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CN1149869A - Substituted sulfonamides as selective beta3 agonists for treatment of diabetes and obesity - Google Patents

Substituted sulfonamides as selective beta3 agonists for treatment of diabetes and obesity Download PDF

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Publication number
CN1149869A
CN1149869A CN95192821A CN95192821A CN1149869A CN 1149869 A CN1149869 A CN 1149869A CN 95192821 A CN95192821 A CN 95192821A CN 95192821 A CN95192821 A CN 95192821A CN 1149869 A CN1149869 A CN 1149869A
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Prior art keywords
ethyl
phenyl
amino
pyridyl
hydroxy
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CN95192821A
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Inventor
M·H·费希尔
E·M·内勒
D·岳
A·E·韦伯
T·史
H·岳
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from US08/404,566 external-priority patent/US5541197A/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of CN1149869A publication Critical patent/CN1149869A/en
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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Abstract

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

Description

Selectivity β as treatment diabetes and obesity 3The substituted sulfonamides of agonist
The cross reference document
The application is that the application number of applying on April 26th, 1994 is U S.S.N.08/233, the part continuation application of determining and apply in 166 common end; On the application's integrity, the document is hereby incorporated by reference.
Background of invention
Since 1967, B-adrenergic receptor is subdivided into β 1And β 2It is β that heart rate is accelerated 1The main result of-acceptor excitement, and bronchiectasis and smooth muscle loosening generally are by β 2Excitement causes.Originally lipocyte steatolysis be considered to just β 1The process of-transmission, but the nearest steatolysis that studies show that the acceptor transmission comes down to non-type.These were called as β afterwards 3The nonstandard acceptor of-adrenergic receptor finds that in white and brown fat cell surface the excitement of described adipocyte has promoted steatolysis (decomposition of fat) and energy expenditure.
In this field, the previous development and production of people have gone out to have than atrium speed (β 1) and the lax (β of tracheae 2) excited higher steatolysis (β 3Activity) compound of excited agonist activity.What these were disclosed in previous research in the United States Patent (USP) 4,478,849 and 4,396,627 of Ainsworth et al. is the phenylethyl alcohol sulfonamide derivatives.
This β 3The selectivity of-adrenergic receptor makes this compounds can be used as antiobesity agent effectively.In addition, these compounds have been reported as in the animal model of non-insulin-dependent diabetes mellitus (NIDDM) and have demonstrated anti-high-blood-sugar function.
Treatment has β 3The subject matter of agonist chronic disease is to make other beta receptor excitement, therefore has side effect; Most probable phenomenon comprises muscular tremor (β 2) and heart rate quickening (β 1).Although these phenylethyl alcohol sulfonamide derivativess have some β really 3Selectivity, such side effect has been observed in people volunteer, therefore has reason to infer that these side effects are by part β 1And/or β 2Excitement causes.
In this field, nearest result of study is disclosed in the United States Patent (USP) 5 of Ainsworth et al., 153,210, the United States Patent (USP) 4 of Caulkett et al., 999,377, the United States Patent (USP) 5,017 of Alig et al., 619, the European patent 455006 of the European patent 427280 of Lecount et al. and Bloom et al..
Although claiming to disclose, nearest result of study has the β of ratio 1And β 2Active higher β 3Selectivity, but this selectivity by utilize rodent particularly rat as experimental animal and definite.Even since on the people this class of test by aforesaid method measure have the compound of highly selective the time, also demonstrate β by remnants 1And β 2Therefore the vestige of the side effect that agonist activity causes is used to predict people's β 3Optionally rodent obviously is not a good animal model.
Developed the measuring method of the effect that more can calculate to a nicety that is expected to be used for the people recently.The human cloning β that this mensuration uses Chinese hamster gonad cell to express 3Acceptor is referring to Emorine etal., Science, 1989,245:1118-1121; And Liggett, Mol.Pharmacol., 1992,42:634-637.Different compounds have indicated that to the excitement and the antagonistic action of culturing cell these compounds have anti-obesity and antidiabetic effect to the people.Brief summary of the invention
