SK100099A3 - Thiazole benzenesulfonamides as 'beta'3 agonists for the treatment of diabetes and obesity - Google Patents

Abstract

Thiazole substituted benzenesulfonamides are beta 3 adrenergic receptor agonists with very litte beta 1 and beta 2 adrenergic receptor activity and as such the compounds are capable of increasing lipolysis and energy expenditure in cells. The compounds thus have potent activity in the treatment of Type II diabetes and obesity. The compounds can also be used to lower triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to decrease gut motility. In addition, the compounds can be used to reduce neurogenic inflammation or as antidepressant agents. The compounds are prepared by coupling an aminoalkylphenyl-sulfonamide with an appropriately substituted epoxide. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for decreasing gut motility are also disclosed.

Description

Thiazolobenzenesulfonamides, pharmaceutical composition containing them and their use

Technical field

The present invention relates to thiazole substituted benzenesulfonamides useful as anti-obesity compounds and antidiabetic agents. Another

Particularly preferred are stereoisomers of substituted sulfonamides. It is a further object of the invention to provide methods for making these compounds. A further object is to provide compositions in which said compounds are included as an active ingredient.

BACKGROUND OF THE INVENTION Since 1967, β-adrenoceptors have been classified into βι and β ₂ groups. The main consequence of βι-receptor stimulation is increased heart rate, while β- ₂ receptor stimulation results in bronchodilation and smooth muscle relaxation. Adipocyte lipolysis was thought to be mediated exclusively by the βι receptor. Recent studies, however, show that receptor-mediated lipolysis is not typical in nature. These atypical receptors, later called β ₂ -adrenoceptors, are found on the cell surface of both white and brown adipocytes, where their stimulation promotes both lipolysis (fat loss) * and energy delivery.

In this area, compounds with greater agonist effects were first developed to stimulate lipolysis (β ₃ activity) than to stimulate atrial frequency (βι) and tracheal relaxation (β ₂ ). These first findings, described in Ainsworth et al., US Patents 4,478,849 and 4,396,627, deal with phenylethanolamine derivatives.

This selectivity to β 3 -adrenoceptors allows the potential utility of these compounds as anti-obesity agents. In addition, it has been found that these compounds have antihyperglycemic effects independently of insulin in animal models of diabetes mellitus.

The main disadvantage of treating chronic diseases with β ₃ receptor agonists is the following side effects. These side effects are mainly muscle shaking (β ₂ ) and increased heart rate (β ^. Although these phenylethanolamine derivatives have some selectivity to β ₃ receptors, these side effects have been observed in healthy volunteers. they arise as a result of partial agonism towards βι and / or β ₂ receptors.

Recent research in this field is described in Ainsworth et al., US Patent 5,153,210, Caulkett et al., US Patent 4,999,377, Alig et al., US Patent 5,017,619, Lecount et al., European Patent 427480 and Bloom et al., European Patent 455006.

Although these recent studies describe compounds with greater selectivity to the β _3ι receptor than effects on the βι and β ₂ receptors, this selectivity has been determined in rodents, especially in rats used as test animals. Since the compounds of the highest selectivity determined by the tests are some signs of side effects due to residual agonist activity towards receptors βι and β _2, the test compounds in humans has shown that the prediction of selectivity for the human receptor β ₃ is a rodent good model .

Recently, tests have been developed that predict the expected effects in humans more accurately. These assays utilize cloned human _β3β receptors that have been expressed in Chinese hamster ovary cells (see Emorin et al., Science, 1989, 245: 1118-1121; Liggett, Mol. Pharmacol., 1992, 42: 634-637; and Grannemann et al. et al., Mol Pharmacol., 1992, 4: 964-970. The agonistic and antagonistic effects of various compounds on cultured cells then suggest the anti-obesity and antidiabetic effects of the compounds in humans.

US Patent 5,451,677 describes selective β ₃ receptor agonists of the formula:

(R ') "

-3US patent 5,561,142 published November 2, 1995 discloses selective β ₃ receptor agonists of the formula:

The novel compounds of the present invention are based on the general basis of US Patent 5,561,142.

SUMMARY OF THE INVENTION

where

X is (1) a bond, (2) C 1 -C ₃ alkylene, optionally substituted with 1 or 2 groups selected from methyl and halogen, (3) C 1 -C 3 alkylene, wherein said alkylene contains an oxygen atom optionally substituted with 1 or 2 groups selected from methyl and halogen;

m is 0 to 5;

A is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a benzene ring fused to a C5-C10 carbocyclic ring,

-4 (4) a 5- or 6-membered heterocyclic ring having from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5- or 6-membered heterocyclic ring having from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or ( 5) a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, fused to a C ₅ -C ₁₀ carbocyclic ring;

R ¹ is (1) C 1 -C 10 alkyl optionally substituted with up to 5 groups selected from (a) hydroxy, (b) halogen, (c) cyano, (d) QR ² , (e) C ₃ -C 6 cycloalkyl, (f) ) A is optionally substituted with up to 5 groups selected from halogen, C1-C10 alkyl and C1-C10 alkoxy, (g) Q'COR ³ , (h) S (O) n R ³ , wherein n is 0 to 2, ( (i) NR ² SO ₂ R ³ ;

G) NR ² CO ₂ R ² and (k) CO ₂ R ² , (2) C ₃ -C ₈ cycloalkyl, (3) oxo, (4) halogen, (5) cyano, (6) QR ² , (7) ) S (O) _n R ³ , where n is 0 to 2, (8) Q'COR ³ , (9) NR ² SO ₂ R ³ , (10) NR ² CO ₂ R ² , (11) A group optionally substituted with up to 5 groups selected independently from (a) R ² , (b) QR ² , (c) halogen, and

-5 (d) oxo, or (12) CO ₂ R ² ;

R ² is (1) hydrogen, (2) C 1 -C 10 alkyl optionally substituted with up to five groups selected from (a) hydroxy, (b) halo, (c) CO 2 R ^4, (d) S (O) n _R a C _O alkyl wherein n is 0 to 2, (e) C ₃ -C ₈ cycloalkyl, (f) C 1 -C 10 alkoxy and (g) a group A optionally substituted with up to 5 groups selected from halogen, C 1 -C 10 alkyl and C 1 -C 10 alkoxy , (3) C ₃ -CE cycloalkyl or (4) a optionally substituted with up to five groups selected from (a) halogen, (b) nitro, (c) oxo, (d) NR ⁴ R ^4, (e) C1 -C10 alkoxy, (f) SfIN 11 -C 1 -C 10 alkyl, wherein n is 0 to 2 and (g) C 1 -C 10 alkyl optionally substituted with up to 5 groups selected from hydroxy, halogen, CO ² R ⁴ , S (O) _n -C 1 -C 1 _O- alkyl, wherein n is 0 to 2, C ₃ -C ₃ cycloalkyl, C 1 -C 10 alkoxy and A is optionally substituted with up to 5 groups selected from halogen, C 1 -C 10 alkyl and C 1 -C 10 alkoxy;

R ³ is (1) R ² or (2) NR ² R ² ;

R ⁴ is (1) H or (2) C 1 -C 10 alkyl;

Q is (1) N (R ² ), (2) O or (3) S (O) _n , and n is 0 to 2;

Q'je (1) N (R ^2),

-6 (2) O or (3) a bond or or a pharmaceutically acceptable salt or prodrug thereof.

A preferred subgroup of compounds of formula J include those wherein X is (1) a bond, (2) CH ₂ , (3) CH ₂ O, wherein C is bound to a thiazole and O is bound to A;

Another subgroup of formula I are compounds wherein

R ¹ is (1) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms, (2) halogen, (3) QR ² , (4) Q'COR ³ , (5) phenyl;

R ² is (1) a hydrogen atom, (2) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms;

R ³ is (1) C 1 -C 10 alkyl and Q is (1) O.

There is a sub-group of compounds of formula I in which a thiazolyl group is attached to the benzenesulfonamide moiety through a carbon atom at the 2-position (C2) of the thiazole ring. There is another sub-group of compounds of formula I in which a thiazolyl group is attached to X or wherein X is a bond, directly to the A group via a carbon atom at the 2-position of the thiazole ring. Preferably, either the benzenesulfonamide group or X (or A if X is a bond) is attached to the C2 thiazole ring or to the C4 thiazole ring.

Another subgroup of Formula I are those wherein A is selected from phenyl, naphthyl, a 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from an oxygen, sulfur or nitrogen atom fused to the benzene ring and a 5- or 6-membered heterocyclic ring with 1 up to 4 heteroatoms selected from oxygen, sulfur and nitrogen. Preferably, the group A is selected from phenyl, naphthyl, thienyl, pyridinyl, benzothienyl, quinolinyl, indolyl and benzofuranyl.

In a preferred embodiment of the compounds of formula I X is (1) a bond,

-7 (2) CH _2; (3) CH ₂ O, wherein C is bound to a thiazole and O is bound to A; m is 0 to 5;

A is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a benzene ring fused to a C ₅ -C ₁₀ carbocyclic ring, (4) A 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (5) 5 or 6 a membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, fused to a C 5 -C 10 carbocyclic ring;

R ¹ is (1) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms, (2) halogen, (3) QR ² , (4) Q'COR ³ , (5) phenyl;

R ² is (1) hydrogen, (2) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms,

R ³ is (1) C 1 -C 10 alkyl and

Q is (1) O; or a pharmaceutically acceptable salt thereof.

In a more preferred embodiment, compounds of Formula I are those wherein X is (1) a bond, (2) CH ₂ , (3) CH ₂ O, wherein C is bound to a thiazole and O is bound to A; m is 0 to 5;

A is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) naphthyl, or

-8 (4) a 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to the benzene ring;

R ¹ is (1) C 1 -C ₁₀ alkyl optionally substituted with up to 5 halogen atoms, (2) halogen, (3) QR ² , (4) Q'COR ³ , (5) phenyl;

R ² is (1) hydrogen, (2) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms,

R ³ is (1) C 1 -C 10 alkyl and Q is (1) O; and either the benzenesulfonamide moiety or X (or A when X is a bond) is bonded to the C2 thiazole ring and the other to the C4 position of the thiazole ring; or a pharmaceutically acceptable salt thereof.

