfonyl-phenylamino) -thiazol-5-yl]-(4-methyl-pyridin-3-yl) -methaneone;

92. (2,5-Dimethyl-thiophen-3-yl)-[2- (3-methanesulfonyl-phenylamino) -thiazol-5-yl] -methanone;

93. 4- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile;

94. 4- [5- (3-Methyl-pyridine-2-carbonyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile;

95. 4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile;

96. 4- [5- (2-chloro-benzoyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile;

97. 4- [5- (2-fluoro-benzoyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile;

98. 3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

99. 3- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

100. 3- [5- (4-hydroxy-2-methyl-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

101. 3- [5- (2-trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

102. 3- [5- (2-fluoro-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

103. 3- [5- (2-chloro-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

104. 3- [5- (2-methoxy-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

105. 3- [5- (3-fluoro-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

106. 3- [5- (3-Chloro-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide;

107. 3- [5- (4-Methyl-pyridine-3-carbonyl) -thiazol-2-ylamino] -benzenesulfonamide;

108. 3- [5- (3-methyl-pyridine-2-carbonyl) -thiazol-2-ylamino] -benzenesulfonamide;

109. 3- [5- (3-ethyl-pyrazin-2-carbonyl) -thiazol-2-ylamino] -benzenesulfonamide;

110. 3- [5- (3-methyl-thiophen-2-carbonyl) -thiazol-2-ylamino] -benzenesulfonamide;

111. 3- [4-Methyl-5- (2-trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile and

112. Phenyl- (2-m-tolylamino-thiazol-5-yl) -methanone.

Particularly preferred examples of compounds of formula I are as follows:

3- [5- (2-Fluoro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

3- [5- (2-Chloro-benzoyl) -thiazol-2-ylamino] -benzonitrile;

(2-Chloro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

o-tolyl- [2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone;

1- {3- [5- (2-Methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -ethanone;

3- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

3- [5- (2-Trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile;

3- [5- (3-Methyl-pyridine-2-carbonyl) -thiazol-2-ylamino] -benzonitrile;

[2- (3-Methanesulfonyl-phenylamino) -thiazol-5-yl] -o-tolyl-methanone;

(2-ethyl-phenyl)-[2- (3-methanesulfonyl-phenylamino) -thiazol-5-yl] -methanone;

4- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile;

4- [5- (2-Methyl-benzoyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile;

3- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide; And

3- [5- (2-Trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide.

A process for the preparation of compounds of formula I is an object of the present invention.

The preparation of compounds of formula (I) of the invention can be carried out in sequential or convergent routes. The synthesis of the present invention is shown in the following scheme. The skills required for carrying out the reaction and purification of the resulting product are known in the art. Substituents and indices used in the following description of the route have the meanings given above unless indicated otherwise.

Compounds of formula IA (R ⁴ = H) can be prepared according to the following scheme 1:

(a) Thiourea IB, commercially available or available by various procedures described in the literature, readily reacts with N, N-dimethylformamide dimethyl acetal in the presence or absence of a solvent. There is no particular limitation on the nature of the solvent used, provided it is capable of dissolving at least to some extent without adversely affecting the reaction or related reagents. Examples of suitable solvents include DMF, dioxane and the like. The reaction can occur over a wide temperature range and the exact reaction temperature is not critical to the invention. The inventors have observed that it is easy to carry out the reflux heating reaction from normal temperature. The time required for the reaction can also vary widely depending on many factors, especially the temperature and the nature of the reactants. However, a period of 0.5 hours to several days is usually sufficient to obtain a dimethylaminomethylene-thiourea derivative IC. Reaction conditions described in the literature affecting this reaction are described, for example, in Heterocycles 11, 313-318; 1978].

