JP3149186B2 - Substituted sulfonamides as selective beta-3 agents for the treatment of diabetes and obesity - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND β- adrenergic receptors invention are further classified into ₁ and beta ₂ and beta 1967. An increase in heart rate is a major consequence of β ₁ receptor stimulation, and bronchodilation and smooth muscle relaxation are typically caused by β ₂ stimulation. Adipocyte lipolysis was initially have simply considered to be a process that beta ₁ is involved. However, more recent results indicate that receptor-mediated lipolysis is atypical in nature. Both of these atypical receptor is referred to hereinafter as beta ₃ adrenergic receptor, found on white and brown adipocytes both cell surface and these adipocytes is stimulated lipolysis (breakdown of fat) and energy expenditure Is promoted.

Early development of this field, compounds with high agent activity by for stimulation of atrial heart rate (beta ₁₎ and tracheal relaxation (beta ₂₎ lipolysis (beta ₃ activity) than for stimulation of produced . Ainswort
h) et al., U.S. Pat. Nos. 4,478,849 and 4,396,627, these early developments relate to derivatives of phenylethanolamine.

The selectivity to such beta ₃ adrenergic receptors were able to make the kind of the compound having potent activity as an anti-obesity drug. In addition, these compounds have been reported to exhibit antihyperglycemic effects in animal models of non-insulin dependent diabetes.

The major drawback in treatment of chronic diseases using beta ₃ agonists are other beta receptor stimulation, the potential for side effects expressed accordingly. The most likely side effects include muscle tremor (β ₂ ) and increased heart rate (β ₁ ). Although these phenylethanolamine derivatives do have some β ₃ selectivity, this type of side effect has been observed in those volunteered to experiment. It is reasonable to expect that these side effects will result from partial β ₁ and / or β ₂ effects.

More recent developments in this area include U.S. Pat. No. 5,153,210 to Ainsworth et al., U.S. Pat. No. 4,999,377 to Caulkett et al., U.S. Pat. European Patent 42
7480 and Bloom et al. In EP 455006.

These more recent development is directed to compounds having a high beta ₃ selective than beta ₁ and beta ₂ activity, Rodentia this selectivity as test animals, particularly investigated using rats. Even if the most selective compound examined by these assays still shows signs of side effects due to residual β ₁ and β ₂ agonist activity when the compound is tested in humans, rodent ₃ revealed that it is not a good model for the expected selectivity.

Recently, assays have been developed that more accurately predict the effects that can be expected in humans. These assays utilize human beta ₃ receptor, cloned was expressed in Chinese hamster ovary cells. Science of Emorine et al., 1989, 245, 1118-1121.
See pages and Liggett, Mol. Pharmacol, 1992, 42, 634-637. The effect of various compounds as agonists and antagonists on cultured cells indicates the anti-obesity and anti-diabetic effects of those compounds in humans.

SUMMARY OF THE INVENTION The present invention relates to substituted sulfonamides useful as anti-obesity and anti-diabetic compounds. That is, an object of the present invention is to describe such compounds.
A further object is to describe particularly preferred structural isomers of the substituted sulfonamides. A still further object is to describe a method for preparing such a compound. Another object is to describe compositions and methods using these compounds as active ingredients. Further objects will become apparent from reading the following description.

DESCRIPTION OF THE INVENTION The present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof: Wherein n is 0-5; m is 0 or 1; r is 0-3; A is (1) 5 having 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. Or a 6-membered heterocycle, (2) a benzene ring fused to a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) from oxygen, sulfur and nitrogen A 5- or 6-membered heterocycle having 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, fused to a 5- or 6-membered heterocycle having 1-4 heteroatoms selected, 4) phenyl, or (5) a benzene ring fused to a C ₃ -C ₈ cycloalkyl ring; R ¹ is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5) ^{) NR 8 R 8, (6} ) SR 8, (7) trifluoromethyl, (8) C ₁ ~C ₁₀ ^{Alkyl, (9) OR 8, (} 10) SO 2 R 9, (11) OCOR 9, (12) NR 8 COR 9, (13) COR 9, (14) NR 8 SO 2 R 9, (15) NR ⁸ CO ₂ R ⁸ , or (16) hydroxy, halogen, cyano, NR ⁸ R ⁸ , SR ⁸ , trifluoromethyl, OR ⁸ , C ₃ -C ₈ cycloalkyl, phenyl, NR ⁸ COR ⁹ , COR ⁹ , SO ₂ R ⁹ , OCOR ⁹ , NR ⁸ SO2R ⁹ or N
R ₁ -C ₁₀ alkyl substituted by R ⁸ CO ₂ R ⁸ ; R ² and R ³ are independently (1) hydrogen, (2) C ₁ -C ₁₀ alkyl, or (3) hydroxy, C ₁ -C ₁₀ alkyl having 1-4 substituents selected from C ₁ -C ₁₀ alkoxy and halogen; X _{is, (1) -CH 2 -,} (2) -CH 2 -CH 2 -, (3) —CH ＝ CH—, or (4) —CH ₂ O—; R ⁴ and R ⁵ are independently: (1) hydrogen, (2) C ₁ -C ₁₀ alkyl, (3) halogen, ^{(4) NHR 8, (5} ) oR 8, (6) SO 2 R 9 or ^{_{(7) NHSO 2 R 9,}} ; R 6 is (1) hydrogen or, (2) C ₁ -C ₁₀ alkyl; R ⁷ is Z- (R ^1a ) _n ; R ^1a is (1) R ¹ , provided that when A is phenyl, R ^1a is not C ₁ -C ₁₀ alkyl; (2) C ₃ -C ₈ cycloalkyl; ^{3) R 8, NR 8 R} 8, oR 8, selected independently from SR ^8, and halogen Phenyl or or unsubstituted substituted by groups of up to four to be, or (4) oxo, from ^{R 8, NR 8 R 8,} OR 8, SR 8 , and halogen up to 4 substituents independently selected A 5- or 6-membered heterocycle having 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted by a group; Z is (1) phenyl, (2) naphthyl, ( 3) oxygen, 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to (4) C ₃ -C ₈ cycloalkyl ring, (5) oxygen A benzene ring fused to a 5- or 6-membered heterocycle having 1-4 heteroatoms selected from sulfur and nitrogen; (6) 1-4 heteroatoms selected from oxygen, sulfur and nitrogen 5- or 6-membered hete Ring fused to, oxygen, 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (7), C ₃ ~C ₈ is fused to a cycloalkyl ring, oxygen,
5 or 6 membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁸ is (1) hydrogen, (2) C ₁ -C ₁₀ alkyl, (3) C ₃ -C ₈ Cycloalkyl, (4) halogen, nitro, oxo, NR ¹⁰ R ¹⁰ , C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylthio, and hydroxy, halogen, CO ₂ H, CO ₂ -C ₁ -C ₁₀ alkyl, SO ₂ -C ₁ ~C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₁₀ alkoxy and 1 to 3 halogens, C ₁
-C ₁₀ alkyl or C ₁ -C 1-4 substituents selected from C ₁ -C ₁₀ alkyl having ₁₀ 1-4 substituents selected from Z, which is optionally substituted by alkoxy Optionally having Z; (5) hydroxy, halogen, CO ₂ H, CO ₂ -C ₁ -C ₁₀ alkyl, SO ₂ -C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl,
C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkyl and 1-4 halogen selected from Z optionally substituted by C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkoxy C ₁ -C ₁₀ alkyl having a substituent; R ⁹ is, (1) R ⁸ or (2) NR ⁸ R ^8,; and R ^10, (1) C ₁ -C ₁₀ alkyl or (2) C ₁ together with the N to which two R ¹⁰ groups are attached
Optionally substituted by -C ₁₀ alkyl 5 or 6
And two R ¹⁰ groups that form a membered ring. ).

In one embodiment of the present invention, A has 5 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
A 6-membered heterocycle, a benzene ring fused to a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or 1 selected from oxygen, sulfur and nitrogen 5 having up to 4 heteroatoms
Or a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 6-membered heterocycle.

In another embodiment of the present invention, A is phenyl or benzene fused to a C ₃ -C ₈ cycloalkyl ring.

A preferred compound of the present invention is a compound of the formula I, wherein R ² and R ³ are hydrogen or methyl: X is —CH ₂ —; n is 0 to 3, m is 1; r is 0 to 2, and R ⁴ , R ⁵ and R ⁶ are hydrogen;

Another preferred compound of the present invention is a compound of the above formula I wherein A is a 6-membered heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen and sulfur or phenyl; R ¹ is hydroxy, halogen, cyano C ₁ -C ₆ alkyl optionally substituted with trifluoromethyl, NR ⁸ R ⁸ , NR ⁸ SO ₂ R ⁹ , NR ⁸ COR ⁹ , NR ⁸ CO ₂ R ⁸ , or hydroxy; Or a compound that is 2.

More preferred compounds are represented by the following formula Ia: (Wherein, n is 0 to 3; m is 1; R ¹ is (1) hydrogen, or (2) NR ⁸ R ⁸ ; R ² and R ³ are independently halogen or methyl, R ^1a Are (1) halogen, (2) C ₁ -C ₁₀ alkyl, (3) NR ⁸ R ⁸ , (4) NR ⁸ COR ⁹ , (5) NR ⁸ CO ₂ R ⁸ , (6) COR ⁹ , ( 7) OCOR ⁹ , or (8) oxo, halogen, R ⁸ , NR ⁸ R ⁸ , OR ⁸ and SR ⁸ , oxygen substituted or unsubstituted or substituted by up to 4 groups independently selected from: A 5- or 6-membered heterocycle having 1-4 heteroatoms selected from sulfur and nitrogen; Z is (1) phenyl, (2) naphthyl, (3) 1-selected from oxygen, sulfur and nitrogen A 5- or 6-membered heterocycle having 4 heteroatoms, (4) a 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen (5) oxygen fused to a C ₃ -C ₈ cycloalkyl ring,
5 or 6 membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; X is -CH ₂ -; and R ⁸ and R ⁹ represent the definition of formula I. ).

An even more preferred compound is represented by the following formula Id: Wherein n is 0 or 1; R ¹ is NR ⁸ R ⁸ ; R ² and R ³ are independently (1) hydrogen, or (2) methyl; B is (1) hydrogen, 2) benzene fused to a benzene ring to form naphthyl, or (3) 5- or 6-membered 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to the benzene ring Heterocycle; R ^1a represents (1) halogen, (2) C ₁ -C ₁₀ alkyl, (3) NR ⁸ R ⁸ , (4) NR ⁸ COR ⁹ , (5) NR ⁸ CO ₂ R ⁸ , (6) ) COR ^9, or (7) oxo, whether unsubstituted are substituted by a radical from R ^8, SR ^8, oR ⁸ and NR ⁸ R ⁸ to 4 substituents selected independently from oxygen, sulfur and nitrogen R ^1a is attached to either ring when B and the benzene ring form a condensed ring; 5 or 6 membered heterocyclic ring having 1-4 heteroatoms selected R ⁸ is (1) hydrogen, (2) C ₁ -C ₁₀ alkyl, 1 selected from (3) nitro, oxo and NR ¹⁰ R ¹⁰
Z having 〜4 optional groups, or (5) hydroxy, halogen, C ₁ -C ₁₀ alkyl, C ₃ -C
₈ cycloalkyl and 1-4 halogen, C ₁ ~ having 1-4 substituents selected from Z, which is optionally substituted by C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkoxy
C ₁₀ alkyl; R ⁹ is, (1) R ⁸ or (2) NR ⁸ R ^8,; R ¹⁰ is, (1) C ₁ -C ₁₀ alkyl, or (2) two R ¹⁰ groups are bonded to Together with N, C
5 or 6 are optionally substituted by ₁ -C ₁₀ alkyl
Two R ¹⁰ groups forming a membered ring; and Z is a 5- or 6-membered heterocyclic ring having 1-4 heteroatoms selected from (1) phenyl, (2) oxygen, sulfur and nitrogen. , (3) oxygen, benzene ring fused to a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) C ₃ -C ₈ fused to a cycloalkyl ring Being, oxygen,
A 5- or 6-membered heterocycle having 1-4 heteroatoms selected from sulfur and nitrogen; ).

Other more preferred compounds are represented by Formula Ib below: (Wherein n is 0 to 3; m is 1; R ¹ is (1) hydroxy, (2) cyano, (3) NR ⁸ R ⁸ , or (4) halogen; R ^1a is (1 ) Halogen, (2) NR ⁸ R ⁸ , (3) NR ⁸ COR ⁹ , (4) NR ⁸ CO ₂ R ⁸ , (5) OCOR ⁹ , or (6) oxo, halogen, R ⁸ , NR ⁸ R ⁸ Selected from oxygen, sulfur and nitrogen, substituted or unsubstituted by up to four groups independently selected from OR ⁸ and SR ⁸
A 5- or 6-membered heterocycle having from 4 to 4 heteroatoms; Z has from 1 to 4 heteroatoms selected from (1) phenyl, (2) naphthyl, or (3) oxygen, sulfur and nitrogen benzene ring fused to a 5 or 6-membered heterocyclic ring; X is -CH ₂ -; and R ² and R ³ are independently hydrogen or methyl; representative of. ).