Compounds of the present invention that are based on the generic structure described in US Patent 5,561,142 represent a new choice for these compounds. The present compounds have potent B3 receptor agonist activity and have improved oral bioavailability in animals.

The compounds with anti-obesity and anti-diabetic activity of the present invention include the following:

1- N- [4- [2 - [[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4- [4- (2-naphthylmethyl) thiazol-2-yl] benzenesulfonamide,

2. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethyl) phenyl] thiazol-2-yl] benzenesulfonamide .

3. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethoxy) phenyl] thiazol-2-yl] benzenesulfonamide .

4. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,4-difluorophenylmethyl) thiazole-2- yl] benzenesulfonamide,

5. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3-pyridyl) thiazol-2-yl] benzenesulfonamide,

-96. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-fluorophenyl-methyl) thiazol-2-ylJbenzénsulfónamid,

7. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,4-difluorophenyl) thiazole-2- yl] benzenesulfonamide,

8. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethyl) phenylmethyl] thiazol-2 yl] benzenesulfonamide,

9. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-pyridyl) thiazol-2 * yl] benzenesulfonamide;

10. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [1- (2-phenyl) ethyl] N - [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-)] - thiazol-2-yl] benzenesulfonamide fluorophenyl) thiazol-2-ylJbenzénsulfónamid,

12. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-naphthyl) thiazol-2-yl] benzenesulfonamide,

13. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,4 _I, 5-trifluoro-phenyl) -thiazol 2-yl] benzenesulfonamide,

14. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-hexylphenyl) thiazol-2-yl] benzenesulfonamide .

15. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethoxy) phenylmethyl] thiazol-2 16. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) phenyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethoxy) -yl] benzenesulfonamide. ) phenoxymethyl] thiazol-2-yl] benzenesulfonamide,

17. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-benzo [6] thienyl) thiazole] 2-yl] benzenesulfonamide,

18. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3-quinolinyl) thiazol-2-yl] benzenesulfonamide,

19. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (6-quinolinyl) thiazol-2-yl] benzenesulfonamide,

20. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-benzoyl) furyl] thiazole-2- yl] benzenesulfonamide,

-1021. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3-indolyl) thiazol-2yljbenzénsulfónamid,

22. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2,4-difluorophenyl) thiazole-2- yljbenzénsulfónamid.

23. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,5-difluorophenyl) thiazole-2- yl] benzenesulfonamide,

24. N- [4- [2 - [[2-Hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (1,1) -dimethylethyl) phenyl] thiazol-2-yl] benzenesulfonamide,

25. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2,3-difluorophenyl) thiazole-2- yl] benzenesulfonamide,

26. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [3- (trifluoromethyl) phenyl] thiazol-2] yl] benzenesulfonamide,

27. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (difluoromethyl) phenyl] thiazol-2] yl] benzenesulfonamide,

28. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2,4-dichlorophenyl) thiazole-2- ylJbenzénsulfónamid.

29. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [2- (trifluoromethyl) phenyl] thiazol-2] yl] benzenesulfonamide,

30. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [2-fluoro-4- (trifluoromethyl) phenyl] ] thiazol-2-yl] benzenesulfonamide,

31. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4-fluoro-2- (trifluoromethyl) phenyl] ] thiazol-2-yl] benzenesulfonamide,

32. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [2,4-bis (trifluoromethyl) phenyl] thiazol-2-yl] benzenesulfonamide,

33. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [5- (4-fluorophenyl) thiazol-2-yl] benzenesulfonamide .

34. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethylphenyl) thiazol-4-yl] ] benzenesulfonamide,

35. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethylphenyl) thiazol-5-yl] ] benzenesulfonamide,

-11 36. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-phenylphenyl) thiazole-2- yl] benzenesulfonamide,

37. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,4-dihydroxyphenyl) thiazole-2- yl] benzenesulfonamide,

38. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-hydroxyphenyl) thiazol-2-yl] benzenesulfonamide

39. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-acetoxyphenyl) thiazol-2-yl] benzenesulfonamide

40. N- [4- [2 - [[2-Hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-acetamidophenyl) thiazol-2-yl] benzenesulfonamide

41. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethoxyphenyl) thiazol-4-yl] ] benzenesulfonamide.

The compounds of the present invention all have at least one asymmetric center as shown in structural formula I by an asterisk. Other asymmetric centers may be present in the molecule. Each such asymmetric center will provide two optical isomers, all of which optical isomers, whether in separate, pure or partially purified form or in the form of a racemic mixture, are within the scope of the present invention. In the case of the asymmetric center represented by the asterisk in the formula I, it has been found that compounds in which the hydroxyl substituent is above the plane of the structure as seen in formula ic is more active and thus more advantageous than those in which the hydroxyl substituent is located below the plane of the structure.

Preferred stereoisomers of the present invention are represented by the following stereospecific structures:

(R) m

The -12-thiazolyl group is numbered as follows:

In the present application, the following terms have the following meanings:

"Alkylene" means - (Cfhjp-, where p is the specified number of carbon atoms, one or two hydrogen atoms may optionally be replaced by methyl or halogen. If the optionally substituted alkylene contains an oxygen atom, the oxygen atom may be at either end of the alkylene chain or Examples of such groups are OCH 2, CH 2 O, CH 2 OCH 2, C (CH ₃ ) 2 O, and the like.

The alkyl groups mentioned above are intended to include alkyl groups of the indicated length which are either straight or branched. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

The alkoxy groups mentioned above are intended to include straight or branched chain alkoxy groups of the stated length. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term "halogen" is intended to refer to fluorine, chlorine, bromine and iodine halogen atoms.

The term "carbocyclic ring" refers to both aromatic and non-aromatic rings containing only carbon atoms. For example, a benzene ring fused to a C ₅ C 10 carbocyclic ring may be, for example, naphthyl, tetrahydronaphthyl, indanyl and indenyl. A 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to the C 5 -C 10 carbocyclic ring includes benzene fused to the heterocyclic ring as well as a non-aromatic carbocyclic ring fused to the heterocyclic ring. The carbocyclic ring is preferably a C5-C7 ring.

The aromatic and unsaturated non-aromatic heterocycles may be a 5 and 6-membered heterocyclic ring, whether isolated or as part of a fused ring system wherein the heterocyclyl is part of a fused ring, and at least one of the rings is aromatic. Examples of the 5- or 6-membered ring include pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, oxazolyl, imidazolidinyl, pyrazolyl, isoxazolyl. Examples of a benzene ring fused to a 5 or 6-membered heterocyclic ring include benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, 2,3-dihydrobenzofuranyl, quinololinyl, quinololinyl, 2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl. Examples of 5 or 6-membered heterocyclic rings fused to a 5 or 6-membered heterocyclic ring are purinyl, furopyridine and thienopyridine. Examples of a 5- or 6-membered heterocyclic ring fused to a non-aromatic carbocyclic ring are tetrahydrobenzothiazolyl, 5,6,7,8-tetrahydroquinolinyl, 2,3cyclopentenopyridyl, 4,5,6,7-tetrahydroindolyl, 5,6,7,8 -tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl.

The term "pharmaceutical composition" is intended to include an article comprising the active ingredient (s) and the inert ingredient (s) which constitute the carrier as well as any product which is the direct or indirect result of the combination, complexing or aggregation of any two or more ingredients or one or more components or other types of reaction or interaction of one or more of these components. Thus, the pharmaceutical compositions of the present invention include any pharmaceutical composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

Where reference is made in the present application to "compounds of formula I", these compounds are intended to include pharmaceutically acceptable salts and prodrugs, unless otherwise indicated. Prodrugs are derivatives of compounds of formula I that convert in vivo to the active drug molecule; precursors include derivatives of free hydroxyl, amine or carboxyl groups such as esters, ethers, amides, carbonates, carbamates, and N-alkyl derivatives. Specific examples of prodrugs of the compounds of formula I are: (a) secondary amine derivatives such as N-alkyl (methyl, ethyl, isopropyl and 2-methoxyethyl) and N-acylated (1-pyrrolidinylacetyl, 4-morpholinylacetyl,

-14 (1-acetoxy) -ethoxycarbonyl and dimethylaminoacetyl) derivatives; (b) secondary hydroxyl group derivatives such as O-alkylated (ethyl) and O-acylated (acetyl, t-butoxycarbonyl, benzoyl, cyclopropylcarbonyl) derivatives; and (c) vicinally located secondary amines and secondary hydroxyls forming a group of formula

wherein U and V are independently a bond, carbonyl, methylene, CH (OH) or C (OH) (CH ₃ ). Precursors of the above types can be readily prepared from compounds of Formula I using methods known to those skilled in the art.

Some of the above groups may occur more than once in the above formula, in which case each such occurrence of each group will be defined independently of other occurrences; For example, the DB ^from R ² denotes NH 2, NHCH 3, N (CH3) CH2CH3, and the like.

The compounds of formula I of the present invention can be prepared as described in the following schemes. Thiazoles 1a, Ib and Ic are prepared by Hantzsch's thiazole synthesis (Sainsbury, M. in "Rodds ¹ Chemistry of Carbon Compounds", Coffey, S., Ausell, MF, ed .; Elsevier: Amsterdam, 1986; Vol. IV C, 399-39) 455) in a suitable thioamide and a 2-halocarbonyl derivative. As shown in Schemes 1 for thiazoles 1a, 4-bromothiobenzamide (EP Papadopopoulos, J. Org. Chem. 1976, 41, 962) is condensed with a suitable chloroketone 2, typically by heating in ethanol for 6 and 24 hours, to give Bromophenylthiazole 3. Treatment of n-butyllithium, conveniently in tetrahydrofuran at -78 ° C and then with sulfur dioxide with warming to room temperature, yields the resulting lithium sulfinate. This can be easily converted to the corresponding sulfonyl chloride 4 by treatment with a chlorinating agent such as N-chlorosuccinimide. The protected aniline derivative 5 (Fisher, et al, U.S. 5,561,142 of 1 October 1996) by treatment with sulfonyl chloride, and 4 of a base such as pyridine in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at a temperature of from -20 to ⁵⁰ and C

-15 preferably 0 ° C followed by deprotection, in the case of tert-butylcarbamate with an acid such as trifluoroacetic acid or methanolic hydrogen chloride solution, is converted to thiazole 1a.