(b) The dimethylaminemethylene-thioureido derivatives IC is characterized in that IA is converted to α-bromoketone ID (known compound or compound prepared by a known method, in a solvent such as ethanol or the like in the presence or absence of a base, Can be converted to thiazole derivative IA (R ⁴ = H) by reaction with the α-bromoketone source used, indicated as appropriate). There is no particular limitation on the nature of the solvent used, provided it is capable of dissolving at least to some extent without adversely affecting the reaction or related reagents. Examples of suitable solvents include dichloromethane, chloroform or dioxane, methanol, ethanol and the like. There is no particular limitation on the nature of the base used in this step and any base commonly used for this type of reaction may equally be used herein. Examples of such bases include triethylamine, diisopropylethylamine, and the like. The reaction can occur over a wide temperature range and the exact reaction temperature is not critical to the present invention. The inventors observed that the reaction was easily carried out by heating to reflux from normal temperature. In addition, the time required for the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain thiazole derivative IA. The reaction conditions described in the literature affecting this reaction are described, for example, in J. Heterocycl. Chem., 16 (7), 1377-83; 1979]. The resulting compound of formula (IA) (R ⁴ = H, R ² = H) is a compound of the present invention and may be a preferred product; Alternatively, simultaneous reactions, such as the removal of protecting groups, can be carried out by methods broadly described in the literature to obtain the preferred thiazole derivative IA. However, the resulting compound of formula (IA) is a compound of the present invention and may be a preferred product; Alternatively, simultaneous reactions can be performed. The introduction of R ² alkyl or cycloalkyl (when R ² is H) in IA can be effected by reductive amination of aldehydes and IA, respectively, under reducing conditions in a solvent. There is no particular limitation on the nature of the solvent used, provided it is capable of dissolving at least to some extent without adversely affecting the reaction or related reagents. Examples of suitable solvents include dichloromethane, chloroform, dioxane, THF and the like. There is no particular limitation on the nature of the reducing agent used in this step and any reducing agent conventionally used for this type of reaction may equally be used herein. Examples of such reducing agents include NaBH ₄ , NaCNBH _3, and the like. The reaction can occur over a wide temperature range and the exact reaction temperature is not critical to the present invention. The inventors have observed that it is easy to carry out the reaction of heating at reflux from room temperature. The time required for the reaction can also vary widely depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the preferred thiazole derivative IA (R ² = alkyl or cycloalkyl). Reaction conditions described in the literature affecting reductive amination are described, for example, in Reductive amination in; A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999]. The resulting compound of formula (IA) (R ² = alkyl or cycloalkyl) is a compound of the invention and may be a preferred product; Alternatively, simultaneous reactions such as removal of protecting groups can be carried out by methods described broadly in the literature to afford thiazole derivatives IA.

Compounds of formula (IA) (R ⁴ = alkyl or cycloalkyl) can be prepared according to the following Scheme 2:

(a) Thioisocyanate IIA is commercially available or can be prepared from suitable starting materials according to methods known in the art. The synthesis of thioisocyanate residues, such as in IIA, at thiouureido residues, such as in IIC, can be influenced by the methods described in the literature. For example, a compound of formula (IA) may be prepared by amidine or a salt thereof (R ⁴ = alkyl, cycloalkyl), a known compound or a compound prepared by a known method in a solvent such as THF and a base such as NaOH. Condensation. There are no particular restrictions on the nature of the solvents used, provided they are capable of dissolving at least to some extent without adversely affecting the reaction or related reagents. Examples of suitable solvents include dichloromethane, chloroform, dioxane, THF and the like. There is no particular restriction on the nature of the base used in this step, and any base commonly used in this type of reaction may be used identically herein. Examples of such bases include aqueous NaOH, aqueous KOH, NEt ₃ and the like. The reaction can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It was observed that the reaction was easily carried out by heating from 0 ° C. to the reflux temperature of the solvent. In addition, the time required for the reaction can vary widely depending on many factors, especially the reaction temperature and the nature of the reagent. However, a period of 0.5 hours to several days is usually sufficient to obtain the thioureido derivative IIC. For reaction conditions described in the literature affecting this reaction, see for example CR Seances Acad. Sci., Ser. 2, 294 (19), 1183-6; 1982). The dimethylaminemethylene-thioureido derivative IC is used to prepare IA in a solvent such as ethanol or the like, in the presence or absence of a base, an α-bromoketone ID (a known compound or a compound prepared by a known method, α used). -Bromoketone source, indicated as appropriate), to be converted to thiazole derivative IA (R ⁴ = H). There is no particular limitation on the nature of the solvent used, provided it is capable of dissolving at least to some extent without adversely affecting the reaction or related reagents. Examples of suitable solvents include dichloromethane, chloroform, DMF, dioxane, methanol, ethanol and the like. There is no particular limitation on the nature of the base used in this step and any base commonly used for this type of reaction may equally be used herein. Examples of such bases include triethylamine, diisopropylethylamine, and the like. The reaction can occur over a wide temperature range and the exact reaction temperature is not critical to the present invention. The inventors observed that the reaction was easily carried out by heating to reflux from normal temperature. In addition, the time required for the reaction can also vary widely depending on many factors, in particular the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain thiazole derivative IID. Reaction conditions described in the literature affecting such reactions are described, for example, in Org. Chem., 65 (21), 7244-7247; 2000]. The resulting compound of formula IID (R ⁴ = alkyl or cycloalkyl, R ² = H) is a compound of the invention and may be a preferred product; Alternatively, simultaneous reactions, such as the removal of protecting groups, can be carried out by methods broadly described in the literature to obtain the preferred thiazole derivative IA (R ⁴ = alkyl or cycloalkyl, R ² = H). However, the resulting compound of formula IID is a compound of the present invention and may be a required product; Alternatively, simultaneous reactions can be performed. The introduction of R ² alkyl or cycloalkyl can be effected by reductive amination of aldehydes and IIDs respectively under reducing conditions in a solvent. There is no particular limitation on the nature of the solvent used, provided it is capable of dissolving at least to some extent without adversely affecting the reaction or related reagents. Examples of suitable solvents include dichloromethane, chloroform, dioxane, THF and the like. There is no particular limitation on the nature of the reducing agent used in this step and any reducing agent conventionally used for this type of reaction may equally be used herein. Examples of such reducing agents include NaBH ₄ , NaCNBH _3, and the like. The reaction can occur over a wide temperature range and the exact reaction temperature is not critical to the present invention. The inventors have observed that it is easy to carry out the reaction of heating at reflux from room temperature. The time required for the reaction can also vary widely depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the preferred thiazole derivative IA (R ⁴ = alkyl or cycloalkyl, R ² = alkyl or cycloalkyl). Reaction conditions described in the literature affecting reductive amination are described, for example, in Reductive amination in; A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999]. The resulting compound of formula (IA) (R ⁴ = alkyl or cycloalkyl, R ² = alkyl or cycloalkyl) is a compound of the invention and may be a preferred product; Alternatively, simultaneous reactions, such as the removal of protecting groups, can be carried out by methods broadly described in the literature to obtain thiazole derivatives IA (R ⁴ = alkyl or cycloalkyl, R ² = alkyl or cycloalkyl).