Representative anti-obesity and anti-diabetic compounds of the present invention include:
Including: N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nil] -4- (hexylaminocarbonylamino) ben
Zensulfonamide, N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nyl] -4-iodobenzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nyl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nyl] -2-naphthalenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nyl] -3-quinoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nyl] -5-benzisoxazole sulfonamide, N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nil] -4-[(hexylmethylaminocarbonyl) a
Mino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nyl] -4-[(dimethylaminocarbonyl) amino]
Benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] ethyl] fe
Nil] -4- (3-hexyl-2-imidazolidone-1
-Yl) benzenesulfonamide, N- [4- [3-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] propyl] f
Enyl] -4- (hexylaminocarbonylamino)
Benzene sulfonamide, N- [4- [3-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] propyl] f
Enyl] -4-iodobenzenesulfonamide, N- [4- [3-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] propyl] f
Enyl] benzenesulfonamide, N- [4- [3-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] propyl] f
Enyl] -2-naphthalenesulfonamide, N- [4- [3-[[2-hydroxy-2- (6-amido)
Nopyridin-3-yl) ethyl] amino] propyl] f
Enyl] -3-quinoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(Hexylaminocarbonylamino) benzenesulfone
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-i
Sopropylbenzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -2-na
Phthalenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -3-ki
Norin sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[(Hexylmethylaminocarbonyl) amino] benze
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-hexyl-2-imidazolidinone-1-yl) be
Benzene sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-io
Benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[5- (3-cyclopentylpropyl)-[1,2,4]-
Oxadiazol-3-yl] benzenesulfonami
, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[(1-oxoheptyl) amino] benzenesulfone
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[(1-oxo-4-phenylbutyl) amino] benze
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[(Propoxycarbonyl) amino] benzenesulfone
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[[[(Ful-2-ylmethyl) amino] carbonyl]
Amino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[[[(2-phenylethyl) amino] carbonyl] a
Mino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[[[(2-Indol-3-ylethyl) amino] ca
Rubonyl] amino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri)
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[[(Octylamino) carbonyl] amino] benzene
Sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[(Hexylamino) carbonyl] -5-indoline
Rufonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[(Octylamino) carbonyl] -5-indoline
Rufonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[(N-methyl-N-octylamino) carbonyl]-
5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(1-Oxononyl) -5-indoline sulfonami
, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-methylthiazol-2-yl) -5-indoline
Sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-octylthiazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-ethyl-5-methylthiazol-2-yl) -5
-Indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-octyl-2-imidazolidinone-1-yl) be
Benzene sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (4,4,4-trifluorobutyl) -2-imidazo
Ridinone-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-phenylpropyl) -2-imidazolidino
N-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (4,4,5,5,5-pentafluoropentyl) -2-
Imidazolidinone-1-yl] benzenesulfonami
, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (2-cyclohexylethyl) -2-imidazoli
Dinon-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- [3- (4-chlorophenyl) propyl] -2-
Imidazolidinone-1-yl] benzenesulfonami
, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-pentyl-2-imidazolidinone-1-yl] be
Benzene sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-cyclopentylpropyl) -2-imidazo
Lydinone-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri)
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (2-cyclopentylethyl) -2-imidazoli
Dinon-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-cyclohexylpropyl) -2-imidazo
Lydinone-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri)
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (2,2-dimethylhexyl) -2-imidazolidy
Non-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-hexyl-2-imidazolone-1-yl) benze
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (4,4,4-trifluorobutyl) -2-imidazo
Ron-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-octyl-2-imidazolone-1-yl) benze
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-cyclopentylpropyl) -2-imidazo
Ron-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-octyl-3-oxo- [1,2,4] -triazoe
Ru-4-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-hexyl-5-tetrazolone-1-yl) benze
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-octyl-5-tetrazolone-1-yl) benze
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[(3-cyclopentylpropyl) -5-tetrazolone
-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-pentyloxazol-5-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-octyloxazol-5-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (2-cyclopentylethyl) exazole-5
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[(4-ethyl-5-methylthiazol-2-yl) a
Mino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[(4,5,6,7-tetrahydrobenzothiazole-2-i
L) amino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-hexylimidazol-4-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(1-methyl-2-octylimidazol-5-yl)
Benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[1-Methyl-2- (2-cyclopentylethyl) imi]
Dazol-5-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[1-methyl-2- [2- (4-fluorophenyl) e
[Tyl] imidazol-5-yl] benzenesulfonami
, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-pentyl- [1,2,4] -oxadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[5- (2-cyclopentylethyl)-[1,2,4] -o
Xadiazol-3-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-heptyl- [1,2,4] -oxadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-octyl- [1,2,4] -oxadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-hexylthio- [1,2,4] -triazole-3-
Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[[4- (4-propylpiperidin-1-yl) -1,1
-Dioxo- [1,2,5] -thiadiazol-3-yl]
Amino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[[4- (hexylmethylamino) -1,1-dioxo-
[1,2,5] -thiadiazol-3-yl] amino] ben
Zensulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[[4- (N-Peptyl, N-methylamino) -1,1-di
Oxo- [1,2,5] -thiadiazol-3-yl] amido
No] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(1-octyl-2,4-imidazolidinedione-3-i
B) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-nitrophenyl) -5-pyrazolone-1-
Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[4- (1-hydroxy-1-hexylpeptyl) -5
-Methyl- [1,2,3] -triazol-2-yl] ben
Zensulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[4- (1-hydroxyheptyl) -5-methyl- [1,
2,3] -Triazol-2-yl] benzenesulfone
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] -2-methylpropyl] fe
Nyl] -4- (3-hexyl-2-imidazolidinone-
1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri)
Dinyl) ethyl] amino] -2-methylpropyl] fe
Nyl] -4-iodobenzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] -2-methylpropyl] fe
Nyl] -4-[[(hexylamino) carbonyl] ami
No] benzenesulfonamide, N- [4- [2-[(2-hydroxy-2-phenyle
Tyl) amino] ethyl] phenyl] -4-iodobenze
N- [4- [2-[(2-hydroxy-2-phenyle)
Tyl) amino] ethyl] phenyl] -2-naphthalene
Rufonamide, N- [4- [2-[(2-hydroxy-2-phenyle
Tyl) amino] ethyl] phenyl] -3-quinoline sulf
Honamide, N- [4- [2-[[2-hydroxy-2- (3-chloro
Lphenyl) ethyl] amino] ethyl] phenyl] -3
-Isopropylbenzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-chloro
Lphenyl) ethyl] amino] ethyl] phenyl] -2
-Naphthalenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-chloro
Lphenyl) ethyl] amino] ethyl] phenyl] -3
-Quinoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (4-amido)
No-3,5-dichlorophenyl) ethyl] amino] ethyl
L] phenyl] -4- (hexylaminocarbonylamido
C) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (4-amido)
No-3,5-dichlorophenyl) ethyl] amino] ethyl
Ru] phenyl] -1-[(octylamino) carboni
] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (4-amido)
No-3,5-dichlorophenyl) ethyl] amino] ethyl
L] phenyl] -4- (3-hexyl-2-imidazoli
Dinon-1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (4-amido)
No-3,5-dichlorophenyl) ethyl] amino] ethyl
L] phenyl] -4- (3-octyl-2-imidazoli
Dinon-1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (4-hydrido)
Roxyphenyl) ethyl] amino] ethyl] phenyl]
-Benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (4-hydrido)
Roxyphenyl) ethyl] amino] ethyl] phenyl]
-4-iodobenzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-cia)
Nophenyl) ethyl] amino] ethyl] phenyl] -4
-(Hexylaminocarbonylamino) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-sia
Nophenyl) ethyl] amino] ethyl] phenyl] -3
-Quinoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-hexyl- [1,2,4] -oxadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-heptyl-5-methyl- [1,2,3] -triazolate
Ru-2-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-hexyl-2,4-imidazolidinedione-1-i
B) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-octyl-2,4-imidazolidinedione-1-i
B) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-cyclopentylpropyl) -2,4-imida
Zolidinedione-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-pentyl- [1,2,4] -oxadiazole-5-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy- (3-pyridini)
Ru) ethyl] amino] ethyl] phenyl] -4- (3-
Hexyl- [1,2,4] -oxadiazol-5-yl)
Benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-heptyl- [1,2,4] -oxadiazole-5-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-octyl- [1,2,4] -oxadiazole-5-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (2-cyclopentylethyl)-[1,2,4] -o
Xadiazol-5-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-cyclopentylpropyl)-[1,2,4]-
Oxadiazol-5-yl] benzenesulfonami
, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-pentyl- [1,2,4] -thiadiazole-5-i
B) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-hexyl- [1,2,4] -thiadiazole-5-i
B) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-heptyl- [1,2,4] -thiadiazole-5-i
B) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(3-octyl- [1,2,4] -thiadiazole-5-i
B) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (2-cyclopentylethyl)-[1,2,4] -h
Adiazol-5-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-cyclopentylethyl)-[1,2,4] -h
Adiazol-5-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-pentyl)-[1,2,4] -thiadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-hexyl)-[1,2,4] -thiadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-heptyl)-[1,2,4] -thiadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-octyl)-[1,2,4] -thiadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[5- (2-cyclopentylethyl)-[1,2,4] -h
Adiazol-3-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[5- (3-cyclopentylethyl)-[1,2,4] -h
Adiazol-3-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-pentyl-3-oxo- [1,2,4] -triazoe
Ru-2-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-hexyl-3-oxo- [1,2,4] -triazoe
Ru-2-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-heptyl-3-oxo- [1,2,4] -triazoe
Ru-2-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-octyl-3-oxo- [1,2,4] -triazoe
Ru-2-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[4- (2-cyclopentylethyl) -3-oxo-
[1,2,4] -Triazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[4- (3-cyclopentylpropyl) -3-oxo-
[1,2,4] -Triazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-pentyloxazol-2-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-hexyloxazol-2-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-heptyloxazol-2-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-octyloxazol-2-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[5- (2-cyclopentylethyl) oxazole-2
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[5- (3-cyclopentylpropyl) oxazole-
2-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-pentyloxazol-2-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-hexyloxazol-2-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-heptyloxazol-2-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-octyloxazol-2-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[4- (2-cyclopentylethyl) oxazole-2
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[4- (3-cyclopentylpropyl) oxazole-
2-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-hexyloxazol-5-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-heptyloxazol-5-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (3-cyclopentylpropyl) oxazole-
5-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (4-cyclohexylbutyl) oxazole-5
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- [2- (4-fluorophenyl) ethyl] oxa
Zol-5-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-pentyloxazol-4-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-hexyloxazol-4-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-heptyloxazol-4-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-octyloxazol-4-yl) benzenesul
Honamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (2-cyclopentylethyl) oxazole-4
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (3-cyclopentylpropyl) oxazole-
4-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-pentylthiazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-hexylthiazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-heptylthiazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(5-octylthiazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[5- (2-cyclopentylethyl) thiazole-2-
Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[5- (3-cyclopentylpropyl) thiazole-2
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-pentylthiazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-hexylthiazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-heptylthiazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(4-octylthiazol-2-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[4- (2-cyclopentylethyl) thiazole-2-
Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[4- (3-cyclopentylpropyl) thiazole-2
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-pentylthiazol-4-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-hexylthiazol-4-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-heptylthiazol-4-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-octylthiazol-4-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (2-cyclopentylethyl) thiazole-4-
Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (3-cyclopentylpropyl) thiazole-4
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-pentylthiazol-5-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-hexylthiazol-5-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-heptylthiazol-5-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
(2-octylthiazol-5-yl) benzenesulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (2-cyclopentylethyl) thiazole-5-
Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (3-cyclopentylpropyl) thiazole-5
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-methylthiazol-2-yl) -5-indoline
Sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-pentylthiazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-hexylthiazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-Peptylthiazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-octylthiazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[5- (2-cyclopentylethyl) thiazole-2-
Yl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[5- (3-cyclopentylpropyl) thiazole-2
-Yl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-pentylthiazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-hexylthiazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-heptylthiazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[4- (2-cyclopentylethyl) thiazole-2-
Yl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[4- (3-cyclopentylpropyl) thiazole-2
-Yl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-methyloxazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-pentyloxazol-2-yl) -5-india
Phosphorus sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-hexyloxazol-2-yl) -5-indo
Phosphorus sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-Peptyloxazol-2-yl) -5-indo
Phosphorus sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-octyloxazol-2-yl) -5-indo
Phosphorus sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[5- (2-cyclopentylethyl) oxazole-2
-Yl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[5- (3-cyclopentylpropyl) oxazole-
2-yl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-methyloxazol-2-yl) -5-indori
N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-pentyloxazol-2-yl) -5-india
Phosphorus sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-hexyloxazol-2-yl) -5-indo
Phosphorus sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-heptyloxazol-2-yl) -5-indo
Phosphorus sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(4-octyloxazol-2-yl) -5-indo
Phosphorus sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[4- (2-cyclopentylethyl) oxazole-2
-Yl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[4- (3-cyclopentylpropyl) oxazole-
2-yl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(3-methyl- [1,2,4] -oxadiazole-5-i
) -5-Indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(3-pentyl- [1,2,4] -oxadiazole-5-
Yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(3-hexyl- [1,2,4] -oxadiazole-5-
Yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(3-heptyl- [1,2,4] -oxadiazole-5-
Yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(3-octyl- [1,2,4] -oxadiazole-5-
Yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[3- (2-cyclopentylethyl)-[1,2,4] -o
Xiadiazol-5-yl] -5-indoline sulfone
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[3- (3-cyclopentylpropyl)-[1,2,4]-
Oxadiazol-5-yl] -5-indoline sulfo
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-Methyl- [1,2,4] -oxadiazole-3-i
) -5-Indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-pentyl- [1,2,4] -oxadiazole-3-
Yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-hexyl- [1,2,4] -oxadiazole-3-
Yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-heptyl- [1,2,4] -oxadiazole-3-
Yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
(5-octyl- [1,2,4] -oxadiazole-5-
Yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyri
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[5- (2-cyclopentylethyl)-[1,2,4] -o
Xiadiazol-3-yl] -5-indoline sulfone
Amide, N- [4- [2-[[2-hydroxy-2- (3-pyr
Dinyl) ethyl] amino] ethyl] phenyl] -1-
[5- (3-cyclopentylpropyl)-[1,2,4]-
Oxadiazol-3-yl] -5-indoline sulfo
Amide.