Scheme 1

N H

(R ¹ )

1) nBuLi

2) S0 ₂

3) NCS

(R ¹ )

Chloroketones 2 are commercially available, known from the literature, or are readily prepared by known methods. The corresponding acid chloride 6 is suitably treated with diazomethane and then with hydrogen chloride to give the chloroketone 2 as shown in Scheme 2.

Scheme 2

Vx - (a \ 1 _c re

1) ch ₂ n ₂

2) HCl

An alternative approach to the synthesis of thiazoles 1a is illustrated in Scheme 3. Nitrile 7 (Fisher et al, US 5,561,142, October 1, 1996) is converted to the corresponding thiamide by treatment with hydrogen sulfide in the presence of a base such as triethylamine. The thiazole is formed from chloroketone 2 as described above. Removal of the t-butoxycarbonyl protecting group (Boe) with an acid such as trifluoroacetic acid in dichloromethane or a solution of hydrogen chloride in methanol affords the desired thiazole (Ia).

-17 Scheme 3 - continued

x- (a \ (R ’) m

The thiazoles Ib are prepared as shown in Scheme 4. The thioamide 8 is mixed with the appropriate 2-bromoaldehyde 9 at elevated temperatures suitably in an inert solvent such as acetonitrile or acetonitrile / chloroform at reflux to give, after deprotection, as described above, thiazole ib.

Scheme 4

NH;

Br.

O =>

d. ',.

2) TFA / CH ₂ Cl ₂

-18 Scheme 4 - continued

Bromaldehydes 9 are known from the literature or are readily prepared by methods known in the art. The corresponding alcohol 10 is preferably oxidized to the aldehyde 11, for example by treatment with o-iodoxybenzoic acid in DMSO (Frigerio and Santagostino, Tetrahedron Lett., 1994, 35, 8019). Bromination can be accomplished by treatment with a brominating agent, preferably a t-butyldimethylsilyl bromide / DMSO mixture (Bellesia et al., J. Chem. Research (S), 1986, 428), to provide the desired bromaldehydes 9.

Scheme 5

[ABOUT]

TBS-Br, DMSO acetonitrile · 0 ° C

V-X '(aY,

The thiazoles Ic are synthesized as shown in Scheme 6. The corresponding nitrile 12, which is commercially available, known from the literature, or can be readily synthesized in the art, is mixed with hydrogen sulfide in the presence of a base such as triethylamine and the thioamide obtained mixed with 4-dibromoacetophenone 13 at elevated temperature, preferably boiling ethanol under reflux, to give the thiazole 14. This compound is then protected at the 5-position, for example in the form of

Of the -195-trimethylsilyl derivative by treatment with n-butyllithium and then trimethylsilyl chloride. Conversion of the obtained bromo derivative 15 to the corresponding sulfonyl chloride followed by sulfonamide formation by aniline 5 and removal of the Boe protecting group by TFA proceeds as described above for Scheme 1. The silyl group is then removed, preferably by treatment with hydrogen fluoride in acetonitrile to give the desired thiazole Ic.

Scheme 6

2) TFA-CH ₂ Cl ₂

3) HF-acetonitrile

OH H

The thiazoles 1d can be made as shown in Scheme 7. Aminoacetophenone 18 is prepared from bromo derivative 13 by modified Delepion reaction (Goddard, CJJ Heterocyclic Chem., 1991, 28, 17) by reacting compound 13 with hexamethylenetetraamine 17 and then treatment with hydrochloric acid in methanol. . The amine 18 is then reacted with a suitable acid chloride to give the ketone 20. The thiazole is formed by treatment with Lawesson's reagent at elevated temperature, preferably in refluxing toluene. The resulting bromo derivative 21 is converted to the desired thiazole Id as described in Scheme 1 for thiazole a.

Acid chlorides 19 are commercially available, known from the literature, or can be readily made by methods known in the art.

Scheme 7

O n Ύ 1 ¹ ) NL · -N _ Λ-N ^ y 17

2) HCl-MeOH

2) TFA-CH ₂ Cl ₂

-21 Scheme 7 - continued

^ -X- (a \

N (R ¹ ) m

In some cases, the product I obtained by the reactions of Schemes 1 through 7 can be further modified by removing the protecting groups or changing the substituents to R ¹ . Such treatments may include, without limitation, reduction, oxidation, alkylation, acylation, and hydrolytic reactions known to those skilled in the art.

The compounds of formula I contain one or more asymmetric centers and can therefore exist in the form of racemates and racemic mixtures, individual enantiomers, diastereomers of mixtures and individual diastereomers. The present invention is intended to include all of these isomeric forms of the compounds of Formula I.

Some of the compounds described above contain olefinic double bonds and, unless otherwise specified, are intended to include geometric isomers E and Z.

Some of the disclosed compounds may exist as tautomers, such as keto-enol tautomers. The compounds of formula I of the present invention include the individual tautomers and mixtures thereof.

The compounds of formula I may be resolved into diastereomeric pairs of enantiomers, for example, by fractional crystallization from a suitable solvent, such as methanol or ethyl acetate, or mixtures thereof. The pair of enantiomers thus obtained can be resolved into the individual stereoisomers by methods such as using an optically active acid as a resolving agent.

Alternatively, any enantiomer or compound of Formula I or Ia may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.

The term "pharmaceutically acceptable salts" refers to salts made from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic

-22bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferrous and ferric, lithium, magnesium, manganese, manganese, potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N'-dibiyl ethylene. diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, polymorphine, piperazine, thepiperidine, the piperidine, the piperidine, the piperidine , triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. These acids include acetic, benzenesulfonic, benzoic, gaphrosulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, almond, methanesulfonic, mucic, nitric, nitric, nitric, nitric, , sulfur, wine, p-toluenesulfonic and the like.

The compounds of the present invention have potent β ₃ adrenoceptor agonist activity and as such are useful in the treatment or prevention of diseases or conditions mediated by β ₃ -adrenoceptor activation. The compounds of the present invention can treat, reduce, or prevent a disease or condition in a mammal by administering to the mammal in a therapeutically effective amount. The term "mammal" includes both human and animal such as dogs and cats and the like. Diseases, disorders or conditions for which the compounds of the present invention are useful as therapeutic or preventive agents include, but are not limited to (1) diabetes mellitus, (2) hyperglycemia, (3) obesity, (4) hyperlipidemia, (5) hypertriglyceridemia, ( 6) hypercholesterolaemia, (7) atherosclerosis of cardiac, cerebrovascular and peripheral arteries, (8) gastrointestinal disorders including peptic ulcer, esophagitis, gastritis and duodenitis (including diseases)

-23 induced H-pyrrole), intestinal ulceration (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis) and gastrointestinal ulceration, (9) neurogenic airway inflammation including cough and asthma, (10) depression, (11) prostate disease such as is benign prostatic hyperplasia; (12) irritable bowel syndrome and other diseases with the need to reduce bowel mobility; and (13) elevated intraocular pressure and glaucoma.

For administration to a mammal, particularly a human, any suitable route of administration of the compound of the present invention may be selected. For example, the oral, rectal, topical, parenteral, ocular, pulmoral, nasal, and the like route may be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. The compounds of formula I are preferably administered orally.

The effective dose of the active ingredient used in the treatment may vary depending upon the particular compound employed, the route of administration, the species of mammal being treated, the condition being treated and the severity of the disease. Dosage can be readily determined by one skilled in the art of human or veterinary medicine.

In the treatment of obesity (in association with sdiabetes and / or hyperglycemia or alone) in humans or animals such as dogs and cats, generally satisfactory results are obtained when the compounds of the present invention are administered when the compounds of the present invention are administered at a daily dose of 0.01 mg to about 100 mg per kg of animal body weight, preferably administered in a single dose or in divided doses two to six times a day or in a sustained release form. In the case of an adult human weighing 70 kg, the total daily dose will generally be from about 0.7 mg to about 3500 mg. This dosage regimen will be adjusted to achieve an optimal therapeutic response.

For the treatment of diabetes mellitus and / or hyperglycemia as well as for the treatment of other diseases or disorders treatable by the compounds of formula I, generally, satisfactory results are obtained when the compounds of the invention are administered at a daily dose of about 0.001 mg to about 100 mg per kilogram animal body weight. a single dose or divided doses two to six times a day or in a delayed release form. In the case of an adult human weighing 70 kg, the total daily dose will generally be from about 0.07 mg to

-24 about 350 mg. This dosage regimen can be adjusted to achieve an optimal therapeutic response.

Another aspect of the present invention provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts made from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

Pharmaceutical compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most appropriate route in any given case will depend on the condition to be treated, the severity and nature of the disease and the nature of the active ingredient. The active ingredients may conveniently be administered in the form of a unit dose made by any of the methods known in the art.

In practice, the compounds of formula I may be combined as active ingredients by intimately mixing with a pharmaceutical carrier by conventional pharmaceutical procedures. The carrier may be in a variety of forms depending on the form of administration of the desired preparation, for example, oral or parenteral (including intravenous). Any pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid compositions such as suspensions, elixirs and solutions or carriers can be used in the manufacture of pharmaceutical compositions for oral dosage forms. such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, glidants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, solid oral preparations being more preferred than liquid preparations.

Because of their ease of administration, tablets and capsules are the most preferred oral dosage unit, in which case solid pharmaceutical carriers are conventionally employed. If desired, the tablets may be coated with a

-25 standard methods with or without water. These pharmaceutical compositions and preparations should contain at least 0.1% by weight of the active compound. The amount of active compound in these compositions will, of course, vary and may be between 2 to about 60% by weight, based on the unit as a whole. The amount of active compound in these therapeutically useful pharmaceutical compositions is such that an effective dosage will be obtained. The active compounds may also be administered intranasally, such as in the form of liquid drops or a nebulizer.