Conversion of the compounds of formula (I) to pharmaceutically acceptable salts can include inorganic acids (e.g. hydrochloric acid, such as hydrochloric acid or bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (e.g. acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, Methanesulfonic acid or p-toluenesulfonic acid) and the treatment of these compounds. Corresponding carboxylate salts can also be prepared from compounds of formula I by treating physiologically suitable bases.

Conversion of the compound of formula (I) to pharmaceutically acceptable esters or amides is carried out by carboxylic acids such as acetic acid, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) or N, N- Carboxylic esters or carboxyl amides can be prepared by treatment of condensation reagents such as dicyclohexylcarbodiimide (DCCI) with appropriate amino or hydroxyl groups present in the molecule.

Preferred methods for the preparation of compounds of formula (I)

(a) reacting a compound of formula (IIC) in the presence of a compound of formula (ID) to obtain a compound of formula (I) (Scheme 3); And

(b) reacting the compound of formula (IID) in the presence of R ² -CHO to obtain a compound of formula (I) (Scheme 4):

[Wherein,

R ¹ to R ⁴ are as defined above]

[Wherein,

R ¹ , R ³ and R ⁴ are as defined above and R ² means alkyl or cycloalkyl]

Under reducing conditions, the reaction is particularly preferred in the presence of reducing agents such as NaBH ₄ or NaCNBH ₃ .

Preferred intermediates are as follows:

1-dimethylaminomethylene-3- (3-methanesulfonyl-phenyl) -thiourea;

1- (2-cyano-pyridin-4-yl) -3-dimethylaminomethylene-thiourea;

1-dimethylaminomethylene-3- (3-cyano-phenyl) -thiourea;

1-dimethylaminomethylene-3-pyridin-3-yl-thiourea;

1-dimethylaminomethylene-3-pyridin-4-yl-thiourea;

1-dimethylaminomethylene-3- (3-bromo-phenyl) -thiourea;

1-dimethylaminomethylene-3- (3-acetyl-phenyl) -thiourea;

1-dimethylaminomethylene-3- (3-acetyl-phenyl) -thiourea; And

3-thioureido-benzenesulfonamide.

The compounds of formula (I) described above for use as therapeutically active substances are a further object of the present invention.

It is also an object of the present invention for the preparation of a medicament for the prevention and treatment of diseases caused by disorders associated with NPY receptors, in particular for the preparation of medicaments for arthritis, cardiovascular disease, diabetes, renal failure and especially eating disorders and obesity Compound.