All compounds of the present invention have at least one asymmetric center, denoted by an asterisk in Structural Formula I. Various substituents on the molecule, in particular depending on the type of R ² and R ^3, additional asymmetric centers may be present on the molecule. Each asymmetric center gives rise to two optical isomers, and separated pure or partially pure optical isomers or racemic mixtures of all such optical isomers are within the scope of the present invention. It is intended to be. In the case of an asymmetric center indicated by an asterisk in Formula I, a compound wherein the hydroxy substituent is above the plane of the structure, as found in Formula Ic, is
It has been found that the hydroxy substituent is more active, ie, more preferred, than the compound below the plane of the structure.

The following structure-specific structures indicate preferred structural isomers of the invention: (Wherein, n, m, r, A , R 1, R 2, R 3, R 4, R 5, R 6, R 7
And X are as defined in formula I above. ) Throughout the specification, each term has the following meaning.

The alkyl group includes a linear or branched alkyl group having a specified chain length. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

The alkoxy group includes a linear or branched alkoxy group having a specified chain 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" includes the halogen atoms fluorine, chlorine, bromine and iodine.

Examples of 5- and 6-membered and fused heterocycles of A, Z and R ^1a are pyridyl, quinolinyl, pyrimidyl,
Pyrrolyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl,
Benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl,
Including benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridine and thienopyridine.

A and Z are preferably a benzene ring fused to phenyl, naphthyl, or a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or oxygen or sulfur. And / or 1-4 independently selected from one and / or 1-4 nitrogen atoms
Is a heterocycle having two heteroatoms.

More preferred of A are phenyl, pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl and thiazolyl.

More preferred Z are phenyl, naphthyl, quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl,
Benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, triazolyl,
Tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydrobenzothiazolyl and tetrahydroquinolinyl. Z is -NSO ₂ (CH ₂₎ r _- when bound to, Z is phenyl, naphthyl, or oxygen, to the 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Condensed benzene rings are preferred. When Z is part of the definition of R ⁸ , Z is preferably phenyl; 1 selected from oxygen, sulfur and nitrogen
5 or 6-membered heterocycle having to 4 heteroatoms; oxygen, benzene ring fused to a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; C ₃ ~ Oxygen fused to a C ₈ cycloalkyl ring,
5- or 6-membered heterocycle having 1-4 heteroatoms selected from sulfur and nitrogen.

Preferred heterocycles for R ^1a are thienyl, thiadiazolyl, thiazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl and pyrazolyl.

Certain of the terms defined above may appear more than once in the above formula, in which case each term is defined independently of the other. For example, NR ⁸ R ⁸ is NH ₂ , NHC
H ₃ , N (CH ₃ ) CH ₂ CH _{3 and the} like.

 The following abbreviations are used in the description:

Boc: 3-butoxycarbonyl Cbz: Carbobenzyloxy DIP-Cl: Diisopinocampheylchloroborane DMF: Dimethylformamide DMSO: Dimethylsulfoxide HPLC: High-performance liquid chromatography Me: Methyl MPLC: Medium-speed liquid chromatography Ms: Methane Sulfonyl (mesyl) NBS: N-bromosuccinimide NCS: N-chlorosuccinimide nHex: n-hexyl TBAF: tetrabutylammonium fluoride TBS (TBDMS): t-butyldimethylsilyl TFA: trifluoroacetic acid THF: tetrahydrofuran Compound of the present invention (I) can be prepared from an epoxide intermediate as shown in Formula II and an amine intermediate as shown in Formula III. The preparation of these intermediates is described in the following scheme.

(Wherein, n, m, r, A , R 1, R 2, R 3, R 4, R 5, R 6, R 7
And X are as defined above. Compound II can be conveniently prepared by various methods known in the literature or well known to those skilled in the art. One general route is shown in Scheme 1.
The acid chloride 1, which is commercially available or easily prepared from the corresponding acid, for example by treatment with thionyl chloride or oxalyl chloride, is treated with diazomethane in a solvent such as diethyl ether. The resulting diazoketone is then treated with hydrogen chloride to give chloroketone 2 (X = Cl)
Get. Next, the haloketone 2 is reduced with a reducing agent such as sodium borohydride. The resulting alcohol 3 is treated with a base such as potassium carbonate under acetone reflux to give the desired epoxide II. The enantiomerically enriched (R) and (S) epoxides II are (-) or (+)-DIP-Cl, (R) or (S) -Alpine (Alp
ine) borane or (R) or (S) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo [1,
2-c] [1,3,2] oxyazaborole-borane ((R)
Or it can be easily obtained by asymmetric reduction of the haloketone 2 using chiral reducing agents such as _{(S) -OAB · BH 3)} .

An alternative route to the desired haloketone 2 is shown in Scheme 2. Methyl ketone 4 is known to those skilled in the art and is available from Larock's Comprehensive Organic.
Transformations (Comprehensive Organic)
Transformations); VCH: New York, 1989, 369-372
Can be converted to the corresponding haloketones using various reagents described in. Conveniently, the methyl ketone 4 is treated with chlorine or N-chlorosuccinimide in acetic acid using an additional acid source such as hydrogen chloride or aluminum chloride. For the synthesis of 2 (X = Br), bromine, dibromobarbituric acid or NBS and hydrogen bromide or aluminum bromide can be used. In some cases, the chloro or bromo ketone 2 is commercially available.

Many of the methyl ethyl ketones 4 are commercially available or are readily prepared by methods described in the literature and known to those skilled in the art. The R ¹ substituent on acid chloride 1 or methyl ketone 4 may need to be protected during subsequent processing. The description of such protecting groups should be
Groups in Organic Synthesis (Protec
tive Groups in Organic Synthesis, 2nd edition, TWGreene and PGMWuts, John Wiley and So
ns), New York, 1991.

Compound III can be conveniently prepared by various methods well known to those skilled in the art. A convenient preparation route when R ⁶ is hydrogen is shown in Scheme 3. Compound 5 is selectively protected as a suitable carbamate derivative 6, for example, by di-tert-butyl dicarbonate or carbobenzyloxychloride. The compound is then prepared in an anhydrous solvent such as dichloromethane or chloroform at a temperature of -20 to 50 ° C., preferably 0 ° C., with a sulfonyl halide, preferably a sulfonyl chloride 7, and a base such as pyridine for 0.5 to 0.5. Treatment for 24 hours gives sulfonamide 8. The protecting group is then removed, for example by trifluoroacetic acid in the case of Boc or by catalytic hydrogenation in the case of Cbz, to give the desired amine 9.

Compound III where R ⁶ is not hydrogen can be conveniently prepared as shown in Scheme 4. The sulfonamide 8 prepared as described above is alkylated with a suitable alkylating agent 10 in the presence of a base to give the sulfonamide 11
give. Removal of the protecting group as described above gives the desired compound 9a.

Many of the sulfonyl chlorides are also commercially available and can be prepared by a number of methods well known to those skilled in the art. One suitable method is Batachara (SNBhat
tacharya) et al., J. Chem. Soc. (C), 1265-1267 (1969).
Adding an organolithium reagent or a Grignard reagent to sulfuryl chloride according to the procedure of Another convenient method is described in Chemistry Letters of YJPark et al., 1483-1486 (199).
Treating the thiol with metal nitrate and sulfuryl chloride according to the procedure of 2). Also, sulfonic acid is
It is conveniently converted to the corresponding sulfonyl chloride by treatment with PCl _5, PCl ₃ or SOCl ₂ (March (J.Marc
h) Advanced Organic Chemistry (A
advanced Organic Chemistry), 4th edition, John Wiley and Sons,
New York, 1992, p. 1297, and references cited therein). Aromatic and heteroaromatic compounds can be directly chlorosulfonylated by treatment with Vilsmeier reagent or chlorosulfonic acid (Organic Synthesis, I, 8).

Diamine 5 is commercially available or easily prepared by methods described in the literature or known to those skilled in the art. Compound 5 wherein R ² or R ³ is methyl
Bloom et al., J. Med. Chem., 35, 3081-3084.
It can be prepared from the corresponding amino acid according to the method described in (1992). When R ³ is methyl, as shown in Scheme 5, the appropriate (R) amino acid
Esterification of 12 by treatment with methanolic hydrochloric acid conveniently followed by treatment with di-tert-butyl dicarbonate gives compound 13. The ester group is reduced by a hydride source such as lithium borohydride and the resulting alcohol is converted to a leaving group such as mesylate. Removal of the Boc protecting group gives diamine 14. This compound is
Catalytic hydrogenation in the presence of a base such as sodium acetate gives the desired α-methylamine 15. Corresponding (S)
Other enantiomers can be obtained by a similar route starting from amino acids.

Sulfonamide amines 9 or diamine 5 X is -CH ₂ O-m is 1 are also readily prepared by methods known to or skilled person and are described in the literature.
For example, as shown in Scheme 6, the sodium salt of 4-nitrophenol 16 can be converted to 1-bromo-2 under reflux of 2-butanone using a base such as potassium carbonate.
Conveniently alkylating with chloroethane to give the chloro derivative 17. The chloride is converted to the corresponding amine by treatment with lithium azide followed by reduction with, for example, triphenylphosphine in aqueous tetrahydrofuran. Treatment of the resulting amine with di-tert-butyl dicarbonate, conveniently protecting its t-butyl carbamate, affords derivative 18. next,
The nitro group is reduced, for example, by catalytic hydrogenation to give the amine 19
give. Intermediate 19 is acylated with sulfonyl chloride 7
Subsequent deprotection with an acid such as trifluoroacetic acid gives the desired intermediate 20.

Alternatively, X- is a diamine 5 is 1 -CH ₂ O-a and m, can be obtained from intermediate 19 by treatment with trifluoroacetic acid. The diamine can then be modified as shown in Scheme 3.

X is -CH ₂ CH ₂ - and is sulfonamide amines 9 and diamine 5 where m is 1 are also readily prepared by methods known to or skilled person and are described in the literature. For example, as shown in Scheme 7, treatment of bromo derivative 21 with sodium cyanide gives nitrile 22. The nitro group is selectively reduced by treatment with hydrogen and catalytic palladium to give amine 23. Acylation of amine 23 with sulfonyl chloride 7 gives the corresponding sulfonamide 24. Compound 24 is reduced with cobalt chloride and sodium borohydride to give the desired amine 25.

Alternatively, X is -CH ₂ CH ₂ - and are diamine 5 m is 1, can be obtained from intermediate 23 by reduction, for example, cobalt chloride and sodium borohydride by the nitrile group. The diamine can then be modified as shown in Scheme 3.

Intermediates II and III can be used as shown in Scheme 8 as a solution in a polar solvent such as methanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide or N-methylpyrrolidinone, or neat,
Coupling is achieved by heating at a temperature of 150150 ° C. for 1 to 24 hours. The reaction is conveniently performed under methanol reflux. Also, salts of amine III such as trifluoroacetate or hydrochloride can be used. In these cases, a base such as sodium bicarbonate or diethylisopropylamine is added to the reaction mixture. The product
Recrystallization, trituration, preparative thin-layer chromatography, WCStill et al., J. Org. Chem, 43, 2923.
Purify from unwanted by-products by flash chromatography on silica gel, medium speed liquid chromatography or HPLC as described in (1978). Compounds purified by HPLC can be isolated as the corresponding salt. Purification of the intermediate is performed by the same method.

In some cases, the coupling product I from the reaction described in Scheme 8 is further modified, for example, by removing protecting groups or specifically treating substituents on R ¹ and R ^7. Can be. These treatments include, but are not limited to, reduction, oxidation, alkylation, acylation and hydrolysis reactions commonly known to those skilled in the art.

Another method for synthesizing Compound I is described in Scheme 9. Coupling of epoxide II to amine 5 as described above for the coupling of intermediates II and III (Scheme 8) gives the aniline derivative 27.
The secondary amine is selectively protected as a carbamate by treatment with, for example, di-tert-butyl dicarbonate to give carbamate 29. When nitroamine 26 is used in the coupling reaction, 28 is obtained. Following the aforementioned protection, the nitro group is reduced to give intermediate 29, for example by catalytic hydrogenation with a palladium catalyst or Raney nickel. In some cases, other groups can be reduced at the same time. For example, if R ¹ is a halogen in intermediate 28, it can be converted to hydrogen in intermediate 29. Treatment of the sulfonamide I by treatment with a sulfonyl chloride in the presence of a base such as pyridine followed by removal of the protecting group in the case of tert-butyl carbamate with an acid such as trifluoroacetic acid or methanolic hydrogen chloride. obtain.

In some cases, Compound I from the reaction pathway shown in Scheme 9 can be used, for example, by removing protecting groups as described above, or in particular by treating substituents on R ¹ and R ^7. Can be further modified. In addition, substituents on any of the intermediates in the reaction pathway shown in Scheme 9 can be treated. One such example is shown in Scheme 10. Compound 30 prepared as outlined in Scheme 9 from the corresponding epoxide is reduced with tin (II) chloride to give compound 31. Other examples of substituents on compound I that can be reduced to the corresponding amine by methods generally known to those skilled in the art include nitro groups, nitriles and azides.