Tablets, pills, capsules and the like may also contain a binder from the group of gums such as tragacanth, acacia, corn starch or gelatin, excipients such as dibasic calcium phosphate and a disintegrant such as corn starch, potato starch, alginic acid, glidant such as magnesium stearate and a sweetening agent such as sucrose, lactose or saccharin. When the dosage unit is a capsule, it may contain, in addition to the above materials, a liquid carrier such as a fatty oil.

Various other materials may be used as a coating material or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a coloring agent and flavoring agents such as cherry or orange flavor.

The compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water in a suitable mixture with a surfactant such as hydroxypropylcellulose. Dispersion can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of injectable sterile solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it can be dispensed with a syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of micro-organisms such as bacteria and

-26huby. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycols), suitable mixtures thereof, and vegetable oils.

The compounds of formula I may be used in combination with other drugs that are used in the treatment / prevention / suppression or amelioration of diseases or conditions for which the compounds of formula I are useful. These additional drugs may be administered for these drugs in the usual manner and in an simultaneously with a compound of formula I or sequentially. When a compound of formula I is used with one or more other drugs, a pharmaceutical composition comprising such additional drug in conjunction with a compound of formula I is preferred. The pharmaceutical compositions of the present invention thus also include compositions that also contain one or more additional active ingredients in addition to the compound of formula I. Examples of other active ingredients that may be combined with a compound of formula I administered separately or in the same pharmaceutical composition are without limitation:

a) insulin sensitivity baths including (i) PPARγ agonists such as glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like) and compounds disclosed in WO 97/27857, WO 97/28115, WO 97/28137 and WO 97/27847; (ii) biguanides such as metformin and phenformin;

(b) insulin or insulin mimics;

c) sulfonylureas such as tolbutamine and glipizide;

d) α-glucosidase inhibitors (such as acarbose);

e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin and other statins), (ii) sequestrants (cholestyramine, colestipol and dialkylaminoalkyl derivatives of cross-linked dextran), , nicotinic acid or salts thereof, (iii) a proliferator activator of receptor agonists and as derivatives of fenofibric acid (gemfibrozite, cloibrat, fenofibrate and benzafibrate), (iv) cholesterol absorption inhibitors such as beta-sitosterol and (acyl CoA-cholesterol acyltransferase) inhibitors such as melinamide, (v) probucol, (vi) vitamin E, and (vii) thyromimetic agents;

f) PPARÔ agonists such as those described in WO 97/28149;

-27g) anti-obesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat and other β ₃ adrenergic receptor agonists;

h) food modifiers such as neuropeptide Y antagonists (e.g. neuropeptide Y5) such as those described in WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97 / 20823;

i) PPARα agonists described in WO 97/36570 by the company

Glaxo;

j) PPARγ antagonists described in WO 97/10813; and

k) serotonin reuptake inhibitors such as fluoxetine and sertraline.

Testing of compounds for β3-agonist effects and determination of selectivity for β ₃ receptor against βι / β ₂ receptors · ₍

Functional test

The response of cAMP production to the ligand is measured according to Barton et al. (1991, Agonist-induced desensitization of D2 dopamine receptors in human Y-79 retinoblastoma cells. Mol. Pharmacol. V3229: 650-658) with the following modification. Chinese hamster ovary (CHO) cells stably transfected with the cloned β-adrenergic receptor (βι, β ₂ or β ₃ ) are harvested 3 days after subculturing. Cell harvesting is performed with Enzyme-free Dissociation Media (Specialty Media). Cells are counted and resuspended in Tris buffer (ACC buffer: 75 mM Tris, pH 7.4, 250 mM sucrose, 12.5 mM MgCl ₂ , 1.5 mM EDTA, 0.2 mM sodium metabisulfite, 0.6 mM IBMX) containing antioxidant and phosphodiesterase inhibitor are contemplated. The reaction is started by mixing 200,000 cells in 100 μΙ with 20 μΙ 6x concentrated ligand / unknown stock for testing. The tubes were shaken at 275 rpm for 45 minutes at room temperature. The reaction is terminated by boiling the tubes for 3 minutes. The cell lysate is diluted five times in 0.1 N HCl and then acetylated with a 150 μΙ sample diluted in acid with 6 μΙ acetylation mixture (acetic anhydride / triethylamine, 1: 2.5). cAMP produced in response to

The -28ligand is measured in the lysate by a competition assay against ¹²⁵ I-cAMP for binding of an anti- ¹²⁵ I-CAMP antibody using an automatic RIA instrument (ATTOFLO, Atto Instruments, Baltimore, MD, Brooker et al., 1979, Advances in Cyclic Nucleotide Research, Vol. 10: 1-32). The unknown level of cAMP is determined by comparing the values to a standard curve. cAMP is alternatively measured using the Amersham cAMP SPA (RPA 556) kit according to the manufacturer's instructions. Samples tested in this way need not be acetylated.

A non-selective, fully agonistic β-adrenergic ligand isoproterenol is used to determine maximal stimulation at all three receptors. As a control, a human β ₃ adrenergic receptor (AR) selective ligand compound (S) -N- [4- [2 - [[2-hydroxy-3- (4-hydroxyphenoxy) propyl] amino] ethyl] is used in all assays. phenyl] -4-iodo-benzenesulfonamide. Isoproterenol is titrated at a final test concentration of 10 ^-1 M to 10 ^-5 M for β3 AR and a concentration of 10 ¹¹ M to 10 ⁶ M for βι AR and β2 AR. (S) N- [4- [2 - [[2-hydroxy-3- (4-hydroxyphenoxy) propyl] amino] ethyl] phenyl] -4-iodobenzenesulfonamide is titrated as the β3 receptor at a concentration of 10 ¹¹ M to 10 ^{- 6} M. For βι AR, concentrations of 10 ' ⁸ M, 10' ⁷ M, 3 x 10 ' ⁷ M, 10 ⁶ M, 3 x 10 ⁶ M and 10' ⁵ M are used. ⁵ M.

Unknown ligands are first tested for β ₃ AR at a final concentration in the 10 * ⁷ M assay. Compounds having an activation at that concentration equal to or greater than 35% of the isoproterenol stimulation value are titrated to β ₃ AR at the concentrations used. for the titration of control (S) N- [4- [2 - [[2-hydroxy-3- (4-hydroxyphenoxy) propyl] amino] ethyl] phenyl] -4-iodobenzenesulfonamide to determine the EC ₅₀ value. The EC ₅₀ value is defined as the concentration of compound that gives 50% activation compared to the maximum activation value achievable by the compound. Data is analyzed by the Prism program (GraphPan, San Diego, CA).

Binding test

Compounds are also tested at β1 and β2 receptors to determine selectivity. The assay is performed for all compounds using a six-point binding assay

-29 carried out as follows. CHO cells express β! and β ₂ are allowed to grow 3 to 4 days after partitioning. The adherent cells were washed with PBS and lysed in 1 mM Tris, pH 7.2 for 10 minutes on ice. The bottles were scraped and the membranes centrifuged at 38,000 xg for 15 minutes at 4 ° C. Membranes are resuspended in TME buffer (75 mM Tris, pH 7.4, 12.5 mM MgCl ₂ , 1.5 mM EDTA) at a concentration of 1 mg protein / ml. Multiple membranes can be prepared at once and aliquoted and stored at -70 ° C for up to one year without loss of efficacy. The binding assay is performed by co-incubating the membranes (20 to 50 gg protein), the radiolabeled ¹²⁵ L-cyanopindolol probe ( ¹²⁵ I-CYP, 45 mP) and the test compounds at final concentrations from 10 ^-1 ° M to 10 ^-5 M in the final assay. volume 250 μΙ of TME buffer. The tubes were incubated for 1 hour with shaking at room temperature and samples were filtered on an IMSCO 96-well cell harvester. The filtrates are read on a Gamma counter and data are analyzed by a program in RS1 with four parameters translated (custom program developed using well-described statistical analysis programs) to determine the IC 50 value. IC 50 is defined as the concentration of compound capable of inhibiting 50% of the binding of a radiolabeled probe ( ¹²⁵ I-CYP). The selectivity of the compound to the β ₃ receptor can be determined by calculating the ratio (IC ₅₀ βι AR, β ₂ ΑΡ) / (ΕΟ ₅₀ β ₃ ΑΡ).

The following examples will be given to fully understand the invention. However, these examples are not to be considered as limiting the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

-30 (R) -N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-naphthylmethyl) -thiazol 2-yl] benzenesulfonamide

Step A: 2-naphthylmethylchloromethylketone

A mixture of 2-naphthylacetic acid (0.75 g) and 5 mL thionyl chloride was refluxed for 1 hour. Excess thionyl chloride was removed under reduced pressure, followed by azeotropic distillation with two portions of benzene. The residual yellow liquid was dissolved in 10 mL dry ether and added dropwise to an ice solution of excess diazomethaneterate (made from Diazald and aqueous potassium hydroxide at 0 ° C). The reaction mixture was stirred at 0 ° C for 1 hour and then concentrated under reduced pressure. The yellow oily residue was dissolved in 40 mL dry ether, cooled in ice, and a solution of hydrochloric acid in methanol (prepared from 0.30 mL acetyl chloride and 2.0 mL methanol at 0 ° C) was added dropwise. After 1 hour, the solution was concentrated under reduced pressure. The waxy solid was recrystallized from hexane to give 0.81 g of the title compound, mp 78-79 ° C.

¹ H NMR (400 MHz, CDCl ₃ ) δ:

7.80 (m, 3H), 7.68 (s, 1H), 7.47 (m, 2H), 7.31 (dd, J = 8.4 and 1.8 Hz), 4.13 (s 2H, 4.04 (s, 2H).

Step B: 2- (4-bromophenyl) -4- (2-naphthylmethyl) thiazole

A solution of 0.50 g of 4-bromothiobenzamide (E.P. Papadopoulos, J, Org. Chem., 1976, 41, 962) and 0.44 g of the 2-naphthylmethylchloromethyl ketone obtained above in 10 ml of absolute ethanol were refluxed for 18 hours. The mixture was cooled in ice and the solid was collected and washed with cold ethanol to give 0.53 g of a light brown powder, mp 136-138 ° C.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.85 (d, J = 8.6 Hz, 2H), 7.74-7.84 (m, 4H), 7.67 (d, J = 8) 6 Hz, 2H), 7.44 (m, 3H), 7.28 (s, 1H), 4.40 (s, 2H).