Another object of the present invention is a pharmaceutical composition containing a compound of formula (I) as described above and a therapeutically inert carrier.

The object of the present invention is also the use of the compounds described above for the manufacture of a medicament, in particular for arthritis, cardiovascular disease, diabetes, renal failure and in particular eating disorders and obesity.

A further object of the present invention includes compounds prepared according to one of the described methods.

A further object of the present invention is a method of treating and preventing arthritis, cardiovascular disease, diabetes, renal failure and especially eating disorders and obesity and administering an effective amount of the compounds described above.

According to a further aspect of the invention, humans in need of treatment of obesity comprising administering to a human a therapeutically effective amount of a compound according to formula (I) and a therapeutically effective amount of a lipase inhibitor (particularly preferably the lipase inhibitor is orlistat) Provides a way to treat obesity. In addition, the subject of the present invention is the above method and is administered simultaneously, separately or sequentially.

A further preferred embodiment of the invention is the use of a compound of formula (I) in the manufacture of a medicament for the treatment and prevention of obesity in a patient treated with a lipase inhibitor (particularly preferably the lipase inhibitor is an anti-obesity agent).

It is also an object of the present invention the compounds described above for the preparation of medicaments for the prevention and treatment of alcoholism.

A further object of the invention is a method for the treatment and prevention of alcoholism.

Analytical Process

Cloning of Mouse NPY5 Receptor cDNA:

Whole cDNAs designed based on open sequences encoding mouse NPY5 (mNPY5) receptors were amplified from mouse brain cDNA and Pfu DNA-polymerase using specific primers. Amplification products were subcloned into mammalian expression vector pcDNA3 using EcoRI and XhoI restriction enzyme sites. Positive clones were sequenced and one clone encoding the open sequence was selected from the generation of stable cell clones.

Stable Transfection:

Human fetal kidney 293 (HEK 293) cells were transfected with 10 μg of NPY5 DNA using lipofectamine reagent. Two days after transfection, geneticin selection (1 ma / ml) was initiated and some stable clones were isolated. One clone was used additionally for pharmaceutical properties.

Radioligand Competitive Combination:

Human fetal kidney 293 cells (HEK293) expressing recombinant mouse NPY5-receptor (mNPY5) were disrupted by three freeze / thaw cycles in hypotonic Tris buffer (5 mM, pH 7.4, 1 mM MgCl ₂ ), homogenized and 72,000xg Centrifuged for 15 minutes at. The pellet was washed twice with 75 mM Tris buffer containing 25 mM MgCl ₂ and 250 mM sucrose, 0.1 mM phenylmethylsulfonfluoride and 0.1 mM 1,10-phenanthroline, resuspended in the same buffer and aliquots at -80 ° C. Stored at. Proteins were quantified according to Lowry's method using bovine serum albumin (BSA) as standard.

Radioligand competition binding assays were performed on hepse buffer (pH 7.4, 2.5 mM CaCl ₂ , 1 mM MgCl ₂ , 1% bovine serum albumin and 0.01% NaN ₃ , 100 pM [ ¹²⁵ I] labeled peptide YY (PYY) containing 5 μg protein). And 100 μL DMSO containing an increased amount of unlabeled test compound After incubation for 1 hour at 22 ° C., the binding and free ligand were separated by filtration through a glass fiber filter. Specific binding is defined as different between total binding and non-specific binding, IC ₅₀ value as the concentration of the antagonist altering 50% of the binding of labeled [ ¹²⁵ I] neuropeptide Y. Defined by linear regression analysis after logger / log conversion of binding data.

The results obtained in this test using representative compounds of the invention as test compounds are shown in the following table:

The compounds described above have IC ₅₀ values of less than 1000 nM; Preferred compounds have IC ₅₀ values below 100 nM, in particular below 10 nM. Most preferred compounds have IC ₅₀ values of less than 2 nM. These results were obtained by the above test.

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments (eg in the form of pharmaceutical preparations). Pharmaceutical preparations may be administered internally, such as orally (eg in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasal (eg nasal sprays). Formally) or rectally (eg in the form of suppositories). However, administration can also be effective at the source, for example intramuscularly or intravenously (eg in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be treated with inert, inorganic or organic adjuvants for the preparation of pharmaceutically purified, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as an adjuvant for tablets, dragees and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid materials and liquid polyols and the like.

Suitable auxiliaries for the preparation of solutions and syrups are, for example, water, polyols, saccharose, inert sugars, glucose and the like.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable adjuvants for suppositories are, for example, natural or cured oils, waxes, fats, semisolid or liquid polyols and the like.