Compound (I) of the present invention can also be prepared from an amine intermediate, such as the intermediate of Formula III, and a haloketone intermediate, such as the intermediate of Formula 2, as shown in Scheme 11. The amine III is alkylated with the haloketone derivative 2 by conveniently treating the mixture of III and 2 with a base such as potassium carbonate or trimethylamine in a polar solvent such as acetonitrile, acetone or dimethylformamide. The resulting aminoketone 32 is reduced with, for example, sodium borohydride in methanol to give the desired amino alcohol I.

In some cases, the product I from the reactions described in Scheme 11 is further modified, for example, by removing protecting groups or, in particular, by treating substituents on R ¹ and R ^7. can do. These treatments include, but are not limited to, reduction, oxidation, alkylation, acylation and hydrolysis reactions commonly known to those skilled in the art.

Another synthesis of key intermediate 29 is shown in Scheme 12. The alcohol of Intermediate 3 can be protected, for example, as its t-butyldimethylsilyl ether to give the TBS derivative 3
Give 3 The compound is then converted to a solvent, typically
In polar solvents such as acetonitrile, 25-150
Treat with amine 5 and a base such as diisopropylamine at a temperature of <RTIgt; Typically, an iodide source such as sodium iodide is added to facilitate the reaction. Next, when the protecting group is a silyl ether,
The resulting amine 34 is removed by treatment with a fluoride source such as tetrabutylammonium fluoride. Protection of the secondary amine as described above provides the key intermediate 29.

In some cases, compound I can be synthesized directly from intermediate 27 without protecting the secondary amine. For example, when both R ² and R ³ are methyl, the aniline derivative
Treatment of 27 with a sulfonyl chloride 7 and a base such as pyridine in a solvent such as dichloromethane at a temperature of -30 to 50 ° C, typically 0 ° C, gives compound I.

In some cases, the product I from the reaction described in Scheme 13 is treated, for example, by removing protecting groups as described above or in particular treating substituents on R ¹ and R ^7. Can further be modified.

Compounds (I) of the present invention wherein R ² and R ³ are hydrogen can also be prepared from an acid intermediate of formula 36 and an amino alcohol of formula 37, as shown in Scheme 14. acid
36 is obtained from the corresponding ester 35, typically a methyl or ethyl ester, by treatment with sulfonyl chloride 7 and a base such as pyridine, and hydrolyzing the ester with an aqueous acid or base solution. Acid 36 is benzotriazolyl-N-oxytris (dimethylamino) phosphonium hexafluorophosphate or 1
Using a coupling agent such as-(3-dimethylaminopropyl) -3-ethylcarbodiimide methiodide to the amine 37 known in the literature or readily prepared by methods known to those skilled in the art. Coupling gives amide 38. This is treated with a reducing agent, typically borane, to provide the desired compound I.

The compound represented by the general formula I is, for example, a suitable solvent,
For example, it can be separated into diastereomeric pairs of enantiomers by fractional crystallization from methanol or ethyl acetate or a mixture thereof. The enantiomeric pairs thus obtained can be separated into individual stereoisomers by conventional means, for example by using an optically active acid as a resolving agent.

Also, any enantiomer of the compound of general formula I can be obtained by stereospecific synthesis using optically pure starting materials of known structure.

The compounds of the present invention can be isolated in the form of pharmaceutically acceptable acid addition salts, such as those derived with inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, and the like.
In addition, compounds containing an acid function, such as carboxy or tetrazole, can be used with sodium, potassium,
It can be isolated from lithium, calcium, magnesium and the like as an inorganic salt which can also be selected from organic bases.

As already indicated, the compounds according to the invention have effective pharmacological properties.

The present invention provides a compound of general formula I for use as an active therapeutic substance.
Or a pharmaceutically acceptable salt thereof.

The present invention provides a compound of general formula I or a pharmaceutically acceptable ester or salt thereof for use in treating obesity in a human or non-human animal.

The present invention further provides a compound of general formula I or a pharmaceutically acceptable ester or salt thereof for use in treating hyperglycemia (diabetes) in humans or non-human animals.

Diabetes cannot maintain adequate blood sugar levels.
It is characterized by metabolic defects in glucose production and utilization. These deficiencies result in elevated blood glucose or hyperglycemia. Research on the treatment of diabetes
It focuses on fasting and attempts to normalize postprandial blood glucose. Treatment is parenteral administration of exogenous insulin, oral administration of drugs and diet.

Currently, two major types of diabetes are recognized.
Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone that controls glucose utilization. Type II diabetes, or non-insulin-dependent diabetes, often occurs when insulin levels are normal or elevated, and may be the result of tissue becoming inadequately responsive to insulin. Most Type II diabetics are also obese.

In addition, the compounds of the present invention lower triglyceride and cholesterol levels and increase high density lipoprotein levels, and thus may be useful in resolving conditions in which such reduction (and increase) may be effective. Useful. That is, the compounds of the present invention are useful for treating atherosclerosis, cardiovascular disease and related diseases of the coronary, cerebrovascular and peripheral arteries, as well as for hyperglyceridemia, hypercholesterolemia and low HDL (high density lipoprotein ) Values can be used in the treatment of symptoms.

Accordingly, the present invention reduces triglyceride and / or cholesterol levels comprising administering to a animal in need thereof a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. And / or increasing high density lipoprotein levels. The invention further comprises administering to a animal in need of treatment for atherosclerosis a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. To provide a method of treating. The compositions are formulated and administered according to the same general methods as detailed below for the treatment of diabetes and obesity. They are other active ingredients known to be used to treat atherosclerosis and related conditions, e.g. fibrates such as clofibrate, bezafibrate and gemfibrozil; HMG
-Inhibitors of cholesterol biosynthesis, such as inhibitors of CoA reductase, such as lovastatin, simvastatin and pravastatin; inhibitors of cholesterol absorption, such as beta-sitosterol and (acyl-CoA: cholesterol acyltransferase) inhibitors, such as melinamide; Exchange resins such as cholestyramine, colestipol (co
lestipol) or dialkylaminoalkyl derivatives of cross-linked dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimectis (thyr
omimetics).

The compounds of the present invention also have the effect of reducing intestinal motility and are useful in assisting in the treatment of various gastrointestinal diseases such as irritable bowel syndrome. Controlling the movement of the non-conclusion about smooth muscle contraction by activity in beta ₃ adrenergic receptors have been proposed. The usefulness of beta ₁ and is only active in the beta ₂ receptor beta ₃ Specificity agent,
Aids pharmacological control of intestinal motility without affecting the cardiovascular system at the same time. The compounds of the invention are usually administered in the same dosages as used for the treatment of diabetes and obesity, as described below.

Unexpectedly, (including that induced by H. pylori) compounds acting as an agent in the beta ₃ adrenergic receptor gastrointestinal diseases, particularly digestive system ulcer, esophagitis, gastritis and duodenitis, intestinal ulcerations (inflammatory (Including bowel disease, ulcerative colitis, Crohn's disease and proctitis), and gastrointestinal ulcers.

Additionally, beta ₃ adrenergic receptors were shown to be effective in suppressing the release of sensory fibers neuropeptide with the lungs. Because sensory nerves may play an important role in neurogenic inflammation of airways, including cough, the specificity beta ₃ agonists, along with the effect of minimal to cardiorespiratory, neurogenic inflammation, such as asthma It may be useful in therapy.

beta ₃ adrenergic receptors, can also cause selective antidepressant effects by stimulating the beta ₃ receptor in the brain, therefore, a further use of the compounds of the present invention is an antidepressant.

The active compounds of the present invention can be administered orally as a pharmaceutical composition, e.g., with an inert diluent or with an assimilable edible carrier, or packed into hard or soft shell capsules, or compressed into tablets, Alternatively, it can be incorporated directly into the food of the meal. For oral therapeutic administration, including sublingual administration, these active compounds can be incorporated into excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of active compound in these compositions can, of course, be varied,
Conveniently between about 2% and 60% by weight. The amount of active compound in the composition useful in the treatment is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as drops or sprays.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.

When treating diabetes and / or hyperglycemia,
The daily dose of the compound of the present invention is 1 k
Preferred results are obtained when administered from about 0.1 milligram to about 100 milligrams per gram, preferably in 2-6 divided doses per day or in sustained release form. For most large mammals, the total daily dose is from about 1.0 milligram to about 10,000 milligrams, preferably from about 1 milligram to about 50 milligrams. For a 70 kg adult human, the total daily dose will usually be from about 7 milligrams to about 350 milligrams. This dosage rule can be adjusted to give the best therapeutic response.

When obesity is treated with or without diabetes and / or hyperglycemia, the compounds of the present invention will generally be administered in an amount of from 1 milligram to about 1000 milligrams per kilogram of animal body weight per day, preferably 2 to 6 times per day. Satisfactory results are obtained when administered separately or in a sustained release form.
For most large mammals, the total daily dosage is from about 10 milligrams to about 1000 milligrams, preferably about 10 milligrams.
10 milligrams to about 500 milligrams. For a 70 kg adult human, the total daily dose will usually be from about 70 mg to about 35 mg.
00 milligrams. This dosage regime can be adjusted to provide the best therapeutic response.

Tablets, pills, capsules and the like include binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate;
Lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin may also be included. When the dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present to modify the physical form of the dosage unit or as a coating. 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 propylparapenes as preservatives, a dye and a flavoring such as cherry or orange flavor.

These active compounds may be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Suspensions can also be prepared with glycerin, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile powders and sterile aqueous solutions or dispersions for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerin, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Example 1 (R) -N- [2- [4- (aminophenyl)] ethyl] -2-hydroxy-2- (tetrazolo [1,5-a]
Pyrid-6-yl) ethylamine (R) -2- (tetrazolo [1,5-a] pyrid-6-
Yl) oxirane (see Fisher and Wyvratt European Patent Application 0 318 092 A2 for the synthesis of this compound)
mol) and 2- (4-aminophenyl) ethylamine
A solution of 4.1 g (30 mmol) in 30 ml of methanol was heated to reflux for 5 hours. The reaction mixture was concentrated and the residue was chromatographed on silica gel (2% methanol / 98% methylene chloride) to give 1.69 g (56%) of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.01 (d, 1H, J = 1.3 Hz),
8.02 (d, 1H, J = 9.2Hz), 7.82 (dd, 1H, J = 1.3,9.2Hz),
6.94 (d, 2H, J = 6.3Hz), 6.63 (d, 2H, J = 6.3Hz), 4.91
(M, 1H), 2.82 (m, 4H), 2.67 (t, 2H, J = 7.1 Hz).

Example 2 (R) -N- [2- [4- (aminophenyl)] ethyl] -2-hydroxy-2- (tetrazolo [1,5-a]
Pyrid-6-yl) ethylcarbamic acid 1,1-dimethylethyl ester 1.69 g (56.7 mmol) of the amine from Example 1 and di-
A solution of 1.23 g (56.7 mmol) of tert-butyl dicarbonate in 10 ml of tetrahydrofuran (THF) was stirred at 0 ° C. for 2 hours. The reaction mixture was concentrated and the residue was chromatographed on silica gel (4% methanol / 96% methylene chloride) to give 2.2 g (97%) of the title compound. ¹ H NMR (400 MHz, CD3OD) δ 8.96 (s, 1 H), 8.05 (m, 2
H), 7.85 (m, 2H), 6.93 (dd, 2H, J = 7.7, 8.3Hz), 6.66
(D, 2H, J = 8.3Hz), 4.99 (m, 1H), 3.49 (m, 4H), 2.70
(T, 2H, J = 6.5Hz), 1.26 (s, 9H).

Example 3 4- (hexylaminocarbonylamino) benzenesulfonyl chloride 10 ml (9.2 mmol) of phenyl isocyanate in THF (150 m
l) at 0 ° C. to the solution in 12.15 ml (9.2 mmo) of hexylamine.
l) was added dropwise and stirred for 1 hour. The solvent was removed under reduced pressure and the resulting hexylphenyl urea was used without further purification.

6 g (2.7 mmol) were added to chlorosulfonic acid at 0 ° C. over 20 minutes, followed by heating at 60 ° C. for 2 hours. After cooling, the mixture was added to ice / water (100 ml) and the aqueous phase was extracted with EtOAc (3 × 100 m
Extracted in l). The combined organic phases were washed with brine (50 ml), dried over MgSO ₄ , concentrated and purified by flash chromatography (silica gel, 75% hexane / 25% ethyl acetate) to give 6 g (70%) of the title compound. . ¹ H NMR (CDCl ₃ ) δ 7.85 (d, 2H, J = 9.6 Hz), 7.54 (d, 2
H, J = 9.6Hz), 6.79 (br.s, 1H), 4.71 (br.s, 1H), 3.23
(T, 2H, J = 8Hz), 1.54 ~ 1.44 (m, 2H), 1.33 ~ 1.20 (m, 6
H), 0.91-0.79 (m, 3H).

Example 4 (R) -N- [4- [2-N- (1,1-dimethylethoxycarbonyl) -N- [2-hydroxy-2- (tetrazolo [1,5-a] pyrid-6-yl) ethyl] amino]
Ethyl] phenyl] -4- (hexylaminocarbonylamino) benzenesulfonamide A solution of 0.200 g (0.502 mmol) of the Boc-compound from Example 2 in 3 mL of methylene chloride was stirred with 80 mg of pyridine (1.00 m
mol), followed by the sulfonyl chloride from Example 3.
0.16 g (0.75 mmol) was added. After stirring for 5 hours, the reaction mixture was concentrated and the residue was chromatographed on silica gel (10% methanol / 90% methylene chloride) to give 0.303 g (88%) of the title compound. ¹ H NMR (400 Hz, CD ₃ OD) δ 8.95 (s, 1 H), 8.0 to 8.08 (m,
1H), 7.75 to 7.87 (m, 1H), 7.40 to 7.62 (m, 4H), 7.00
(M, 4H), 4.95 (m, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 2.
75 (m, 2H), 1.52 (t, 2H, J = 6.0Hz), 1.33 (m, 8H), 1.21
(S, 9H), 0.90 (t, 3H, J = 6.0Hz).