Step C: 4- [4- (2-naphthylmethyl) thiazol-2-yl] benzenesulfonyl chloride

A solution of the aryl bromide prepared above (0.53 g) in 10 mL of dry tetrahydrofuran was cooled to -78 ° C and a solution of n-butyllithium (1.0 mL in 1.6 M in hexanes) was added dropwise. After 30 minutes, a continuous stream of sulfur dioxide was introduced onto the surface of the dark brown solution for 5 minutes. The resulting yellow solution was stirred at -78 ° C for 10 minutes and was then allowed to warm to room temperature. After 1 hour, the mixture was concentrated under reduced pressure, and the residue was stirred with 20 mL of 1: 1 ether / hexane. The supernatant was decanted and the off-white powder obtained was dried under reduced pressure and then suspended in 10 ml of dichloromethane and cooled in an ice bath. N-Chlorosuccinimide (0.175 g) was added in one portion and the mixture was stirred at 0 ° C for 15 minutes. The cooling bath was removed and after 30 minutes the mixture was diluted with dichloromethane and filtered through a short bed of celite. The residue obtained after evaporation was purified by silica gel flash column chromatography (8% ethyl acetate / hexane) to give 0.042 g of the title compound as an off-white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.93 (d, J = 8.5 Hz, 2H), 7.70 - 7.85 (m, 4H), 7.67 (d, J = 8) 5 Hz, 2H), 7.40 (m, 3H), 7.26 (s, 1H), 4.43 (s, 2H).

Step D: (R) -N- [4- [2 - [[2-Hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-naphthylmethyl) - thiazol-2-yl] benzenesulfonamide

A solution of 0.035 g of (R) -N- [2- [4- (aminophenyl)] ethyl] 2-hydroxy-2- (pyrid-3-yl) ethylcarbamic acid 1,1-dimethylethyl ester (Fisher et al., US 5,561,142, 1). (October 1996) in 1.5 ml of dichloromethane was mixed with the sulfonyl chloride (0.042 g) prepared above and pyridine (0.015 ml). The solution was stirred at 25 ° C for 18 hours and trifluoroacetic acid (3 mL) was added. After stirring for 1.5 hours, the solution was concentrated under reduced pressure. Azeotropic distillation with methanol (10 mL) gave an orange viscous oil which was purified by flash chromatography on silica gel (eluent 9: 1, dichloromethane: 10% ammonium hydroxideMethanol) to give 0.083 g of the title compound as a yellow foam.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.50 (d, J = 2.0 Hz, 1H), 8.41 (dd, J = 4.9 and 1.6 Hz, 1H), 7 83 (d, J = 8.0 Hz, 2H), 7.64-7.80 (m, 4H), 7.58 (s, 1H), 7.3-7.5 (m, 7H),

-327.04 (two overlapping d, J = 8.6 Hz, 4H), 4.79 (dd, J = 7.3 and 5.7 Hz, 1H), 4.36 (s, 2H), 2 4-2.9 (m, 6H). FAB MS m / z 621;

Example 2

(R) -N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-trifluoromethyl-phenyl) -thiazol-2- yl] benzenesulfonamide and salts

Step A: (R) -N- [4- [2- [N- (1,1-dimethylethoxycarbonyl) -N- [2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] 4- (aminocarbonyl) benzenesulfonamide

A continuous stream of hydrogen sulfide was bubbled through a solution of 10.2 g of (R) -N- [4- [2- [N (1,1-dimethylethoxycarbonyl) -N- [2-hydroxy-2- (pyridin-3-yl) -ethyl] ] -amino] -ethyl] -phenyl] -4-cyanobenzenesulfonamide (Fisher et al., US 5,561,142, October 1, 1996) and triethylamine (2.9 mL) in 100 mL of pyridine at 25 ° C for 15 minutes. The green solution was stirred for 2.5 hours and then nitrogen was bubbled through the solution for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 8% methanol in dichloromethane) to give 9.31 g of the title compound as a bright yellow foam.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.45 (m, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.80 (m, 1H), 7.70 (m, 2H), 7.01 (overlapping with, 4H am, 1H), 4.84 (m, 1H), 3.15-3.45 (m, 4H), 2.7 (m, 2H) 1.30 (s, 9H).

Step B: (R) -N- [4- [2 - [[2-Hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (trifluoromethylphenyl) thiazol-2] yl] benzenesulfonamide

Mixtures 1.77 g of thioamide from step A above and 1.02 g of 4- (trifluoromethyl) phenyl chloromethyl ketone (synthesized from 4- (trifluoromethyl) benzoyl chloride and diazomethane as described in Example 1, Step A) in absolute ethanol (10 mL). ) was refluxed for 18 hours. The cooled reaction mixture was concentrated under reduced pressure and the residue was dissolved in 8 mL of dichloromethane and 2 mL of trifluoroacetic acid (TFA). After stirring at room temperature for 1 hour, the solution was concentrated under reduced pressure. The residual TFA was removed by azeotropic distillation with dichloromethane and the residue was purified by flash chromatography (eluent 9: 1 dichloromethane / 10% NH ₄ OH in methanol) to give the title compound (1.36 g) as a white powder.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.49 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 5.0 and 1.5 Hz, 1H), 8.18 (d, J = 7.9Hz, 2H), 8.12 (d, J = 8.6Hz, 2H), 8.09 (s, 1H), 7.82 (d, J = 8) 6 Hz, 2H), 7.77 (m, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.35 (dd, J = 7.9 and 5.0 Hz, 1H 7.09 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 4.80 (dd, J = 7.3 and 5.7 Hz) (1H), 2.70 2.90 (m, 6H). FAB MS m / z 625;

The dihydrochloride salt of the title compound

The free base from Step B above (2.50 g) was briefly stirred with a methanolic hydrochloric acid solution (made by adding 0.64 mL of acetyl chloride to 10 mL of methanol at 0 ° C for 15 minutes). Concentration under reduced pressure and drying in vacuo gave 2.81 g of a pale yellow powder which was dissolved in 35 mL of absolute ethanol, filtered, seeded and allowed to slowly evaporate at room temperature. The obtained crystalline material was collected, washed with cold ethanol, and dried in vacuo to give the title compound (2.60 g), 215-218 ° C.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.96 (s, 1H), 8.82 (d, J = 5.8 Hz, 1H), 8.68 (d, J = 8.2 Hz) 1 H, 8.20 (d, J = 8.2 Hz, 2H), 8.14 (d, J = 8.6 Hz, 2H), 8.13 (s, 1H), 8.08 (dd) J = 8.0 and 5.7 Hz, 1H), 7.87 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 5.30 (dd, J = 10.0 and 2.9 Hz, 1H), 3 44 (dd, J = 12.7 and 2.9 Hz, 1H), 3.20-3.35 (m, 4H), 2.97 (t, J = 8.3 Hz, 2H). FAB MS m / z 625 (M + 1).

-34 The dihydrobromide salt of the title compound

The free base in methanol was mixed with 2.2 equivalents of methanolic hydrogen bromide solution, stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated and dried under reduced pressure. The obtained powder was suspended in 2-propanol and refluxed for 18 hours. The solution was slowly cooled to room temperature with stirring and then cooled in an ice bath. The light yellow crystalline powder was collected, washed with cold 2-propanol and dried in vacuo to give the title compound, mp 199-202 ° C.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.97 (s, 1H), 8.82 (d, J = 5.4 Hz, 1H), 8.68 (d, J = 8.2) Hz, 1H), 8.20 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.6 Hz, 2H), 8.13 (s, 1H), 8.08 ( dd, J = 8.0 and 5.7 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7, 20 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 5.31 (dd, J = 10.0 and 3.1 Hz, 1H), 3.44 (dd, J = 12.8 and 3.1 Hz, 1H), 3.20-3.35 (m, 4H), 2.98 (t, J = 8.3 Hz, 2H).

Dimaleate salt of the title compound

The free base was suspended in 2-propanol and mixed with 2.0 equivalents of maleic acid. The suspension was heated to reflux until all solids had dissolved, filtered, allowed to cool slightly, then seeded and allowed to stand at room temperature overnight. The precipitated solid was collected, washed with 2-propanol and dried in vacuo to give the title compound as an off-white crystalline powder, mp 154-156 ° C.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.60 (d, J = 2.4 Hz, 1H), 8.51 (dd, J = 4.9 and 1.6 Hz, 1H), 20 (d, J = 7.9Hz, 2H), 8.14 (d, J = 8.5Hz, 2H), 8.13 (s, 1H), 7.93 (m, 1H), 7 86 (dd, J = 8.6 Hz, 2H), 7.49 (dd, J = 7.8 and 4.7 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H) 7.12 (d, J = 8.6 Hz, 2H), 6.27 (4H, s, maleic acid), 5.02 (dd, J = 10.1 and 3.3 Hz, 1H), 3.15-3.35 (m, 4H); 2.95 (m, 2H).

-35Example 3

(R) -N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethyl-phenyl) -thiazol-5 yl] benzenesulfonamide

Step A; a-amino-4-brómacetofenónhydrochlorid

A modified Delepin reaction procedure was used (Goddard, C.J.

Heterocyclic Chem., 1991, 28, 17). A mixture of α, 4-dibromoacetophenone (2.78 g) and hexamethylenetetraamine (1.47 g) in 40 mL of chloroform was stirred vigorously overnight. The precipitated solid was collected, washed with chloroform, dried in vacuo and then suspended in a mixture of 6 ml of concentrated hydrochloric acid and 30 ml of methanol and stirred overnight. The precipitated white solid was collected, washed with methanol and dried under vacuum to give 1.38 g of a white powder which was used without further purification.