Pharmaceutical formulations may also include preservatives, solubilizers, thickeners, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for various osmotic pressures, buffers, masking agents or antioxidants. They also contain other therapeutically important substances.

According to the invention, the compounds of formula (I) and their pharmaceutically acceptable salts can be used for the prevention and treatment of arthritis, cardiovascular disease, diabetes, renal failure and especially eating disorders and obesity. Dosages may vary in wide limits and are suitable for the individual needs in each particular case. In the case of oral administration in general, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (eg about 300 mg per person), preferably 1 to 3 individually It is appropriate that the amount is divided by the amount (for example it can be configured in the same amount). However, it is apparent that the upper limit may be exceeded when this is indicated.

The invention is illustrated by the following examples, but not by way of limitation.

Example A

1-dimethylaminomethylene-3- (3-methanesulfonyl-phenyl) -thiourea

To a solution of 7.47 g (36 mmol) of 3-methylsulfonyl aniline hydrogen chloride and 6.15 mL of diisopropylethylamine in 75 mL of THF was added dropwise 5.87 g (36 mmol) of benzoyl isothiocyanate and stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was treated with diethyl ether. The precipitate was filtered off, dried and dissolved in 100 mL of THF and 130 mL (130 mmol) of methanol. 18 g (130 mmol) of potassium carbonate in 45 mL of water were added and the mixture was stirred at rt for 24 h. The reaction mixture was concentrated and diluted with water. The precipitate was filtered off, washed with diethyl ether / ethanol and dried. The crude solid was dissolved in 50 ml of dimethylformamide dimethyl aceal and heated at 90 ° C. for 3 hours. The precipitate was filtered off, washed with THF and dried to give 9.3 g (90%) of the title compound as a white solid.

1-H-NMR (250 MHz-DMSO-d 6): δ = 10.75 (s, br, 1H, NH), 8.78 (s, 1H, H-2), 8.57 (s, br, 1H, H-4), 7.72 (s, br, 1H, H-6), 7.53 (m, 2H, H-5 / N-CH), 3.23 (s, 3H, CH ₃ ), 3.17 (s, 3H, OCH ₃ ), 3.09 ( s, 3H, OCH ₃ ).

MS (m / e): 286.2 (M + H, 100%)

Example B

(2-Fluoro-phenyl)-[2- (3-methanesulfonyl-phenylamino) -thiazol-5-yl] -methanone

To a solution of 37 mg (0.13 mmol) of 1-dimethylaminomethylene-3- (3-methanesulfonyl-phenyl) thiourea in 0.33 ml of DMF was added 28 mg (0.13 mmol) of 2-fluorophenacyl bromide and the mixture was Stir at room temperature for 16 hours. 17 mg (0.13 mmol) of diisopropylethylamine were added and preparative HPLC separation was carried out in reverse phase, eluting the mixture with an acetonitrile / water gradient to evaporate the product fractions to give 38.5 mg (79%) of the title compound.

1-H-NMR (500 MHz-DMSO): δ = 8.31 (s, br, 1 H, H-2), 7.88 (s, br, 1 H, H-4), 7.78 (s, br, 1 H, H-6 ), 7.63 (m, 4H, H-5 / H-3 '/ H-6', thiazole-H), 7.37 (m, 2H, H-4 '/ H-5'), 3.37 (s, 3H) , CH ₃ ).

MS (m / e): 377.4 (M + H, 100%)

Example C

1- (2-Cyano-pyridin-4-yl) -3-dimethylaminomethylene-thiourea

The title compound (MS (m / e): 234.2 (M + H, 100%)) was synthesized according to the procedure in Example 1 from 2-cyano-pyridin-4-yl-amine.

Example D

1-dimethylaminomethylene-3- (3-cyano-phenyl) -thiourea

A mixture of 3 g (16.9 mmol) of 1- (3-cyanophenyl) -2-thiourea and 20 ml of N, N-dimethylformamide dimethyl acetal was heated to 100 ° C. for 1 hour. After evaporating the volatiles, the precipitate was suspended in DCM, filtered and dried to give 3.56 g (91%) of the title compound.                 

1-H-NMR (400 MHz-DMSO-d 6): δ = 10.6 (s, br, 1H, NH), 8.76 (s, 1H, CH), 8.10 (d, br, 2H, Ar-H), 7.48 ( s, br, 2H, Ar-H), 3.23 (s, 3H, CH ₃ ), 3.08 (s, 3H, CH ₃ ).