Example 5 (R) -N- [4- [2-[[2-hydroxy-2-
(6-aminopyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- (hexylaminocarbonylamino) benzenesulfonamide 0.302 g (0.44 mmol) of tetrazine from Example 4, tin (II) chloride dihydrate 0.20 g (0.88 mmol) of the hydrate and 0.3 ml of concentrated hydrochloric acid
Of methanol in 2 ml of methanol was heated to reflux for 5 hours. The reaction mixture was concentrated, and reversed-phase MPLC (C8, 47% methanol / 53 0.
Purified with 1% trifluoroacetic acid buffer) to give the title compound 0.3
2 g (78%) were obtained as its bistrifluoroacetate. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.96 (dd, 1 H, J = 2.0, 9.2 H
z), 7.86 (d, 1H, J = 2.0 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.
43 (d, 2H, J = 8.8 Hz), 7.14 (d, 2H, J = 8.4 Hz), 7.07 (d,
2H, J = 8.4Hz), 7.03 (d, 1H, J = 9.2Hz), 4.92 (m, 1H),
3.23 (m, 2H), 3.15 (m, 2H), 2.93 (m, 2H, 4.0 Hz), 1.49
(T, 2H, J = 6.0Hz), 1.32 (m, 8H), 0.91 (t, 3H, J = 6.0H)
z); CI MS m / z 555 (M + 1).

Following the procedures outlined in Examples 1-5, the compounds listed in Table 1 were prepared.

Example 14 3- (2 Chloroacetyl) pyridine hydrochloride To a solution of 12 g (11 ml, 100 mmol) of 3-acetylpyridine in 100 ml of ethyl ether was added 100 ml of 1M ethereal hydrogen chloride. The resulting precipitate was filtered and 15.0 g (95.2 mmo
l) was collected and charged to a 500 ml round bottom flask equipped with a magnetic stir bar. To this was added 95 ml of 1M hydrogen chloride in acetic acid. After stirring the mixture until all solids were dissolved, 12.7 g (95.2 mmol) of N-chlorosuccinimide (NCS) was added in one portion. The solution turned yellow and the NCS gradually dissolved.
After 4 hours, a white precipitate had formed. The mixture was stirred for 2.5 days. Then the mixture was filtered. Acetic acid collected solid
Wash with 10 ml and 200 ml of ethyl ether to wash the title compound 15.
2 g (83%) were obtained as a white solid. ¹ H NMR (200 MHz, d ₆ -DMSO) δ 9.22 (t, 1 H, J = 1 Hz), 8.
29 (dd, 1H, J = 1.6,5.1Hz), 8.55 (td, 1H, J = 2,8.1Hz),
7.82 (ddd, 1H, J = 0.8, 5.1, 8.1 Hz), 5.27 (s, 2H).

Example 15 A solution of 3.67 g (11.5 mmol) of (R) -α-chloromethyl-3-pyridinemethanol (-)-B-chlorodiisopinocamphenylborane [(−)-DIP-Cl] in 11 ml of THF was stirred under stirring. At −25 ° C., 1.00 g of the product from Example 14.
A slurry of (5.21 mmol) in 5 ml of THF was added via cannula. After addition of 0.80 ml (5.79 mmol) of triethylamine, the reaction mixture was stirred at −25 ° C. for 4 days. To this mixture was added 10 ml of water, which was allowed to warm to room temperature. 20 ml of ethyl acetate were added to the mixture and the organic phase was separated. The aqueous phase was neutralized with saturated NaHCO ₃ solution and then extracted six times with ethyl acetate. The combined organic phases were concentrated under reduced pressure to give a yellow oil. Flash chromatography (silica gel, 75%
-100% ethyl acetate-hexane) to give the title compound (561 mg, 68%) as a pale-yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.58 (d, 1 H, J = 1.8 Hz), 8.4
6 (dd, 1H, J = 4.9, 1.5Hz), 7.90 (d, 1H, J = 7.9Hz), 7.44
(Dd, 1H, J = 7.9,4.9Hz), 4.93 (m, 1H), 3.75 (m, 2H).

Example 16 (R)-(Pyrid-3-yl) oxirane 557 mg (3.55 mmol) of the product from Example 15 in acetone 1
To the solution in 6 ml was added 1.80 g of potassium carbonate. The mixture
Heated to reflux for 20 hours, then cooled to room temperature, the mixture was filtered and the filtrate was evaporated under reduced pressure. Purification by flash chromatography (silica gel, 2% methanol-methylene chloride) gave 262 mg (61%) of the title compound as a pale yellow oil. ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.54 (m, 2H), 7.52 (m, 1
H), 7.24 (m, 1H), 3.86 (dd, 1H, J = 4.0, 2.5 Hz), 3.17
(Dd, 1H, J = 5.4,4.0Hz), 2.80 (dd, 1H, J = 5.4,2.5H
z).

Example 17 (R) -N- [2- [4- (aminophenyl) ethyl]
2-hydroxy-2- (pyrid-3-yl) ethylamine In a solution of 377 mg (2.44 mmol) of 4-aminophenethylamine in 10 ml of methanol, 300 mg of the product from Example 16
A solution of (2.48 mmol) in 15 ml of methanol was added. The mixture was heated at reflux for 16 hours, then cooled to room temperature. The methanol was removed under reduced pressure and the residue was purified by chromatography (silica gel, 6-8% methanol, 1% ammonia-methylene chloride) to give 279 mg of a mixture with 101 mg (16%) of the title compound, which was again chromatographed. Chromatography (5% methanol, 1% ammonia-methylene chloride) gave an additional 54 mg (9%) of the title compound as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.52 (d, 1 H, J = 1.8 Hz), 8.4
3 (dd, 1H, J = 4.8,1.4Hz), 7.81 (m, 1H), 7.40 (m, 1H),
6.95 (d, 2H, J = 8.3Hz), 6.67 (d, 2H, J = 8.3Hz), 4.81
(M, 1H), 2.90 to 2.65 (m, 6H).

Example 18 (R) -N- [2- [4- (aminophenyl) ethyl]
-2-Hydroxy-2- (pyrid-3-yl) ethylcarbamic acid 1,1-dimethylethyl ester 386 mg (1.77 mmol) of di-tert-butyl dicarbonate
Of 3.5 g of THF from 3.5 ml of the product from Example 17 (1.7 mg).
To a slurry of (7 mmol) in 3.6 ml THF cooled to 0 ° C. was added via cannula under stirring. The yellow solution was stirred at 0 ° C. for 3 hours, then the THF was removed under reduced pressure.
Purification by flash chromatography (silica gel, 10% methanol, 1% ammonia-methylene chloride) gave 549 mg (87%) of the title compound as a whitish solid. ¹ H NMR (500 MHz, CD ₃ OD, mixture of rotamers) δ8.45 (m,
2H), 7.83 (d, 0.6H, J = 7.4Hz), 7.78 (d, 0.4H, J = 6.9H
z), 7.41 (m, 1H), 6.94 (d, 0.8H, J = 8.0Hz), 6.89 (d,
1.2H, J = 7.8Hz), 6.66 (d, 2H, J = 7.3Hz), 4.89 (m, 1
H), 3.41 to 3.21 (m, 4H), 2.67 (m, 2H), 1.39 (s, 5.4
H), 1.36 (s, 3.6H).

Alternative methods for synthesizing the aniline derivative in Example 18 are described in Examples 19-23.

Example 19 2-Chloro-5- (2-bromoacetyl) pyridine hydrochloride A solution of 784 mg of 2-chloro-5-acetylpyridine in 10 ml of THF is treated with 1.44 g of dibromobarbituric acid (DBBA) in 10 ml of THF.
The medium solution was added via cannula. The resulting solution
Heated at 50-55 ° C for 12 hours, then added a further 0.72 g of DBBA. After stirring at 50-55 ° C for 2.5 hours or more, 0.36 g of DBBA was added. The mixture was stirred for 2 hours, at which point a portion was
Analysis by NMR showed 87% conversion. The reaction mixture was cooled, diluted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, with water and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate / hexane) provided 0.86 g (73%) of the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.96 (d, 1 H, J = 2.6 Hz), 8.2
1 (dd, 1H, J = 2.5,8.3Hz), 7.46 (d, 1H, J = 8.4Hz), 4.37
(S, 2H). NMR also indicated the presence of the corresponding 2-bromo derivative. During the synthesis, a 44: 1 mixture was used.

Example 20 (R) -α-bromomethyl-3- (6-chloropyridine) methanol To a solution of 602 mg (1.88 mmol) of (−)-DIP-Cl in 0.5 ml of THF at −25 ° C., 200 mg of the ketone from Example 19. THF1.5m
The solution in I was added via cannula at -25 ° C. The reaction mixture was stirred at -25 C for 17 hours. Next, the reaction mixture was quenched by the addition of water and extracted with ether. The ether phase was diluted with ethyl acetate, washed twice with a saturated aqueous sodium bicarbonate solution, with water and brine, dried over magnesium sulfate and concentrated. Flash chromatography (silica gel, 15% and 25% ethyl acetate / hexane)
To give 170 mg (84%) of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, 1H), 7.70 (dd, 1
H), 7.32 (d, 1H), 4.97 (m, 1H), 3.61 (dd, 1H), 3.50
(Dd, 1H), 2.85 (d, 1H).

Example 21 (R)-(2-chloropyrid-5-yl) oxirane 100 mg of bromoalcohol from Example 20 in 1: 1 THF: water
To the solution in 2 ml was added 1 ml of a 5N aqueous sodium hydroxide solution. The mixture was stirred for 10 minutes. It was then extracted three times with dichloromethane. The combined organic phases were washed twice with water and with brine, dried over magnesium sulfate and concentrated to give 98 mg (93%) of the title compound, which was used without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, 1H), 7.48 (dd, 1
H), 7.29 (d, 1H), 3.86 (dd, 1H), 3.18 (dd, 1H), 2.78
(Dd, 1H).

Example 22 (R) -N- [2- [4- (nitrophenyl) ethyl]
2-Hydroxy-2- (2-chloropyrid-5-yl) ethylcarbamic acid 1,1-dimethylethyl ester Example 21 according to the procedure outlined in Examples 17 and 18.
The title compound was prepared from epoxide from and 4-nitrophenylethylamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (d, 1 H, J = 1.3 Hz), 8.1
3 (d, 2H, J = 8.6 Hz), 7.66 (br m, 1H), 7.30 (d, 2H, J =
8.1Hz), 7.27 (br m, 1H), 4.94 (br m), 3.38 (br
m, 4H), 2.84 (br m, 2H), 1.40 (s, 9H).

Example 23 (R) -N- [2- [4- (aminophenyl) ethyl]
-2-Hydroxy-2- (pyrid-3-yl) ethylcarbamic acid 1,1-dimethylethyl ester To a solution of 80 mg (0.19 mmol) of the nitro compound from Example 22 in 2 ml of ethanol, 0.114 ml of 5N aqueous sodium hydroxide solution
(0.57 mmol) and 20 mg of Raney nickel were added. The reaction mixture was shaken at room temperature under a hydrogen pressure of 45 psi for 16 hours.
The mixture was neutralized with a saturated aqueous solution of monobasic sodium phosphate and extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried (magnesium sulfate), concentrated and 40 mg (59%) of the same title compound as the sample purified in Example 18.
%).

Example 24 4- (3-Hexyl-2-imidazolone-1-yl) phenylsulfonyl chloride Hexyl iodide (50 mmol, 7.38 ml) was prepared by adding 2-aminoacetaldehyde methyl acetal (100 mmol, 11 ml) and potassium carbonate (50 mmol, 6.9 g). The mixture in DMF (10 ml) was added at 0 ° C. After stirring for 16 hours, it was diluted with ethyl acetate (200 ml) and the solution was filtered through a plug of celite. After concentrating under reduced pressure, N-hexyl 2- was purified by column chromatography (eluent: ethyl acetate).
Aminoacetaldehyde methyl acetal (7.39 g, 78
%) As a colorless oil.

To a solution of the amine (38.6 mmol, 7.3 g) in methylene chloride (100 ml) at 0 ° C. was added 4- (chlorosulfonyl) phenyl isocyanate (38.6 mmol, 8.4 g). The reaction mixture was stirred for 20 minutes until a clear solution formed, 1: 1
Water: trifluoroacetic acid (100 ml total) was added. Stir vigorously for 16 hours, separate the layers and separate the organic layer with ethyl acetate (50
0ml) and saturated sodium bicarbonate solution (4x50m
l), washed with brine (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The title compound was obtained as pale yellow crystals (8.8 g, 67%) by column chromatography (eluent: 3 hexane / 1 ethyl acetate).

Example 25 (R) -N- [4- [2-[[2-hydroxy-2-
(Pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- (hexylaminocarbonylamino) benzenesulfonamide 302 mg (0.845 mmol) of the product from Example 18 and 137 ml (1.69 mmol) of pyridine in 10 ml of methylene chloride. In the medium solution,
296 mg (0.928 mmol) of 4- (hexylaminocarbonylamino) benzenesulfonyl chloride from Example 3
Was added. The reaction was stirred for 12 hours, then the solvent was removed under reduced pressure. Purification by flash chromatography (silica gel, 6% methanol, 0.5% ammonia-methylene chloride) gave 468 mg (87%) of the BOC-protected title compound.