Step B: 4- (Trifluoromethyl) benzamide of α-amino-4-bromoacetophenone

A mixture of the hydrochloride salt produced above (1.38 g) and triethylamine (1.50 min) in 40 mL of chloroform was cooled in an ice-water bath and a solution of 4- (trifluoromethyl) benzoyl chloride (1.21 g) in 5 mL was added dropwise. ml of chloroform. The mixture was stirred at 0 ° C for 1 hour, diluted with 30 mL of chloroform and washed sequentially with water, 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. Drying and removal of the solvent under reduced pressure gave an off-white solid which was triturated with the mixture

-36-acetyl acetate / hexane (6: 1), separated and dried to give 1.20 g of the title compound as a white solid, mp 173-174 ° C.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.96 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 4.92 (apparent d, J = 4.3 Hz, 2H). FAB MS m / z 387.4 (M + 1).

Step C: 5- (4-Bromophenyl) -2- (4-trifluoromethylphenyl) thiazole

A mixture of the amide from Step B above (0.386 g) and Lawesson's reagent (0.410 g) in 6 mL of dry toluene was refluxed for 1.5 hours. The solution was cooled and loaded directly onto a silica gel column. Successive elution with hexane followed by 10% ethyl acetate / hexane gave 0.380 g of the title compound as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.05 (d, J = 8.5 Hz, 2H), 8.03 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.6Hz, 2H), 7.45 (d, J = 8.6Hz, 2H). FAB MS m / z 385.9 (M + 1).

Step D: 5- (4-Chlorosulfonylphenyl) -2- (4-trifluoromethylphenyl) thiazole

A solution of the above aryl bromide (0.356 g) in 6 mL dry THF was mixed with n-butyllithium (0.63 mL 1.6 M in hexanes) followed by addition of sulfur dioxide followed by N-chlorosuccinimide as described in Example 1, step C above. The obtained crude sulfonyl chloride (0.171 g) was used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.09 (d, J = 8.5 Hz, 2H), 8.05 (s, 1H), 7.58 (m, 4H), 7.45 ( d, J = 8.6 Hz, 2H).

Step E: (R) -N- [4- [2 - [[2-Hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethylphenyl) thiazole] 5-yl] benzenesulfonamide

A solution of 0.131 g of (R) -N- [2- [4- (aminophenyl)] ethyl] -2-hydroxy-2- (pyrid-3-yl) ethylcarbamic acid 1,1-dimethyl ester in 1.6 ml of dichloromethane was mixed with the above the above sulfonyl chloride (0.171 g) and 0.040 mL pyridine, followed by the addition of trifluoroacetic acid as described in Example 1, Step D. The crude product was

Purified by flash chromatography on silica gel (eluent 9: 1 dichloromethane: 10% NH ₄ / MeOH) to give 0.227 g of the title compound as a pale yellow foam.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.50 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 5.0 and 1.6 Hz, 1H), 8 27 (s, 1H), 8.14 (d, J = 8.0Hz, 2H), 7.79 (m, 7H), 7.09 (d, J = 8.6Hz, 2H), 7 0.04 (d, J = 8.6 Hz, 2H), 4.78 (dd, J = 7.3 and 5.2 Hz, 1H), 2.7-2.9 (m, 6H). FAB MS m / z 625.3 (M + 1).

Example 4

(R) -N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] -phenyl-4- [4- (4-trifluoromethoxy-phenyl) -thiazol-2-yl ] benzenesulfonamide

The title compound was prepared according to the procedure in Example 2. ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.52 (d, J = 2.0 Hz, 1H), 8.43 (dd, J = 4) 9 and 1.6 Hz, 1H), 8.12 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.6 Hz, 2H), 7.98 (s, 1H ), 7.83 (overlapping d, J = 8.5 Hz, 2H am, 1H), 7.38 (dd, J = 7.9 and 5.0 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 4.85 (dd, J = 8.8 and 4.2 Hz, 1H), 2.7-3.1 (m, 6H). FAB MS m / z 641 (M + 1).

Using the procedures described for Examples 1 and 2, the compounds listed in Table 1 were prepared.

-38Table 1

Example R Selected Ή NMR (CD ₃ OD) 5 3,4-difluorophenyl-methyl 7.97 (d, J = 7.0 Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.12 - 7.20 (overlapping m, 2H and d, J = 7.0 Hz, 2H), 3.86 (s, 2H). 6 3-pyridyl 9.16 (s, 1H); 8.49 (m, 2H); 8.40 (m, 2H); 8.11 (overlapping d, J = 8.5 Hz, 2H and s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 8.4 and 4.8 Hz, 1H), 7.36 (dd, J = 7.9 and 5.0 Hz, 1H) 7 4-fluorophenyl-methyl 7.98 (d, J = 8.6Hz, 2H), 7.77 (d, J = 8.6Hz, 2H), 7.28 (dd, J = 8.5 and 5.5 Hz, 2H), 7.18 (s, 1H), 6.96-7.10 (m, 6H), 4.11 (s, 2H). 8 3,4-difluorophenyl 8.09 (d, J = 8.6 Hz, 2H), 7.94 (s, 1H), 7.91 (m, 1H), 7.75-7.85 (overlapping d, J = 8, 6 Hz, 2H and 2H), 7.25-7.38 (m, 2H). 9 4- (trifluoromethyl) -phenyl- methyl 7.99 (d, J = 8.5Hz, 2H), 7.76 (d, J = 8.5Hz, 2H), 7.58 (d, J = 8.1Hz, 2H), 7.46 (d, J = 8.1Hz, 2H), 7.27 (s, 1H) 4.22 (s, 2H) ). 10 2-pyridyl 8.56 (d, J = 4.8 Hz, 1H), 8.21 (overlapping with, 1H and am, 1H) 8.12 (d, J = 8.6 Hz, 2H), 7.88 (m 1H, 7.80 (overlapping d, J = 8.6 Hz, 2H and m, 1H), 7.36 (m, 2H).

11 1- (2-phenyl) ethyl 8.01 (d, J = 8.3 Hz, 2H), 7.78 (overlapping) d, J = 8.3 Hz, 2H and m, 1H), 7.15-7.25 (m, 6H), 3.06 (m, 4H). 12 4-fluorophenyl 8.10 (d, J = 8.3 Hz, 2H), 8.00 (dd, J = 8.8 and 5.4 Hz, 2H), 7.85 (s, 1H), 7.81 (d J = 8.3 Hz, 2H), 7.14 (apparent t, J = 8.8 Hz, 2H). 13 2-naphthyl 8.12 (d, J = 8.6 Hz, 2H), 8.04 (dd, J = 8.6 and 1.7 Hz, 1H), 7.98 (s, 1H), 7.80-7 95 (overlapping d, J = 8.6 Hz, 2H and am, 4H), 7.77 (d, J = 7.9 Hz, 1 H), 7.46 (m, 2H). 14 3,4,5-trifluorophenyl 8.07 (d, J = 8.6Hz, 2H), 8.01 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.76 (dd, J = 9.3 and 6.7 Hz, 2H). 15 4-hexylphenyl 8.06 (d, J = 8.4Hz, 2H), 7.94 (d, J = 8.4Hz, 2H), 7.79 (m, 3H), 7.23 (d, J = 8.6Hz, 2H), 2.62 (t, J = 7.5Hz, 2H), 1.61 (m, 2H), 1.27 (m, 6H), 0.89 (t, J = 7.3Hz, 3H). 16 4- (trifluoromethoxy) - phenylmethyl 7.99 (d, J = 8.6Hz, 2H), 7.77 (d, J = 8.6Hz, 2H), 7.37 (d, J = 8.4Hz, 2H), 7.24 (s, 1H), 7.18 (d, J = 8.4Hz, 2H), 4.16 (s, 2H). 17 4- (trifluoromethoxy) - phenoxymethyl 8.05 (d, J = 8.5Hz, 2H); 7.80 (d, J = 8.5Hz, 2H), 7.67 (s, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.07 (m, 6H), 5.22 (s, 2H). 18 2-Benzo [d] thienyl 8.08 (d, J = 8.4 Hz, 2H), 7.80 (m, 5H), 7.32 (m, 3 H). 19 3-quinolinyl 9.42 (s, 1H), 8.84 (s, 1H), 8.19 (s, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.97 (m, 2H), 7.83 (d, J = 8.6 Hz, 2H), 7.73 (apparent t, J = 7.0 Hz, 1H) 7.60 (apparent t, J = 7.0 z, 1H).

20 6-quinolinyl 8.84 (d, J = 4.2Hz, 1H), 8.62 (s, 1H), 8.40 (m, 2H), 8.18 (d, J = 8.6Hz, 2H), 8.16 (s, 1H), 8.08 (d, J = 9.1Hz, 1H), 7.85 (d, J = 8.6Hz, 2H), 7.56 (m, IH). 21 2-benzo [b] furyl 8.06 (d, J = 8.6Hz, 2H), 7.82 (d, J = 8.6Hz, 2H), 7.81 (s, 1H), 7.58 (d, J = 7) 1 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.28 (m, 2H), 7.22 (s, 1H). 22 3-indolyl 8.10 (d, J = 8.6 Hz, 2H); 8.05 (d, J = 6.9 Hz, 1H); 7.80 (d, J = 8.6 Hz, 2H); 78 (s, 1H), 7.65 (s, 1H), 7.40 (d, J = 6.8Hz, 1H), 7.16 (m, 2H). 23 2,4-difluorophenyl 8.27 (m, 1H); 8.10 (d, J = 8.6 Hz, 2H); 7.86 (s, 1H), 7.81 (d, J = 8.6Hz, 2H), 7.05 (m, 6H). 24 3,5-difluorophenyl 8.12 (d, J = 8.4Hz, 2H), 8.08 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.62 (dd, J = 8.8 and 2.3 Hz, 2H), 6.93 (tt, J = 8.8 and 2.3 Hz, 1H). 25 4- (1,1-dimethylethyl) phenyl 8.05 (d, J = 8.5Hz, 2H), 7.83 (d, J = 8.5Hz, 2H), 7.79 (d, J = 8.5Hz, 2H), 7.57 (s, 1H), 7.42 (d, J = 8.5Hz, 2H), 1.32 (s, 9H). 26 2,3-difluorophenyl 8.12 (d, J = 8.4Hz, 2H), 8.03 (m, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.25 (m, 2H). 27 3- (trifluoromethyl) phenyl 8.31 (s, 1 H), 8.25 (d, J = 6.5 Hz, 1 H), 8.13 (d, J = 8.5 Hz, 2H), 8.09 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.62 (m, 2H). 28 4- (difluoromethyl) phenyl 8.12 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H), 7.89 (s, 1H), 7.81 (d, J = 8.6Hz, 2H), 7.19 (d, J = 8.7Hz, 2H), 6.87 (t, J = 73Hz 1H).