MS (m / e): 233.1 (M + H, 100%)

Example E

1-dimethylaminomethylene-3-pyridin-3-yl-thiourea

The title compound (MS (m / e): 209.2 (M + H, 100%)) was synthesized according to the procedure in Example 4 from pyridin-3-yl-thiourea and dimethylformamide dimethyl acetal.

Example F

1-dimethylaminomethylene-3-pyridin-4-yl-thiourea

The title compound (MS (m / e): 209.2 (M + H, 100%)) was synthesized according to the procedure in Example 4 from pyridin-4-yl-thiourea and dimethylformamide dimethyl acetal.

Example G

1-dimethylaminomethylene-3- (3-bromo-phenyl) -thiourea

The title compound (MS (m / e): 286.2 (M + H, 100%)) was synthesized according to the procedure in Example 4 from 3-bromophenyl-thiourea and dimethylformamide dimethyl acetal.

Example H

1-dimethylaminomethylene-3- (3-acetyl-phenyl) -thiourea

The title compound (MS (m / e): 250.3 (M + H, 100%)) was synthesized according to the procedure in Example 4 from 3-acetylphenyl-thiourea and dimethylformamide dimethyl acetal.

Example I

1-dimethylaminomethylene-3- (3-acetyl-phenyl) -thiourea

The title compound (MS (m / e): 222.3 (M + H, 100%)) was synthesized according to the procedure in Example 4 from 3-methylphenyl-thiourea and dimethylformamide dimethyl acetal.

Example J

2-bromo-1- (3-ethyl-pyrazin-2-yl) -ethanein dihydrobromide

To a solution of 6 g (40 mmol) of 1- (3-ethyl-pyrazin-2-yl) -ethanone in 21 ml of HBr (33%) and 7 ml of methanol, 2 ml (40 mmol) of bromine were added and the mixture was stirred for 60 hours. Heated at ° C. After removing volatiles under reduced pressure, the residue was washed with diethyl ether and ethyl acetate. 6.4 g (41%) of the title compound ethyl acetate were obtained as a gray solid.

MS (m / e): 229.1 (M + H, 100%).

Example K

2-bromo-1- (3-methyl-pyrazin-2-yl) -ethanone dihydrobromide

The title compound was synthesized from 1- (3-methyl-pyrazin-2-yl) -ethanone and HBr / bromine in 55% yield as a gray solid according to Example 4. MS (m / e): 215.0 (M + H, 100%).

Example L

2-bromo-1- (4-methyl-pyridin-3-yl) -ethanein hydrobromide

The title compound was synthesized from 1- (4-methyl-pyridin-3-yl) -ethanone and HBr / bromine in 85% yield as a gray solid according to Example 4.

Example M

2-bromo-1- (2-ethyl-phenyl) -ethanone

To 15.2 g (88 mmol) of dibromethane in 120 mL of THF was added 44 mL (88 mmol) of LDA 2M solution in THF at 75 ° C., followed by 6.57 g (40 mmol) of ethyl benzoate methyl ester in 80 mL of THF. . 37.5 ml of a 1.6 M n-butyllithium solution in n-hexane was added and after 30 minutes the mixture was carefully treated with 35 ml of HCl (37%) below -65 ° C. The mixture was washed with water and aqueous NaHCO ₃ and the organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified twice by flash chromatography on silica eluting with ethyl acetate / hexanes 1: 9 to give 3.8 g (41%) of the title compound as a yellow oil. MS (m / e): 227.1 (M + H, 100%)

Example N

3-thioureido-benzenesulfonamide

A solution of 10 g (48 mmol) of 3-amino-benzenesulfonamide hydrogen chloride and 8.2 mL (48 mmol) of N, N-diisopropylethylamine in 100 mL of THF was treated with 6.45 mL (48 mmol) of benzoyl isothiocyanate at room temperature. Stirred. After evaporation to dryness the residue was suspended in diethyl ether. The precipitate was filtered off, dried and suspended in 130 ml of methanol and 100 ml of THF. K ₂ CO ₃ (130 mmol) in 45 mL of water was added and the mixture was stirred at rt for 60 h. The mixture was evaporated to dryness and the residue was treated with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was suspended in diethyl ether, filtered and dried to give 8.4 g (76%) of the title compound as a white solid.