A solution of 468 mg (0.731 mmol) of the BOC-protected title compound in 5 ml of methylene chloride and 5 ml of trifluoroacetic acid was stirred for 30 minutes, then the volatile components were removed under reduced pressure. The residue was azeotroped twice with 10% methanol / toluene and twice with methanol, then dried under reduced pressure to give 521 mg (93%) of the title compound as its trifluoroacetate salt. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.88 (s, 1H), 8.79 (d, 1H, J
= 5.5Hz), 8.53 (d, 1H, J = 8.2Hz), 7.99 (m, 1H), 7.59
(Dd, 2H, J = 6.9,1.9Hz), 7.43 (dd, 2H, J = 6.9,1.9Hz),
7.15 (dd, 2H, J = 8.6,2.1Hz), 7.08 (dd, 2H, J = 8.6,2.1H
z), 5.23 (m, 1H), 3.40-3.10 (m, 6H), 2.94 (m, 2H),
1.49 (m, 2H), 1.32 (m, 6H), 0.90 (m, 2H).

Example 26 (N)-[4- [2-[(phenylmethoxycarbonyl) amino] ethyl] phenyl] -4-cyanobenzenesulfonamide According to the procedure outlined in Example 4, 2- (4-aminophenyl) ethylcarbamic acid Phenylmethyl ester (Fisher et al., European Patent Application 0 611)
003 A1, 1994) and 4-cyanobenzenesulfonyl chloride. ¹ H NMR (400 MHz, CD ₃ OD) δ ¹ H NMR (400 MHz, CDCl ₃ ) δ
7.81 (d, 2H, J = 8.7Hz), 7.69 (d, 2H, J = 8.7Hz), 7.32
(M, 5H), 7.06 (d, 2H, J = 8.4Hz), 6.96 (d, 2H, J = 8.4H
z), 6.75 (s, 1H), 5.06 (s, 2H), 4.71 (t, br, 1H), 3.38
(Q, 2H, J = 6.9Hz), 2.74 (t, 2H, J = 7.0Hz).

Example 27 (N)-[4- [2-[(phenylmethoxycarbonyl) amino] ethyl] phenyl] -4-aminooxymidomethyl) benzenesulfonamide The nitrile from Example 26 (2.71 g, 6.23 mmol), absolute ethanol ( 65 ml), the mixture was refluxed for 6 hours milled _{K 2 CO 3 (5.17g, 37.4mmol} ) and hydroxylamine hydrochloride (2.17g, 31.2mmol). The ethanol was removed under reduced pressure. The obtained solid was dissolved in ethyl acetate and washed three times with water. The organic phase was concentrated under reduced pressure to give 2.87 g of the title compound (98
%) As a white powder, which was pure enough to be used in subsequent steps. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.71 (s, 4H), 7.31 (m, 5
H), 7.04 (d, 2H, J = 8.4 Hz), 6.99 (d, 2H, J = 8.4 Hz), 5.
02 (s, 2H), 3.25 (t, 2H, J = 6.8 Hz), 2.67 (t, 2H, J = 6.7
Hz).

Example 28 (N)-[4- [2-[(phenylmethoxycarbonyl) amino] ethyl] phenyl] -4- [5- (3-cyclopentylpropyl)-[1,2,4] -oxadiazol-3-yl To a solution of the compound from Example 27 (0.468 g, 1.00 mmol) in dry pyridine (5.0 ml) was added 4-cyclopentylbutyryl chloride (0.175 g, 1.00 mmol). The mixture was refluxed for 3.5 hours. Pyridine was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (35% ethyl acetate in hexane) to give 0.152 g of the title compound.
(26%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, 2H, J = 8.7 Hz), 7.8
1 (d, 2H, J = 8.7Hz), 7.31 (m, 5H), 7.03 (d, 2H, J = 8.1H
z), 6.97 (d, 2H, J = 8.4 Hz), 6.67 (s, 1H), 5.05 (s, 2
H), 4.70 (t, br, 1H), 3.37 (q, 2H, J = 6.5Hz), 2.91 (t,
2H, J = 7.6Hz), 2.72 (t, 2H, J = 7.0Hz), 1.90-1.70 (m,
5H), 1.65 to 1.30 (m, 6H), 1.06 (m, 2H).

Example 29 N- [4- (2-aminoethyl) phenyl] -4- [5
-(3-Cyclopentylpropyl)-[1,2,4] -oxadiazol-3-yl] benzenesulfonamide Cb _z amine from Example 28 (0.145 g, 0.246 mmol), palladium hydroxide on carbon (0.02 g) and glacial acetic acid (5.0m
The mixture of l) was hydrogenated for 2 hours. Acetic acid was removed under reduced pressure. Silica gel chromatography of the residue (1: 9 10% ammonium hydroxide in methanol: methylene chloride)
To give 0.058 g (52%) of the title compound: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (d, 2 H, J = 8.6 Hz), 7.8
7 (d, 2H, J = 8.5Hz), 7.06 (d, 2H, J = 8.6Hz), 7.02 (d, 2
H, J = 8.7Hz), 2.97 (t, 2H, J = 7.5Hz), 2.84 (t, 2H, J =
6.9Hz), 2.67 (t, 2H, J = 7.5Hz), 1.90-1.75 (m, 5H),
1.70 to 1.40 (m, 6H), 1.12 (m, 2H).

Example 30 (R) -N- [4- [2-[[2-hydroxy-2-
(Pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [5- (3-cyclopentylpropyl)-
[1,2,4] -Oxadiazol-3-yl] benzenesulfonamide To a solution of the amine from Example 29 (0.053 g, 0.117 mmol) in dry methanol (30.0 ml) was added 3- Pyridine epoxide (0.021 g, 0.175 mmol) was added. The resulting solution was refluxed overnight. After concentration, the residue was purified by silica gel chromatography (13% methanol in methylene chloride) to give 0.01 g (15%) of the title compound: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (d, 1H, J = 1.9Hz), 8.4
2 (dd, 1H, J = 1.5,4.8Hz), 8.13 (d, 2H, J = 8.6Hz), 7.85
(M, 3H), 7.40 (dd, 1H, J = 4.8, 7.8Hz), 7.10 (d, 1H, J =
8.6Hz), 7.30 (d, 2H, J = 8.6Hz), 4.81 (dd, 1H, J = 4.9,
8.1Hz), 2.96 (t, 2H, J = 7.5Hz), 2.93 to 2.70 (m, 6H),
1.90 ~ 1.72 (m, 5H), 1.68 ~ 2.48 (m, 4H), 1.42 (m, 2
H), 1.11 (m, 2H).

Example 31 (R) -N- [4- [2-[[2-hydroxy-2-
(Pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- [4- (1-hydroxy-1-hexylheptyl) -5-methyl- [1,2,3] -triazole-2
-Yl] benzenesulfonamide and (R) -N-
[4- [2-[[2-hydroxy-2- (pyridine-3)
-Yl) ethyl] amino] ethyl] phenyl] -4-
[4- (1- (R, S) -hydroxyheptyl) -5-methyl- [1,2,3] -triazol-2-yl] benzenesulfonamide (R) -N- [4- [2- [ [2-hydroxy-2-
(Pyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- (4-methoxycarbonyl-5-methyl-
[1,2,3] -Triazol-2-yl) benzenesulfonamide (prepared according to the procedure outlined in Examples 14 to 19) in a solution of 180 mg in 2 ml of distilled THF under an atmosphere of argon
At 0 ° C., 2 ml of a 2.0 M solution of n-hexylmagnesium bromide in ether was added dropwise. After 5 minutes, the reaction was quenched by the careful addition of 5 ml of aqueous ammonium chloride solution, followed by extraction of the aqueous layer with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. Two bands A (20m2) were obtained by preparative chromatography on a 2 x 0.5mm silica gel plate, eluting with 9: 1 (v / v) dichloromethane: methanol.
g) and B (60 mg) were obtained.

¹ H NMR of A (500 MHz, CD ₃ OD): δ 8.51 (d, 1 H, J = 2 H
z), 8.41 (dd, 1H, J = 1.5, 5 Hz), 8.01 (dd, 2H, J = 2.5, 6.
5Hz), 7.81 (m, 1H), 7.78 (dd, 2H, J = 2.0, 9.0Hz), 7.37
(M, 1H), 7.07; 7.02 (ABq, 4H, Jab = 8.5Hz), 4.86 (s, CD
₃ OH), 4.79 (dd, 1H, J = 7.5, 8 Hz), 2.9 to 2.7 (m, 6H), 2.
44 (s, 3H), 1.85 (m, 4H), 1.40 to 1.15 (m, 16H), 0.83
(T, 6H, J = 7Hz), indicating a dihexyl tertiary alcohol adduct. Mass spectrum: expected 677, measured 67
7.

¹ H NMR of B (500 MHz, CD ₃ OD): δ 8.51 (d, 1 H, J = 2 H
z), 8.41 (dd, 1H, J = 1.5,5Hz), 8.03 (d, 2H, J = 9Hz),
7.78 (d, 2H, J = 9Hz), 7.37 (dd, 1H, J = 4.8,7.7Hz), 7.0
7; 7.02 (ABq, 4H, Jab = 8Hz), 4.86 (s, CD 3 OH), 4.80 (m,
2H), 2.9-2.7 (m, 6H), 2.38 (s, 3H), 1.87 (m, 2H), 1.
44 (m, 1H), 1.4 ~ 1.2 (m, 7H), 0.87 (t, 3H, J = 7Hz),
This indicates a monohexyl adduct. Mass spectrum; expected 591 for hexyl ketone, found 593 (hexyl alcohol, intermediate ketone reduced in situ by Grignard reagent).

Following the procedures outlined in Examples 14-31, the compounds listed in Table 2 were prepared.

Starting from commercially available (R) -styrene epoxide, the compounds listed in Table 3 were prepared according to the procedures outlined in Examples 17, 18 and 25.

Example 93 (R) -N- [4- [2-[[2-hydroxy-2-
(Pyridin-3-yl) ethyl] amino] -2-methylpropyl] phenyl] -4- (3-hexyl-2-imidazolidinone-1-yl) benzenesulfonamide Pyridine epoxide from Example 16 (160 mg, 1.32mmo
l) and a solution of 4-amino-a, a-dimethylphenethylamine (1.2 g, 7.3 mmol) in methanol (8 ml) prepared according to J. Biol. Chem. Was. After cooling, the reaction mixture was concentrated and flash chromatographed (silica gel, 95: 5 CH ₂ Cl ₂ : 10
% NH ₄ OH / CH ₃ OH) to give 23 g (0.080 mmol) of product.
l) was obtained as an oil.

The product (18 mg, 0.063 mmol) was dissolved in CH ₂ Cl ₂ (1ml) and pyridine (0.05 ml). 0 ° C.
And cooled to 4- (3-hexyl-2-imidazolidinone-1-yl) benzenesulfonyl chloride (22 mg, 0.0
63 mmol). The mixture was stirred at 0 ° C. for 20 hours, then flash chromatography (silica gel, 95: 5 C
_{H 2 Cl 2: 10% NH} 4 OH / CH 3 OH) desired product was purified by (21 mg, 0.035 mmol) as an oil. ¹ H NMR (CD ₃ OD) δ 8.53 (s, 1 H), 8.44 (d, 1 H, J = 5.0 H
z), 7.83 (d, 1H, J = 7.9 Hz), 7.63 (m, 4H), 7.40 (dd, 1
H, J = 5.0, 7.9), 6.98 (m, 4H), 4.72 (dd, 1H, J = 4.0, 8.
4), 3.80 (m, 2H), 3.49 (m, 2H), 3.22 (t, 2H, J = 7.2),
2.78 (m, 2H), 2.62 (m, 2H), 1.55 (m, 2H), 1.31 (m, 6
H), 1.01 (s, 3H), 0.99 (s, 3H), 0.89 (m, 3H).

The compounds listed in Table 4 were prepared according to the general procedure described above.

Example 96 (R) -4-amino-α- (bromomethyl) -3,5-dichlorobenzenemethanol, dimethyl-1,1-dimethylethylsilyl ether t-butyldimethylsilyl chloride (1.67 g, 11.1 mm
ol) in DMF (15 ml) was treated with (R) -4-amino-α
-(Bromomethyl) -3,5-dichlorobenzenemethanol (2.1 g, 7.4 mmol, see European Patent Application 0 460 924 to Judkins et al.) And imidazole (0.75 g,
To a solution of 11.1 mmol) in DMF (6 ml) was added slowly with stirring while cooling the ice-water bath. After stirring at room temperature for 3 hours, the reaction mixture was poured into water (300 ml) and the product was extracted with ether. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO ₄ ) and dried by evaporation. The crude product was purified on silica (95/5 hexane / ethyl acetate) to give the title compound (2.73 g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.14 (s, 2H), 4.67 (dd, 1H,
J = 2.1,6.4Hz), 3.33 (m, 2H), 0.87 (s, 9H), 0.89 (s, 6
H).

Example 97 (R) -N- [2- [4- (aminophenyl) ethyl]
-2-[(dimethyl-1,1-dimethylethylsilyl) oxy] -2- (4-amino-3,5-dichlorophenyl)
Ethylamine O-TBDMS bromo compound from Example 96 (2.73 g, 6.86 m
The mol) was dissolved in CH ₃ CN (50ml), was added 4-amino-phenethylamine (1.86g, 13.72mmol), followed by N, N'-diisopropylethylamine (3.58 ml, 20.6 mmol) and sodium iodide (1.03 g, 6.86 mmol) was added. 48
After heating at reflux for an hour, the reaction mixture was concentrated and the residue was chromatographed on silica (50/50 ethyl acetate / hexane) to give the title compound (2.3 g, 75%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.08 (s, 2H), 6.94 (AA ', 2
H, J = 8.4Hz), 6.60 (BB ', 2H, J = 8.4Hz), 4.63 (m, 1
H), 4.37 (s, 2H), 3.53 (br s, 2H), 2.87 ~ 2.60 (m, 6
H), 0.80 (s, 9H), -0.03 (s, 6H).