29 2,4-dichlorophenyl 8.09 (d, J = 8.6 Hz, 2H), 8.07 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8) 6 Hz, 2H), 7.57 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H). 30 2- (trifluoromethyl) phenyl 8.08 (d, J = 8.6Hz, 2H), 7.84 (m, 2H), 7.82 (d, J = 8.6 Hz, 2H), 7.69 (m, 3H), 7.61 (m, 1H). 31 2-fluoro-4- (trifluoromethyl) - phenyl 8.47 (m, 1H), 8.13 (d, J = 8.6 Hz, 2H), 8.11 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.59 (s, 1H), 7.56 (d, J = 5.0Hz, 1H). 32 4-fluoro-2- (trifluoromethyl) - phenyl 8.07 (d, J = 8.6Hz, 2H); 7.80 (d, J = 8.6Hz, 2H), 7.73 (dd, J = 8.4 and 5.5 Hz, 1H), 7.70 (s, 1H), 7.59 (dd, J = 9.2 and 2.8 Hz, 1H) 7.46 (apparent td, J = 8.6 and 2.8 Hz, 1H). 33 2,4-bis (trifluoromethyl) - phenyl 8.10 (m, 3H), 8.02 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.81 (m, 4H). 34 4-biphenyl 8.08 (d, J = 8.6Hz, 2H), 8.00 (d, J = 8.5Hz, 2H), 7.80 (d, J = 8.6Hz, 2H), 7.70-7.73 (m, 2H), 7.64 (d, J = 8.5Hz, 2H), 7, 61 (d, J = 7.2Hz, 2H), 7.42 (t, J = 7.2Hz, 2H), 7.25-7.35 (m, 2H). 35 3,4-dihydroxyphenyl 8.07 (d, J = 8.6 Hz, 2H), 7.79-7.83 (m, 3H), 7.79 (s, 1H), 7.57 (s, 1H), 7.41 (d, J = 2.1 Hz, 1 H), 7.31 (dd, J = 8.2 and 2.1 Hz, 1H), 6.81 (d, J = 8.2 Hz, 2H). 36 4-hydroxyphenyl 8.09 (d, J = 8.5 Hz, 2H), 7.77-7.83 (m, 4H), 7.67 (s, 1H), 6.82 (d, J = 8.7 Hz, 2H). 37 4-acetoxyphenyl 8.08 (d, J = 8.6Hz, 2H), 7.97 (d, J = 8.8Hz, 2H), 7.80 (d, J = 8.6Hz, 2H), 7.74 (s, 1H), 7.14 (d, J = 8.8 Hz, 2H); 2.30 (s, 3H). 38 4-acetamidophenyl 8.11 (d, J = 8.5Hz, 2H). 7.93 (d, J = 8.7Hz, 2H), 7.77-7.83 (m, 4H), 7.62 (d, J = 8.7 Hz, 2H), 2.14 (s, 3H).

-42Example 39

(R) -N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [5- (4-fluorophenyl) thiazol-2-yl] benzenesulfonamide

Step A: 2-Bromo-2- (4-fluorophenyl) ethanal

To a solution of 672 mg o-iodoxybenzoic acid in methylsulfoxide (5 mL) was added 250 µL of 2- (4-fluorophenyl) ethanol and stirring was continued for 3 hours. Water (20 mL) was added and the reaction mixture was filtered, the filtrate was extracted with ether (3 x 20 mL), washed with brine (10 mL), dried over magnesium sulfate and concentrated to give 2- (4-fluorophenyl) ethanol as unstable. oil. The material was immediately dissolved in acetonitrile (3.5 mL) at 0 ° C and 264 μΙ of bromotrimethylsilane and 142 μΙ of methylsulfoxide were added. After stirring for 1 hour, water (10 mL) was added and the reaction mixture was extracted with ether (3 x 20 mL), washed with brine (10 mL), dried over magnesium sulfate and concentrated to give the title compound (220 mg) as unstable. oil which was used immediately without further purification.

Step B: (R) -N- [4- [2 - [[2-Hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [5- (4-fluorophenyl) thiazole] 2-yl] benzenesulfonamide

A mixture of 50 mg of the thiamide of Example 2, Step A and 220 mg of 2-bromo-2- (4-fluorophenyl) ethanal in chloroform / acetonitrile (2/1, 1.5 mL) was refluxed for 16 hours. The cooled reaction mixture was concentrated under reduced pressure and purified by preparative thin layer chromatography (9: 1 eluent).

-43 dichloromethane / methanol) to give (R) -N- [4- [2- [N- (1,1-dimethylethoxycarbonyl) -N- [2hydroxy-2- (pyridin-3-yl) ethyl] amino] - ethyl] -phenyl] -4- [5- (4- (fluorophenyl) thiazol-2-yl] benzenesulfonamide (12 mg), which was dissolved in 2 mL of dichloromethane and 2 mL of trifluoroacetic acid (TFA). The solution was concentrated under reduced pressure, the residual TFA was removed by azeotropic distillation with dichloromethane, and the residue was purified by preparative thin layer chromatography (eluent 9: 1 dichloromethane / 10% NH ₄ OH, methanol) and then by preparative reverse phase HPLC (eluent 65). 35 methanol / 10% TFA in water) to give the title compound (5.0 mg).

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.75 (m, 1H), 8.66 (m, 1H), 8.13 (s, 1H), 8.06 (d, J = 8 Hz) (2H), 7.85 (d, J = 8Hz, 2H), 7.79-7.69 (m, 3H), 7.22-7.09 (m, 6H), 5.16 5.10 (m, 1H), 3.30-3.17 (m, 4H), 2.98-2.91 (m, 2H).

Example 40

(R) -N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethyl-phenyl) -thiazole-4- yl] benzenesulfonamide

Step A: 4- (Trifluoromethyl) thiobenzamide

4- (trifluoromethyl) benzonitrile (3.42 g) was mixed with triethylamine (2.12 g) and a solution of hydrogen sulfide in pyridine, as described in Example 2, step. The crude product was triturated with hexane (150 mL) and collected to give 3.80 g of a yellow powder, mp 133-136 ° C.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.92 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H).

-44Step B: 4- (4-bromophenyl) -2- (4-trifluoromethylphenyl) thiazole

A solution of the above thioamide (0.41 g) and α, 4-dibromoacetophenone (0.56 g) in 5 ml of absolute ethanol was refluxed for 14 hours. The reaction mixture was cooled in ice and the solid was collected and washed with ethanol to give 0.67 g of a white crystalline solid, m.p. 143-1244 ° C.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.12 (d, J = 7.9 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.53 (s, 1H). FAB MS m / z 386.1 (M + 1).

Step C: 4- (4-Bromophenyl) -2- (4-trifluoromethylphenyl) -5- (trimethylsilyl) thiazole

A solution of the aryl bromide obtained above (0.567 g) in 10 mL of dry tetrahydrofuran (THF) was cooled in a dry ice-acetone bath and n-butyllithium solution (1.0 mL of 1.6 M in hexanes) was added dropwise. After a further 15 minutes, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 1 hour. Saturated aqueous ammonium chloride (1 mL) was added and the mixture was concentrated under reduced pressure. Separation-washing of the ether-water mixture gave a white waxy solid which was purified by flash column chromatography on silica gel (5% ethyl acetate-hexane eluent) to give 0.49 g of the title compound as a white solid, mp 88-89 ° C .

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.09 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 0.25 (s, 9H). FAB MS m / z 458.0 (M + 1).

Step D: 4- (4-Chlorosulfonylphenyl) -2- (4-trifluoromethylphenyl) -5- (trimethylsilyl) thiazole

The allyl bromide prepared above (0.456 g) was mixed with n-butyllithium and then sulfur dioxide was added followed by N-chlorosuccinimide as described in Example 1, step C above. The crude product (0.223 g) was used without further purification.

Step E: (R) -N- [4- [2 - [[2-Hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethylphenyl) thiazole] 4-yl] benzenesulfonamide

A solution of 0.150 g of (R) -N- [2- [4- (aminophenyl)] ethyl] -2-hydroxy-2- (pyrid-3-yl) ethylcarbamic acid 1,1-dimethylethyl ester (Fisher et al., US 5,561,142, October 1) .

-451996) in 1.6 mL of dichloromethane was mixed with the sulfonyl chloride (0.223 g) prepared above and 0.040 mL of pyridine, and then trifluoroacetic acid as described in Example 1, step D was added. The crude product was purified by flash chromatography on silica gel (eluent). 9: 1, dichloromethane: 10% ammonium hydroxide / methanol) to give 0.171 g of a pale yellow foam which was dissolved in 2 mL acetonitrile and mixed with 15% HF in acetonitrile. The mixture was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent 9: 1 dichloromethane: 10% ammonium hydroxide / methanol) to give 0.091 g of the title compound as a pale yellow foam.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.49 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 4.9 and 1.6 Hz, 1H), 8 19 (d, J = 7.7Hz, 2H), 8.11 (d, J = 8.6Hz, 2H), 8.05 (s, 1H), 7.78 (apparent t, J = 8) 5 Hz, 4H), 7.35 (dd, J = 5.0 and 7.9, 1H), 7.09 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 4.77 (dd, J = 7.4 and 5.2 Hz, 1H), 2.7-2.9 (m, 6H). FAB MS m / z 625.3 (M + 1).

Example 41

(R) -N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethyl-phenyl) -thiazol 4-yl] benzenesulfonamide

The title compound was prepared according to the procedure in Example 40.

¹ H NMR (400 MHz, CD ₃ OD) δ: 8.50 (d, J = 2.1 Hz, 1H), 8.40 (dd, J = 4.9 and 1.6 Hz, 1H), 8 11 (d, J = 2.9 Hz, 2H), 8.09 (d, J = 2.9 Hz, 2H), 7.99 (s, 1H), 7.78 (apparent d,

-46J = 8.7 Hz, 3H), 7.37 (apparent d, J = 8.7 Hz, 2H), 7.35 (m, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 4.76 (dd, J = 7.4 and 5.1 Hz, 1H), 2.7-2.9 (m, 6H) ). FAB MS m / z 641.3 (M + 1).