1-H-NMR (300 MHz-DMSO-d 6): δ = 10.0 (s, br, 2H, NH ₂ ), 7.94 (d, J = 1.7 Hz, 1H, H-2), 7.71 (dd, J = 7.7 Hz, J = 1.7 Hz, 1H, H-4), 7.56 (m, 2H, H-5 / H-6), 7.36 (s, br, 2H, NH ₂ ).

MS (m / e): 233.1 (M + H, 100%)

Example O

N-dimethylaminomethylene-3- (3-dimethylaminomethylene-thioureido) -benzenesulfonamide

A mixture of 2.3 g (9.9 mmol) of 3-thioureido-benzenesulfonamide and 17 ml of N, N-dimethylformamide dimethyl acetal was heated to 90 ° C. for 2 hours. The precipitate was filtered off, washed with DCM / diethyl ether 1: 3 and dried to give 2.8 g (82%) of the title compound.

1-H-NMR (300 MHz-DMSO-d6): δ = 10.7 (s, br, 2H, NH ₂ ), 8.77 (s, 1H, CH), 8.37 (s, br, 1H, CH), 8.17 ( s, br, 1H, H-2), 7.58 (m, 1H, H-4), 7.40 (m, 2H, H-5 / H-6).

MS (m / e): 340.2 (M + H, 100%).                 

Example P

3- (5-benzoyl-thiazol-2-ylamino) -benzenesulfonamide

A mixture of 44 mg (0.13 mmol) of N-dimethylaminomethylene-3- (3-dimethylaminomethylene-thioureido) -benzenesulfonamide and 26 mg (0.13 mmol) of phenacyl bromide in 0.8 ml of DMF was added for 16 hours. Stir at room temperature. 0.12 mL HCl (37%) was added and the mixture was stirred at 100 ° C. for 69 h. After addition of 0.12 mL of N, N-diisopropylethylamine the preparative HPLC separation was carried out in reverse phase, eluting with acetonitrile / water gradient. The product fractions were evaporated to give 6 mg (13%) of the title compound.

1-H-NMR (500 MHz-DMSO): δ = 11.25 (s, br, 1H, NH), 8.25 (s, 1H, H-2), 7.90 (s, 1H, thiazole H), 7.85 (m, 3H, Ph), 7.60 (m, 5H, Ph), 7.40 (s, br, 2H, NH ₂ ).

MS (m / e): 358 (M-H, 100%)

Example Q (Example 111 in the table)

3- [4-Methyl-5- (2-trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile

To a mixture of 801 mg (5 mmol) of 3-cyanophenylthioisocyanate in 5 ml of 1N NaOH at 0 ° C was added 473 mg of acetamidine hydrogen chloride in 10 ml of THF, followed by stirring at 0 ° C for 16 hours. The mixture was extracted with ethyl acetate and the combined organic layers were dried over MgSO ₄ and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with ethyl acetate / cyclohexane 1: 2 to give 1- (1-amino-ethylidene) -3- (3-cyano-phenyl) -cyde. Ourea 510 mg (47%) were obtained. (MS (m / e): 219.2 (M + H, 100%). 50 mg (0.23) of 1- (1-amino-ethylidene) -3- (3-cyano-phenyl) -thiourea in 1 ml of ethanol mmol), 92 mg (0.345 mmol) of 2-bromo-1- (2-trifluoromethyl-phenyl) -ethanone and 48 μl of triethylamine were stirred for 16 h at rt The mixture was diluted with methanol Preparative HPLC separation was carried out in reverse phase, eluting with an acetonitrile / water gradient directly The product fractions were evaporated to give 10.4 mg (12%) of the title compound ((MS (m / e): 386.2 (MH)). , 100%)).

Also according to Example B an aminothiazole derivative was synthesized from 1-dimethylaminomethylene-thiourea and α-bromoketone. The results are included in the following list corresponding to Examples 1-97 and 112.

According to Example P, further aminothiazole derivatives were synthesized from 1-dimethylaminomethylene-thiourea and α-bromoketone. The results are included in the following list corresponding to Examples 98-110.

Example I

The compounds of formula (I) can be used in known manner as active ingredients for the preparation of tablets of the following composition.

Example II

The compounds of formula I can be used in a known manner as active ingredients for the preparation of capsules of the following composition.