Example 98 (R) -N- [2- [4- (aminophenyl) ethyl]
-2-Hydroxy-2- (4-amino-3,5-dichlorophenyl) ethylamine THF of the silyl compound from Example 97 (2.2 g, 4.8 mmol)
(20 ml), tetrabutylammonium fluoride (10 ml of a 1.0 M THF solution) was added in one portion at room temperature with stirring. After stirring at room temperature for 2 hours, the reaction mixture was concentrated,
Chromatography on silica (10/90 CH ₃ OH / CH ₂ Cl
₂ ) to give the title compound (1.59 g, 97%): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.15 (s, 2H), 6.92 (AA ′, 2).
H, J = 8.3 Hz), 6.60 (BB ', 2H, J = 8.3 Hz), 4.58 (m, 1
H), 2.83-2.65 (m, 6H).

Example 99 (R) -N- [4- [2-[[2-hydroxy-2-
(4-Amino-3,5-dichlorophenyl) ethyl] amino] ethyl] -phenyl] -4- (hexylaminocarbonylamino) benzenesulfonamide Following the procedure outlined in Examples 18 and 25,
The title compound was prepared from the aniline derivative from 98.

NMR (400 MHz, CD ₃ OD) 7.57 (AA ', 2H, J = 2.7 Hz), 7.42
(BB ', 2H, J = 2.7Hz), 7.16 (s, 2H), 7.04 (AA', 2H, J
= 2.0Hz), 7.00 (BB ', 2H, J = 2.0Hz), 4.58 (t, 1H, J =
7.1Hz), 3.14 (t, 1H, J = 7.0Hz), 2.80 (m, 2H), 2.73
(M, 4H), 1.49 (m, 2H), 1.32 (m, 6H), 0.90 (t, 3H, J =
6.7 Hz) .ESI MS m / z 622 (M).

Following the procedures outlined in Examples 96-99, the compounds listed in Table 5 were prepared.

Example 103 (R) -N- [4- [2-[[2-hydroxy-2-
(4-hydroxyphenyl) ethyl] amino] ethyl]
Phenyl] -benzenesulfonamide A solution of 5 g of 4-aminophenethyl alcohol in 50 ml of DMF was treated with t-butyldimethylsilyl chloride (TBDMS-C
l) Silylation with 5.5 g and imidazole 2.5 g overnight at room temperature. O-TBDMS ether 6.6 was obtained by extracting the product following treatment with aqueous ammonia chloride.
g was obtained. This aniline derivative was then coupled to benzenesulfonyl chloride in pyridine-dichloromethane to give the sulfonamide in over 80% yield after purification by chromatography. Sulfonamide TB
The DMS group was removed with methanolic HCl at room temperature for 30 minutes. The crude alcohol was oxidized in acetone with Jones reagent to give the corresponding carboxylic acid (30 minutes at room temperature, extraction with ethyl acetate).

180 mg of (R) -octopamine and the resulting 4-N-
To a solution of 300 mg of benzenesulfonamidophenylacetic acid in 7 ml of DMF was added 0.5 ml of triethylamine and 490 mg of benzotriazolyl-N-oxy-tris (dimethylamino) phosphonium hexafluorophosphate. The reaction mixture was stirred at room temperature for 2 hours and chromatographed on silica gel eluting with 95: 5 chloroform-methanol to give 322 mg of purified amide.

A solution of 220 mg of this amide in 13 ml of 1.0 M borane-THF was refluxed for 2 hours under an argon atmosphere, followed by addition of 3 ml of N, N-dimethylaminoethanol and reflux for another hour. The solvent and excess volatiles are removed under reduced pressure, the residual solid is taken up in acetone and purified by PLC on silica gel (9: 1 ethyl acetate: methanol) to give 61 mg of the title compound
I got ¹ H NMR (500 MHz, CD ₃ OD) δ 7.73 (dt, 2H, J = 2.1, 8.2H
z), 7.53 (tt, 1H, J = 1.4, 7.6Hz), 7.44 (t, 2H, J = 8H)
z), 7.18 (d, 2H, J = 8.4 Hz), 7.05 (ABq, 4H, Jab = 8.5H
z), 6.76 (d, 2H, J = 8.4Hz), 4.75 (dd, 1H, J = 7.5,7.6H
z), 3.05-2.90 (m, 4H), 2.81 (t, 2H, J = 7.6 Hz). Mass spectrum: calculated 412.5, found 413.2.

Example 104 (R) -N- [4- [2-[[2-hydroxy-2-
(4-hydroxyphenyl) ethyl] amino] ethyl]
Phenyl] -4-iodobenzenesulfonamide The title compound was prepared according to the procedure outlined in Example 103. ¹ H NMR (500 MHz, CD ₃ OD) δ 7.77 (d, 2H, J = 8.5 Hz), 7.4
3 (d, 2H, J = 8.5 Hz), 7.15 (d, 2H, J = 8.5 Hz), 7.02 (AB
q, 4H, Jab = 8.7Hz), 6.75 (d, 2H, J = 8.5Hz), 4.67 (dd, 1
H, J = 4.4, 6.6 Hz), 2.90 to 2.66 (m, 6H). Mass spectrum; calculated value 538.4, measured value 538.9.

Example 105 3- (2-bromoacetyl) benzonitrile To a solution of 1.02 g (7.04 mmol) of 3-acetylbenzonitrile in 70 ml of ethyl ether was added 1.02 g of dibromobarbituric acid.
g (3.52 mmol, 0.5 eq) was added. The mixture was stirred overnight at room temperature. The obtained white slurry was filtered and the filtrate was concentrated. Flash chromatography (silica gel, 20
Purification with ethyl acetate / hexane) gave 1.28 g (81%) of the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (t, 1 H, J = 1.4 Hz), 8.2
0 (td, 1H, J = 1.5, 8.0 Hz), 7.87 (dd, 1H, J = 1.3, 7.8H
z), 7.64 (t, 1H, J = 7.9 Hz), 4.40 (s, 2H).

Example 106 (R) -α-bromomethyl-3-cyanophenylmethanol (R) -tetrahydro-1-methyl-3,3-diphenyl-1H, 3H-pyrrolo [1,2c] [1,3,2] oxyazaborole -Borane (R-OAB catalyst) 181 mg (0.623 mmol) THF 6m
6.24 ml of a 1M solution of borane in THF (6.
24 mmol) was added dropwise. The resulting clear solution was stirred for 5 minutes and then 1.27 g of the bromoketone from Example 105 (5.67 mmol)
A solution of l) in 6 ml of THF was added slowly over 1 hour. After stirring the reaction solution for 30 minutes or more, it was quenched by dropwise addition of 6 ml of methanol and concentrated. Flash chromatography (silica gel, 20-25% ethyl acetate /
Purification with hexane gave 944 mg of the title compound (74 mg).
%) As a clear oil which crystallized. ¹ H NMR (400 MHz, CDCl ₃ ), δ 7.70 (d, 1 H, J = 1.5 Hz),
7.62−7.60 (m, 2H), 7.48 (t, 1H, J = 7.7Hz), 4.95 (dd,
1H, J = 3.4,8.4Hz), 3.63 (dd, 1H, J = 3.4Hz), 3.49 (dd,
1H, J = 8.4Hz).

Example 107 (R)-(3-cyanophenyl) oxirane To a solution of 937 mg (4.14 mmol) of bromohydrin from Example 106 in 8 ml of methanol was added 601 mg (4.35 mmol) of potassium carbonate.
1,1.05 equiv.). The reaction mixture was stirred at room temperature for 7 hours. It was then diluted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 20% ethyl acetate / hexane) provided 573 mg (95%) of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59-7.55 (m, 2H), 7.49
(Dd, 1H, J = 1.6,7.9Hz), 7.44 (t, 1H, J = 7.7Hz), 3.87
(Dd, 1H, J = 2.5,4.0Hz), 3.17 (dd, 1H, J = 4.1,5.5Hz),
2.74 (dd, 1H, J = 2.5,5.4Hz).

Example 108 (R) -N- [2- [4- (aminophenyl) ethyl]
-2-Hydroxy-2- (3-cyanophenyl) ethylcarbamic acid 1,1-dimethylethyl ester Following the procedures outlined in Examples 17 and 18,
The title compound was prepared from the epoxide from 107. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58-7.52 (br m, 3H), 7.
41 (t, 1H, J = 7.5 Hz), 6.89 (br d, 2H, J = 7.6 Hz), 6.65
(Br d, 2H, J = 7.8Hz), 4.82 (br dd, 1H, J = 2.7,7.9H
z), 3.42 to 3.05 (br m, 4H), 2.75 to 2.55 (br m, 2
H).

Example 109 (R) -N- [4- [2-[[2-hydroxy-2-
(3-Cyanophenyl) ethyl] amino] ethyl] phenyl] -4- (hexylaminocarbonylamino) benzenesulfonamide The title compound was prepared from the Boc aniline derivative from Example 108 according to the procedure outlined in Example 25. . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.70 (s, 1 H), 7.63-7.57
(M, 4H), 7.48 (t, 1H, J = 7.7Hz), 7.43 (d, 2H, J = 8.9H
z), 7.06 (d, 2H, J = 8.5 Hz), 6.99 (d, 2H, J = 8.5 Hz), 4.
77 (dd, 1H, J = 3.9, 8.5Hz), 3.15 (t, 2H, J = 7.0Hz), 2.8
6 ~ 2.69 (m, 6H), 1.49 (br m, 2H), 1.31 (br m, 6H),
0.90 (br t, 3H).

Example 110 (R) -N- [4- [2-[[2-hydroxy-2-
(3-Cyanophenyl) ethyl] amino] ethyl] phenyl] -3-quinoline sulfonamide The title compound was prepared from the Boc aniline derivative from Example 108 and 3-quinoline sulfonyl chloride according to the procedure outlined in Example 25. . ¹ H NMR (400 MHz, CD ₃ OD) δ 9.02 (d, 1 H, J = 2.3 Hz), 8.6
8 (d, 1H, J = 1.9Hz), 8.06 (d, 1H, J = 8.3Hz), 8.02 (d, 1
H, J = 7.9Hz), 7.90 (ddd, 1H, J = 1.4, 7.0, 8.4Hz), 7.72
7.69 (m, 2H), 7.62 to 7.58 (m, 2H), 7.47 (t, 1H, J = 7.
7Hz), 7.07 (d, 2H, J = 8.7Hz), 7.03 (d, 2H, J = 8.7Hz),
4.76 (dd, 1H, J = 4.0, 8.5 Hz), 2.85 to 2.68 (m, 6H).

Following the procedures outlined in Examples 14-31, the compounds listed in Table 6 were prepared.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/4406 A61K 31/4406 31/445 31/445 31/47 31/47 A61P 1/00 A61P 1/00 3/04 3 / 04 3/06 3/06 3/10 3/10 25/02 104 25/02 104 25/24 25/24 C07D 213/38 C07D 213/38 213/73 213/73 215/36 215/36 261 / 20 261/20 263/32 263/32 271/06 271/06 401/12 401/12 413/12 413/12 417/14 417/14 471/04 101 471/04 101 // C07M 7:00 (31 ) Priority number 404,566 (32) Priority date March 21, 1995 (March 21, 1995) (33) Priority country United States (US) (72) Inventor Naylor, Elizabeth M United States of America, New Jersey 07065, Lowway, East Linkane Avenue 126 (72) Inventor, Ok, Don, United States of America You Jersey 07065, Lowway, East Linkane Avenue avenue 126 (72) Inventor Weber, An E United States, New Jersey 07065, Lowway, East Linkane Avenue avenue 126 (72) Inventor See, Thomas, United States, New Jersey 07065, Lowway, East Linkane Avenue avenue 126 (72) Inventor Ok, Hyun Yun United States, New Jersey 07065, Lowway, East Linkane Avenue 126 (56) References JP-A-58-15941 (JP, A) JP-A-58-185554 (JP, A) JP-A-7-10827 (JP, A) (58) Fields investigated (Int. Cl. ⁷⁾ , DB name) C07C 311/00-409/44 A61K 31/18-31/655 C07D 201/00-521/00 CA (STN) REGISTRY (STN)

Claims (9)