The present invention relates to substituted sulfonamides as anti-obesity and antidiabetic compound.Therefore, one object of the present invention is described this compounds exactly, another purpose is to describe the particularly preferred steric isomer of substituted sulfonamides, another purpose is exactly to describe the method for this compounds of preparation, and also having a purpose is exactly to describe to use with method and the composition of this compounds as activeconstituents.Further object of the present invention can obtain from reading following specification sheets significantly.Invention is described
The invention provides formula I compound or its pharmacy acceptable salt: Wherein n is 0 to 5; M is 0 or 1; R is 0 to 3; A contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen for (1),
(2) with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen,
(3) with contain 1 to 4 heteroatomic 5 or 6 yuan of being selected from oxygen, sulphur and nitrogen and heterocyclic fused contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen,
(4) phenyl, or
(5) and C 3-C 8Naphthenic ring condensed phenyl ring; R 1Be (1) hydroxyl
(2) oxo,
(3) halogen,
(4) cyano group,
(5)NR 8R 8，
(6)SR 8，
(7) trifluoromethyl,
(8) C 1-C 10Alkyl,
(9)OR 8，
(10)SO 2R 9，
(11)OCOR 9，
(12)NR 8COR 9，
(13)COR 9，
(14)NR 8SO 2R 9，
(15) NR 8CO 2R 8, or
(16) by hydroxyl, halogen, cyano group, NR 8R 8, SR 8, trifluoromethyl, OR 8, C 3-C 8Cycloalkyl, phenyl, NR 8COR 9, COR 9, SO 2R 9, OCOR 9, NR 8SO 2R 9Or NR 8CO 2R 8The C that replaces 1-C 10Alkyl; R 2And R 3Be independently
(1) hydrogen,
(2) C 1-C 10Alkyl, or
(3) contain 1 to 4 and be selected from hydroxyl, C 1-C 10The C of alkyl and halogen 1-C 10Alkyl; X is (1)-CH 2-,
(2)-CH 2-CH 2-，
(3)-CH=CH-, or
(4)-CH 2O-; R 4And R 5Be independently
(1) hydrogen,
(2) C 1-C 10Alkyl,
(3) halogen,
(4)NHR 8，
(5)OR 8，
(6) SO 2R 9, or
(7) NHSO 2R 9R 6Be (1) hydrogen, or
(2) C 1-C 10Alkyl; R 7Be Z-(R 1a) nR 1aBe (1) R 1, be when A is phenyl, R 1aNot C 1-C 10Alkyl,
(2) C 3-C 8Cycloalkyl,
(3) be independently selected from R by 4 of as many as 8, NR 8R 8, OR 8, SR 8With any phenyl that replaces of the group of halogen,
(4) be independently selected from oxo, R by 4 of as many as 8, NR 8R 8, OR 8, SR 8Contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen with the group of halogen replaces arbitrarily; Z is (1) phenyl,
(2) naphthyl,
(3) contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen,
(4) and C 3-C 8Naphthenic ring condensed phenyl ring,
(5) with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen,
(6) with contain 1 to 4 heteroatomic 5 or 6 yuan of being selected from oxygen, sulphur and nitrogen and heterocyclic fused contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen, or
(7) and C 3-C 8The naphthenic ring condensed contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; R 8Be (1) hydrogen,
(2) C 1-C 10Alkyl,
(3) C 3-C 8Cycloalkyl,
(4) can choose wantonly and have 1 to 4 and be selected from halogen, nitro, oxo, NR 10R 10, C 1-C 10Alkyl, C 1-C 10Alkoxyl group, C 1-C 10Alkylthio and contain 1 to 4 and be selected from hydroxyl, halogen, CO 2H, CO 2-C 1-C 10Alkyl, SO 2-C 1-C 10Alkyl, C 3-C 8Cycloalkyl, C 1-C 10The C that the group of alkoxyl group replaces 1-C 10The substituent Z of alkyl, and can choose wantonly by 1 to 3 halogen, C 1-C 10Alkyl or C 1-C 10The Z that alkoxy base replaces, or
(5) have 1 to 4 and be selected from hydroxyl, halogen, CO 2H, CO 2-C 1-C 10Alkyl, SO 2-C 1-C 10Alkyl, C 3-C 8Cycloalkyl, C 1-C 20Alkoxyl group, C 1-C 10The substituent C of alkyl 1-C 10Alkyl and can choosing wantonly by 1 to 4 halogen, C 1-C 10Alkyl or C 1-C 10The Z that alkoxy base replaces; R 9Be (1) R 8, or
(2) NR 8R 8R 10Be (1) C 1-C 10Alkyl, or
(2) connect into and to choose wantonly by C with N 1-C 10Two R of 5 or 6 yuan of rings that alkyl replaces 10Group.
In one embodiment of the invention, A contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen, with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen, perhaps for contain 1 to 4 heteroatomic 5 or 6 yuan of being selected from oxygen, sulphur and nitrogen and heterocyclic fused contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen.
In another embodiment of the invention, A is phenyl or and C 3-C 8Naphthenic ring condensed phenyl ring.
Preferred compound is among the structural formula I of the present invention: R 2And R 3Be hydrogen or methyl; X is-CH 2-; N is 0 to 3; M is 1; R is 0 to 2; And R 4, R 5And R 6Be hydrogen.
Another preferred compound is among the structural formula I of the present invention: A is phenyl or contains 1 or 2 heteroatomic 6 yuan of heterocycle that are selected from nitrogen and sulphur; R 1For choosing hydroxyl, halogen, cyano group, trifluoromethyl, the NR that replaces by hydroxyl wantonly 8R 8, NR 8SO 2R 9, NR 8COR 9, NR 8SO 2R 9, C 1-C 10Alkyl; And r is 0 or 2.