Claims (28)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula I

Where R ¹ is phenyl or pyridyl, wherein at least one of the two meta positions of each of the phenyl and pyridyl groups is substituted with R ⁵ ; R ² is hydrogen; R ³ is C _3-8 cycloalkyl, phenyl, naphthyl, pyridyl, pyrazinyl or thiophenyl, wherein two ortho positions of each of cycloalkyl, phenyl, naphthyl, pyridyl, pyrazinyl and thiophenyl At least one of is substituted with R ⁶ ; R ⁴ is hydrogen, C _1-6 alkyl or C _3-8 cycloalkyl; R ⁵ is hydrogen, cyano, trifluoromethyl, C _1-6 alkyl, C _1-6 alkyl-SO _2- , amino-SO _2- , halogen, C _1-6 alkoxy, C _1-6 alkylcarbonyl Or aminocarbonyl; R ⁶ is hydrogen, halogen, cyano, nitro, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, hydroxy or C _1-6 alkoxycarbonyl; Provided that one of R ⁵ and R ⁶ is not hydrogen. The method of claim 1, R ⁴ is hydrogen or methyl. delete The method of claim 1, R ³ is cyclohexyl, phenyl, naphthyl, pyridyl, pyrazinyl or thiophenyl, wherein at least one of the two ortho positions of each of the cyclohexyl, phenyl, naphthyl, pyridyl, pyrazinyl and thiophenyl groups is A compound substituted with R ⁶ . The method of claim 1, R ³ is phenyl or pyridyl, wherein at least one of the two ortho positions of each of the phenyl and pyridyl groups is substituted with R ⁶ . delete delete The method of claim 1, R ⁵ is cyano, trifluoromethyl, C _1-6 alkyl-SO ₂ —, amino-SO ₂ —, halogen, C _1-6 alkoxy, C _1-6 alkylcarbonyl or aminocarbonyl. The method of claim 8, R ⁵ is cyano, trifluoromethyl, C _1-6 alkyl-SO ₂ —, amino-SO ₂ — or C _1-6 alkylcarbonyl. The method of claim 9, R ⁵ is cyano, trifluoromethyl, methyl-SO _2- , -NH ₂ -SO ₂ -or methylcarbonyl. The method of claim 1, R ⁶ is halogen, cyano, nitro, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, hydroxy or C _1-6 alkoxycarbonyl. The method of claim 11, R ⁶ is halogen, trifluoromethyl or C _1-6 alkyl. The method of claim 1, 3- [5- (2-Fluoro-benzoyl) -thiazol-2-ylamino] -benzonitrile; 3- [5- (2-Chloro-benzoyl) -thiazol-2-ylamino] -benzonitrile; (2-Chloro-phenyl)-[2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone; 3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzonitrile; o-tolyl- [2- (3-trifluoromethyl-phenylamino) -thiazol-5-yl] -methanone; 1- {3- [5- (2-Methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -ethanone; 3- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile; 3- [5- (2-Trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzonitrile; 3- [5- (3-Methyl-pyridine-2-carbonyl) -thiazol-2-ylamino] -benzonitrile; [2- (3-Methanesulfonyl-phenylamino) -thiazol-5-yl] -o-tolyl-methanone; (2-ethyl-phenyl)-[2- (3-methanesulfonyl-phenylamino) -thiazol-5-yl] -methanone; 4- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile; 4- [5- (2-Methyl-benzoyl) -thiazol-2-ylamino] -pyridine-2-carbonitrile; 3- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide; And 3- [5- (2-Trifluoromethyl-benzoyl) -thiazol-2-ylamino] -benzenesulfonamide Compound selected from the group consisting of. Claims 1, 2, 4, 5 and 8 comprising reacting a compound of formula (IIC) in the presence of a compound of formula (ID) to obtain a compound of formula (I) A method for preparing a compound according to any one of claims 12 to 13. Scheme 3

[Wherein, R ¹ to R ⁴ are as defined in claim 1] delete delete delete Treatment of arthritis, diabetes, eating disorders and obesity comprising the compound according to any one of claims 1, 2, 4, 5 and 8 to 12 and a therapeutically inert carrier. And prophylactic pharmaceutical compositions. delete delete A human in need of treatment of obesity comprising a therapeutically effective amount of a compound according to any one of claims 1, 2, 4, 5 and 8-12 and a therapeutically effective amount of a lipase inhibitor. Pharmaceutical composition for treating obesity in the. The method of claim 21, Pharmaceutical composition wherein the lipase inhibitor is orlistat. The method of claim 21, A pharmaceutical composition administered concurrently, separately or sequentially. delete delete The method of claim 18, A pharmaceutical composition further comprising a therapeutically effective amount of a lipase inhibitor. The method of claim 26, Pharmaceutical composition wherein the lipase inhibitor is orlistat. delete