(57) [Claims] 1. A compound of formula I or a pharmaceutically acceptable salt thereof: Wherein n is 0-5; m is 0 or 1; r is 0-3; A is (1) 5 having 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. Or a 6-membered heterocycle, (2) a benzene ring fused to a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) from oxygen, sulfur and nitrogen A 5- or 6-membered heterocycle having 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, fused to a 5- or 6-membered heterocycle having 1-4 heteroatoms selected, 4) phenyl, or (5) a benzene ring fused to a C ₃ -C ₈ cycloalkyl ring; R ¹ is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5) ^{) NR 8 R 8, (6} ) SR 8, (7) trifluoromethyl, (8) C ₁ ~C ₁₀ ^{Alkyl, (9) OR 8, (} 10) SO 2 R 9, (11) OCOR 9, (12) NR 8 COR 9, (13) COR 9, (14) NR 8 SO 2 R 9, (15) NR ⁸ CO ₂ R ⁸ , or (16) hydroxy, halogen, cyano, NR ⁸ R ⁸ , SR ⁸ , trifluoromethyl, OR ⁸ , C ₃ -C ₈ cycloalkyl, phenyl, NR ⁸ COR ⁹ , COR ⁹ , SO ₂ R ⁹ , OCOR ⁹ , NR ⁸ SO ₂ R ⁹ or N
R ₁ -C ₁₀ alkyl substituted by R ⁸ CO ₂ R ⁸ ; R ² and R ³ are independently (1) hydrogen, (2) C ₁ -C ₁₀ alkyl, or (3) hydroxy, C ₁ -C ₁₀ alkyl having 1-4 substituents selected from C ₁ -C ₁₀ alkoxy and halogen; X _{is, (1) -CH 2 -,} (2) -CH 2 -CH 2 -, (3) -CH = CH-, or _{(4) -CH 2 O-; R} 4 and R ⁵ are independently (1) hydrogen, (2) C ₁ -C ₁₀ alkyl, (3) halogen, (4) NHR ⁸ , (5) OR ⁸ , (6) SO ₂ R ⁹ , or (7) NHSO ₂ R ⁹ ; R ⁶ is (1) hydrogen, or (2) C ₁ -C ₁₀ alkyl; R ⁷ is Z- (R ^1a ) _n ; R ^1a is (1) R ¹ , provided that when A is phenyl, R ^1a is not C ₁ -C ₁₀ alkyl; (2) C ₃ -C ₈ cycloalkyl; ^{3) R 8, NR 8 R} 8, oR 8, selected independently from SR ^8, and halogen Phenyl or or unsubstituted substituted by groups of up to four to be, or (4) oxo, from ^{R 8, NR 8 R 8,} OR 8, SR 8 , and halogen up to 4 substituents independently selected A 5- or 6-membered heterocycle having 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted by a group; Z is (1) phenyl, (2) naphthyl, ( 3) oxygen, 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to (4) C ₃ -C ₈ cycloalkyl ring, (5) oxygen A benzene ring fused to a 5- or 6-membered heterocycle having 1-4 heteroatoms selected from sulfur and nitrogen; (6) 1-4 heteroatoms selected from oxygen, sulfur and nitrogen 5- or 6-membered hete Ring fused to, oxygen, 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or (7), C ₃ ~C ₈ is fused to a cycloalkyl ring, oxygen,
5 or 6 membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁸ is (1) hydrogen, (2) C ₁ -C ₁₀ alkyl, (3) C ₃ -C ₈ Cycloalkyl, (4) halogen, nitro, oxo, NR ¹⁰ R ¹⁰ , C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylthio, and hydroxy, halogen, CO ₂ H, CO ₂ -C ₁ -C ₁₀ alkyl, SO ₂ -C ₁ ~C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, C ₁ -C ₁₀ alkoxy and 1 to 3 halogens, C ₁
-C ₁₀ alkyl or C ₁ -C 1-4 substituents selected from C ₁ -C ₁₀ alkyl having ₁₀ 1-4 substituents selected from Z, which is optionally substituted by alkoxy Optionally having Z, (5) hydroxy, halogen, CO ₂ H, CO ₂ -C ₁ -C ₁₀ alkyl, SO ₂ -C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl,
C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkyl and 1-4 halogen selected from Z optionally substituted by C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkoxy C ₁ -C ₁₀ alkyl having a substituent; R ⁹ is, (1) R ⁸ or (2) NR ⁸ R ^8,; and R ^10, (1) C ₁ -C ₁₀ alkyl or (2) C ₁ together with the N to which two R ¹⁰ groups are attached
Optionally substituted by -C ₁₀ alkyl 5 or 6
Two R ¹⁰ groups forming a membered ring; ). 2. n is 0 to 3; m is 1; r is 0 to 2; A is phenyl or 5 having 1 to 4 nitrogen atoms.
X is —CH ₂ —; R ¹ is (1) hydroxy, (2) halogen, (3) cyano, (4) trifluoromethyl, (5) NR ⁸ R ⁸ , (6 ) NR ⁸ SO ₂ R ⁹ , (7) NR ⁸ COR ⁹ , (8) NR ⁸ CO ₂ R ⁸ , or (16) C ₁ -C ₁₀ optionally substituted by hydroxy
R ² and R ³ are independently (1) hydrogen, or (2) methyl; R ⁴ , R ⁵ and R ⁶ are each hydrogen; R ⁷ is Z— (R ^1a ) _n ; R ^8, R ^9, Z and R ^1a is as defined in claim 1, when R ¹ is part of the definition of R ^1a, R ^1a is claim 1 have the meanings defined in claim 1 Compound. 3. A compound according to claim 1, represented by formula Ia: (Where n is 0 to 3; m is 1; R ¹ is (1) halogen, or (2) NR ⁸ R ⁸ ; R ² and R ³ are independently hydrogen or methyl; R ^1a is (1) halogen, (2) C ₁ -C ₁₀ alkyl, (3) NR ⁸ R ⁸ , (4) NR ⁸ COR ⁹ , (5) NR ⁸ CO ₂ R ⁸ , (6) COR ⁹ (7) OCOR ⁹ , or (8) oxo, halogen, R ⁸ , NR ⁸ R ⁸ , OR ⁸ and SR ⁸ , oxygen or sulfur substituted or unsubstituted or substituted by up to four groups independently selected from A 5- or 6-membered heterocycle having 1-4 heteroatoms selected from nitrogen; Z is (1) phenyl, (2) naphthyl, (3) 1-4 selected from oxygen, sulfur and nitrogen A 5- or 6-membered heterocycle having a heteroatom of (4) fused to a 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen (5) oxygen fused to a C ₃ -C ₈ cycloalkyl ring,
5 or 6 membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; X is -CH ₂ -; and R ⁸ and R ⁹ are as defined in claim 1. ). 4. The compound according to claim 3, wherein R ² and R ³ are each hydrogen. 5. A compound according to claim 1 of the formula Ib: (Wherein n is 0 to 3; m is 1; R ¹ is (1) hydroxy, (2) cyano, (3) NR ⁸ R ⁸ , or (4) halogen; R ^1a is (1 ) Halogen, (2) NR ⁸ R ⁸ , (3) NR ⁸ COR ⁹ , (4) NR ⁸ CO ₂ R ⁸ , (5) OCOR ⁹ , or (6) oxo, halogen, R ⁸ , NR ⁸ R ⁸ , whether or unsubstituted substituted by groups of up to 4 substituents independently selected from oR ⁸ and SR ^8, oxygen, 5 or 6-membered having from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen A heterocyclic ring; Z is benzene fused to (1) phenyl, (2) naphthyl, or (3) a 5- or 6-membered heterocyclic ring having 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. ring; X is -CH ₂ -; and R ² and R ³ are independently hydrogen or methyl; represents a).. 6. A compound according to claim 1 of the formula Id: Wherein n is 0 or 1; R ¹ is NR ⁸ R ⁸ ; R ² and R ³ are independently (1) hydrogen, or (2) methyl; B is (1) hydrogen, (2) benzene fused to a benzene ring to form naphthyl, or (3) 5 or 6 fused to a benzene ring and having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. Membered heterocyclic ring; R ^1a is (1) hydrogen (2) C ₁ -C ₁₀ alkyl, (3) NR ⁸ R ⁸ , (4) NR ⁸ COR ⁹ , (5) NR ⁸ CO ₂ R ⁸ , (6 ) COR ⁹ , or (7) oxo, R ⁸ , SR ⁸ , OR ⁸ and NR ⁸ Oxygen, sulfur and nitrogen substituted or unsubstituted by up to 4 groups independently selected from R ⁸ 1 to be selected from
A 5- or 6-membered heterocycle having 4 heteroatoms; when B and a benzene ring form a condensed ring, R ^1a is bonded to either ring; R ⁸ is (1) hydrogen, (2) C ₁ -C ₁₀ alkyl, (3) 1 selected from nitro, oxo and NR ¹⁰ R ¹⁰
Z optionally having up to 4 substituents, or (5) hydroxy, halogen, C ₁ -C ₁₀ alkyl, C ₃ -C
C ₁ -C ₁₀ alkyl having ₁ to 4 substituents selected from ₈ cycloalkyl and Z, wherein Z is 1 to 4 halogen, C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ alkoxy R ⁹ is (1) R ⁸ , or (2) NR ⁸ R ⁸ ; R ¹⁰ is (1) C ₁ -C ₁₀ alkyl, or (2) two R ¹⁰ Together with the N to which the group is attached, C
5 or 6 are optionally substituted by ₁ -C ₁₀ alkyl
Two R ¹⁰ groups forming a membered ring; and Z is a 5- or 6-membered heterocyclic ring having 1-4 heteroatoms selected from (1) phenyl, (2) oxygen, sulfur and nitrogen. , (3) oxygen, benzene ring fused to a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) C ₃ -C ₈ fused to a cycloalkyl ring Being, oxygen,
A 5- or 6-membered heterocycle having 1-4 heteroatoms selected from sulfur and nitrogen; ). 7. The compound according to claim 1, which is selected from the following group: N- [4- [2-[(2-hydroxy-2-phenylethyl) amino] ethyl] phenyl] -4-iodobenzenesulfone Amide, N- [4- [2-[(2-hydroxy-2-phenylethyl) amino] ethyl] phenyl] -2-naphthalenesulfonamide, N- [4- [2-[(2-hydroxy-2- Phenylethyl) amino] ethyl] phenyl] -3-quinoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (4-amino-3,5-difluorophenyl) ethyl] amino] ethyl ] Phenyl] -4- (hexylaminocarbonylamide) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (4-amino-3,5-dichlorophenyl) ethyl] amido] ] Ethyl] phenyl] -1-[(octylamino) carbonyl] -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (4-amino-3,5-dichlorophenyl) ethyl] ] Amino] ethyl] phenyl] -4- (3-hexyl-2-imidazolidone-1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (4-amino-3, 5-dichlorophenyl) ethyl] amino] ethyl] phenyl] -4- (3-octyl-2-imidazolidone-1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (4 -Hydroxyphenyl) ethyl] amino] ethyl] phenyl]
-Benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] ethyl] phenyl]
-4-iodobenzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-cyanophenyl) ethyl] amino] ethyl] phenyl] -4
-(Hexylaminocarbonylamino) benzenesulfonamide, and N- [4- [2-[[2-hydroxy-2- (3-cyanophenyl) ethyl] amino] ethyl] phenyl] -3
-Quinoline sulfonamide. 8. The compound according to claim 1, which is selected from the following group: N- [4- [2-[[2-hydroxy-2- (6-aminopyridin-3-yl) ethyl] amino] ethyl ] Phenyl] -4- (hexylaminocarbonylamino) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-aminopyridin-3-yl) ethyl] amino] ethyl] phenyl] -4-iodobenzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-aminopyridin-3-yl) ethyl] amino] ethyl] phenyl] benzenesulfonamide, N- [4 -[2-[[2-hydroxy-2- (6-aminopyridin-3-yl) ethyl] amino] ethyl] phenyl] -2-naphthalenesulfonamide, N- [4- [2-[[2-H Roxy-2- (6-aminopyridin-3-yl) ethyl] amino] ethyl] phenyl] -3-quinoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (6-aminopyridine) -3-yl) ethyl] amino] ethyl] phenyl] -5-benzisoxazolesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-aminopyridin-3-yl) ethyl]] Amino] ethyl] phenyl] -4-[(hexylmethylaminocarbonyl) amino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-aminopyridin-3-yl) ethyl] Amino] ethyl] phenyl] -4-[(dimethylaminocarbonyl) amino]
Benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (6-aminopyridin-3-yl) ethyl] amino] ethyl] phenyl] -4- (3-hexyl-2-imidazolidone- 1
-Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(Hexylaminocarbonylamino) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-isopropylbenzenesulfonamide, N- [ 4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -2-naphthalenesulfonamide, N- [4- [2-[[2-hydroxy-2- ( 3-pyridinyl) ethyl] amino] ethyl] phenyl] -3-quinoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4 −
[(Hexylmethylaminocarbonyl) amino] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(3-hexyl-2-imidazolidone-1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-iodo Benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl-4- [3
-(3-cyclopentylpropyl) -2-imidazolidone-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl]- 4-
(3-octyl-2-imidazolidinone-1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4 −
(3-hexyl-2-imidazolone-1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(3-octyl-2-imidazolone-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
[3- (3-cyclopentylpropyl) -2-imidazolone-1-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl ] -1-
(4-octylthiazol-2-yl) -5-indoline sulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(5-pentyl- [1,2,4] -oxadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(5-hexyl- [1,2,4] -oxadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(5-heptyl- [1,2,4] -oxadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(5-octyl- [1,2,4] -oxadiazole-3-
Yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl-4- [5
-(2-cyclopentylethyl)-[1,2,4] -oxadiazol-3-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] ] Amino] ethyl] phenyl] -4-
[5- (3-cyclopentylpropyl)-[1,2,4]-
Oxadiazol-3-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(2-pentyloxazol-5-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(2-hexyloxazol-5-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(2-heptyloxazol-5-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(2-octyloxazol-5-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (2-cyclopentylethyl) oxazole-5
-Yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
[2- (3-cyclopentylpropyl) oxazole-
5-yl] benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(4-hexyl-5-tetrazolone-1-yl) benzenesulfonamide, N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
(4-octyl-5-tetrazolone-1-yl) benzenesulfonamide and N- [4- [2-[[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] -4-
[(3-Cyclopentylpropyl) -5-tetrazolone-1-yl] benzenesulfonamide. 9. A method for treating diabetes or obesity, decreasing triglyceride or cholesterol levels, increasing high density lipoprotein levels, decreasing intestinal motility comprising an inert carrier and an effective amount of the compound of claim 1. A composition for reducing neurogenic inflammation, treating depression, or treating gastrointestinal disorders.