Claims (15)

PATENT CLAIMS A thiazolobenzenesulfonamide of formula I wherein X is (1) a bond, (2) C 1 -C 3 alkylene, optionally substituted with 1 or 2 groups selected from methyl and halogen, (3) C 1 -C 3 alkylene, wherein said alkylene contains an oxygen atom, optionally substituted with 1 or 2 groups selected from the group methyl and halogen; m is 0 to 5; A is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a benzene ring fused to a C ₅ -C ₁₀ carbocyclic ring, (4) A 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (5) 5 or 6 a membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, fused to a C ₅ -C ₁₀ carbocyclic ring; R ¹ is (1) C 1 -C 10 alkyl optionally substituted with up to 5 groups selected from (a) hydroxy, (b) halogen, (c) cyano, (d) QR ² . (e) C ₃ -C ₈ cycloalkyl, (F) A is optionally substituted with up to 5 groups selected from halogen, C 1 -C 10 alkyl and C 1 -C 10 alkoxy, (g) Q'COR ³ , (h) S (O) _n R ³ , wherein n is 0 to 2, (i) NR ² SO ₂ R ³ , G) NR ² CO ² R ² and (k) CO ² R ² , (2) C ₃ -C 6 cycloalkyl, (3) oxo, (4) halogen, (5) cyano, (6) QR ² , (7) S (O) _n R ³ , where n is 0 to 2, (8) Q'COR ³ , (9) NR ² SO ₂ R ³ , (10) NR ² CO ₂ R ² , (11) group A optionally substituted with up to 5 groups selected independently from (a) R ^2nd (b) QR ² , (c) halogen and (d) oxo, or (12) CO ₂ R ² ; R ² is (1) a hydrogen atom, (2) C 1 -C 10 alkyl optionally substituted with up to 5 groups selected from (a) hydroxy, (b) halogen, (c) CO ₂ R ⁴ , (d) S (O) _n -C 1 -C 10 alkyl, wherein n is 0 to 2, (e) C ₃ -C ₈ cycloalkyl, (f) C 1 -C 10 alkoxy and -49 (g) A optionally substituted with up to five groups selected from halogen, C 1 -C 10 alkyl and C 1 -C 10 alkoxy, (3) C ₃ -C ₈ cycloalkyl or (4) A optionally substituted with up to 5 groups being convened from (a) halogen, (b) nitro, (c) oxo, (d) NR ⁴ R ⁴ , (e) C 1 -C ₁₀ alkoxy, (f) S (O) _n -C 1 -C ₁₀ alkyl, wherein n is 0 to 2 and (g) C 1 -C 10 alkyl optionally substituted with up to 5 groups selected from hydroxy, halogen, CO ₂ R ⁴ , S (O) _n -C 1 -C ₁₀ alkyl, wherein n is 0 to 2, C ₃ -C ₈ cycloalkyl , C 1 -C 10 alkoxy and group A optionally substituted with up to 5 groups selected from halogen, C 1 -C 10 alkyl and C 1 -C ₁₀ alkoxy; R ³ is (1) R ² or (2) NR ² R ² ; R ⁴ is (1) H or (2) C 1 -C 6 alkyl; Q is (1) N (R ² ), (2) O or (3) S (O) _n , and n is 0 to 2; Q 1 is (1) N (R ² ), (2) O or (3) a bond or or a pharmaceutically acceptable salt or prodrug thereof. The thiazolobenzenesulfonamides of claim 1, wherein X is (1) a bond, (2) CH ₂ , (3) CH ₂ O, wherein C is bound to a thiazole and O is bound to A; The thiazolobenzenesulfonamides of claim 1, wherein -50R ¹ is (1) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms, (2) halogen, (3) QR ² , (4) Q'COR ³ , (5) phenyl; R ² is (1) a hydrogen atom, (2) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms; R ³ is (1) C 1 -C 10 alkyl and Q is (1) O. The thiazolobenzenesulfonamides of claim 1, wherein X is (1) a bond, (2) CH ₂ , (3) CH ₂ O, wherein C is bound to a thiazole and O is bound to A; m is 0 to 5; A is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a benzene ring fused to a C ₅ -C ₁₀ carbocyclic ring, (4) A 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (5) 5 or 6 a membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, fused to a C ₅ -C ₁₀ carbocyclic ring; R ¹ is (1) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms, (2) halogen, (3) QR ² , (4) Q'COR ³ , (5) phenyl; R ² is (1) hydrogen, (2) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms, -51 R ³ is (1) C 1 -C 10 alkyl and Q is (1) O. The thiazolobenzenesulfonamides of claim 1, wherein either the benzenesulfonamide moiety or group X (or group A if X is a bond) is attached to the C2 position of the thiazole ring and the second group to the C4 position of the thiazole ring. The thiazolobenzenesulfonamides of claim 5, wherein X is (1) a bond, (2) CH ₂ , (3) CH ₂ O, wherein C is bound to a thiazole and O is bound to A; m is 0 to 5; A is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) naphthyl, or (4) a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms. up to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to the benzene ring; R ¹ is (1) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms, (2) halogen, (3) QR ² , (4) Q'COR ³ , (5) phenyl; R ² is (1) hydrogen, (2) C 1 -C 10 alkyl optionally substituted with up to 5 halogen atoms, R ³ is (1) C 1 -C 10 alkyl and Q is (1) O. The thiazolobenzenesulfonamides of claim 6, wherein A is selected from phenyl, naphthyl, thienyl, pyridinyl, benzothienyl, quinolinyl, indolyl and benzofuranyl. -528. The thiazolobenzenesulfonamide according to any one of the preceding claims, which is selected from: N- [4- [2 - [[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4- [4- (2-naphthylmethyl) thiazol-2yljbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethyl) phenyl] thiazol-2 yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethoxy) phenyl] thiazol-2-yl ] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,4-difluorophenyl-methyl) thiazol-2-yl] benzenesulfonamide N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3-pyridyl) thiazole-2yljbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-fluorophenyl-methyl) thiazol-2-yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,4-difluorophenyl) thiazol-2-yl] benzenesulfonamide N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethyl) phenylmethyl] thiazol-2-yl ] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-pyridyl) thiazole -2yljbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) etyljamino] ethyl] phenyl] -4- [4- [1- (2-phenyl) ethyl] -tiazol2-yl] benzenesulfonamide N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-fluoro-phenyl) -thiazole-2yljbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-naphthyl) thiazole-2yljbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,4,5-trifluorophenyl) thiazol-2- yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-hexylphenyl) thiazole-2yljbenzénsulfónamid, -53N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethoxy) phenylmethyl] thiazol-2 yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (trifluoromethoxy) phenoxymethyl] thiazol-2-yl ] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-benzo [b] thienyl) thiazol-2- yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3-quinolinyl) thiazol-2yljbenzénsulfónamíd, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (6-quinolinyl) thiazol-2yljbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2-benzo [b] furyl) thiazol-2- ylJbenzénsulfónamid. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3-indolyl) thiazol-2yljbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2,4-difluorophenyl) thiazol-2-yl] benzenesulfonamide N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,5-difluorophenyl) thiazol-2-yl] benzenesulfonamide N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (1,1-dimethylethyl) phenyl] thiazol-2 -ylJbenzénsulfónamid. N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] Anna's] ethyl] phenyl] -4- [4- (2,3-difluorophenyl) thiazol-2-ylJbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [3- (trifluoromethyl) fenylJtiazol-2-ylJbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4- (difluoromethyl) phenyl] thiazol-2-yl ] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (2,4-dichlorophenyl) -thiazol-2-ylJbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [2- (trifluoromethyl) phenyl] thiazol-2-yl ] benzenesulfonamide, -54N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [2-fluoro-4- (trifluoromethyl) phenyl] thiazol-2-yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [4-fluoro-2- (trifluoromethyl) phenyl] -thiazole 2-yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- [2,4-bis (^ trifluórmetyOfenylJtiazol -yľJbenzénsulfônamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [5- (4-fluorophenyl) -thiazol-2-yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethyl-phenyl) -thiazol-4-yl] benzenesulfonamide N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethyl-phenyl) -thiazol-5-yllbenzénsulfónamid, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-phenylphenyl) thiazol-2-yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (3,4-dihydroxyphenyl) thiazol-2-yl] benzenesulfonamide N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-hydroxyphenyl) thiazol-2-yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-acetoxyphenyl) thiazol-2-yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (4-acetamidophenyl) thiazol-2-yl] benzenesulfonamide, N- [4- [2 - [[2-hydroxy-2- (pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [2- (4-trifluoromethoxy-phenyl) -thiazol-4-yl] benzenesulfonamide . 9. A compound according to claim 1 of the formula -5510. A pharmaceutical composition for the treatment of diabetes or obesity or for lowering triglyceride or cholesterol levels or for increasing high-density lipoproteins or for reducing bowel mobility or for reducing neurogenic inflammation, or for treating depression or for treating gastrointestinal disorders, comprising an effective amount of thiazolbenzenesulfonate. according to claim 1 together with an inert carrier. 11. A pharmaceutical composition comprising a thiazolobenzenesulfonamide of formula I together with a pharmaceutically acceptable carrier. The thiazolobenzenesulfonamides of claim 1 for use in treating diabetes. The thiazolobenzenesulfonamides of claim 1 for use in treating obesity in a mammal. The thiazolobenzenesulfonamides of claim 1 for use in lowering triglyceride and cholesterol levels or increasing high density lipoprotein levels. r «r The thiazolobenzenesulfonamides of claim 1 for use in enhancing bowel mobility. The thiazolobenzenesulfonamides of claim 1 for use in alleviating neurogenic airway inflammation. The thiazolobenzenesulfonamides of claim 1 for use in alleviating depression. The thiazolobenzenesulfonamides of claim 1 for use in the treatment of gastrointestinal disorders.