Preferred compound is represented by formula Ia:
Figure A9519282100181
Wherein n is 0 to 3; M is 1; R 1Be (1) halogen, or
(2) NR 8R 8R 2And R 3Be hydrogen or methyl independently; R 1aBe (1) halogen,
(2) C 1-C 10Alkyl,
(3)NR 8R 8；
(4)NR 8COR 9，
(5)NR 8CO 2R 8，
(6)COR 9，
(7) OCOR 9, or
(8) be independently selected from oxo, halogen, R by 4 of as many as 8, NR 8R 8, OR 8And SR 8Group replace arbitrarily contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; Z is (1) phenyl,
(2) naphthyl,
(3) contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen,
(4) with contain 1 to 3 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen, or
(5) and C 3-C 8The naphthenic ring condensed contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; X is-CH 2-; And R 8And R 9Suc as formula the definition among the I.Further preferred compound is represented by formula Id:
Figure A9519282100191
N is 0 or 1; R 1Be NR 8R 8R 2And R 3Be independently
(1) hydrogen, or
(2) methyl; B is (1) hydrogen,
(2) benzene and phenyl ring condense the naphthyl of formation, or
(3) contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen with the phenyl ring condensed; R 1aBe (1) halogen,
(2) C 1-C 10Alkyl,
(3)NR 8R 8；
(4)NR 8COR 9，
(5)NR 8CO 2R 8，
(6) OCOR 9, or
(7) be independently selected from oxo, R by 4 of as many as 8, SR 8, OR 8And NR 8R 8Group replace arbitrarily contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; When B and phenyl ring formation condensed ring system, R 1aLink to each other with one of them ring; R 8Be (1) hydrogen,
(2) C 1-C 10Alkyl,
(3) can choose wantonly and have 1 to 4 and be selected from nitro, oxo and NR 10R 10Substituent Z; Or
(5) contain 1 to 4 and be selected from hydroxyl, halogen, C 1-C 10Alkyl, C 3-C 8Cycloalkyl and by 1 to 4 halogen, C 1-C 10Alkyl or C 1-C 10The substituent C of the Z that alkoxy base replaces arbitrarily 1-C 10Alkyl; R 9Be (1) R 8, or
(2) NR 8R 8R 10Be (1) C 1-C 10Alkyl, or
(2) connect into by C with N 1-C 10Two R of 5 or 6 yuan of rings that alkyl replaces arbitrarily 10Group; Or Z is (1) phenyl,
(2) contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen,
(3) with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen, or
(4) and C 3-C 8The naphthenic ring condensed contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen.
Other preferred compound is represented by formula Ib:
Figure A9519282100201
Wherein n is 0 to 3; M is 1; R 1Be (1) hydroxyl,
(2) cyano group,
(3) NR 8R 8, or
(4) halogen; R 1aBe (1) halogen,
(2)NR 8R 8；
(3)NR 8COR 9，
(4)NR 8CO 2R 8，
(5) OCOR 9, or
(6) be independently selected from oxo, halogen, R by 3 of as many as 8, NR 8R 8, OR 8And SR 8Group replace arbitrarily contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; Z is (1) phenyl,
(2) naphthyl, or
(3) with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen; X is-CH 2-; And R 2And R 3Be hydrogen or methyl independently.
The present invention is a representative anti-obesity and anti-diabetic compounds include the following: N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] ethyl Yl] phenyl] -4 - (aminocarbonyl hexyl amino) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] ethyl Yl] phenyl] -4 - iodo-benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] ethyl Yl] phenyl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - amino-pyridine-3 - yl) ethyl] amino] ethyl Yl] phenyl] -2 - naphthalenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] ethyl Yl] phenyl] -3 - quinoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-pyridin-3-- yl) ethyl] amino] ethyl Yl] phenyl] -5 - benzisoxazole sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] ethyl Yl] phenyl] -4 - [(cyclohexylmethyl-amino carbonyl) amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] ethyl Yl] phenyl] -4 - (dimethylamino-carbonyl) amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] ethyl Yl] phenyl] -4 - (3 - hexyl-2 - imidazol-one-1 - yl) benzenesulfonamide N-[4 - [3 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] propyl Yl] phenyl] -4 - (aminocarbonyl hexyl amino) benzenesulfonamide; N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] propyl Yl] phenyl] -4 - iodo-benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] propyl Yl] phenyl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] propyl Yl] phenyl] -2 - naphthalenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (6 - Amino-3 - yl) ethyl] amino] propyl Yl] phenyl] -3 - quinoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (Hexyl-amino-carbonyl-amino) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - Isopropyl benzene sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -2 - Naphthalenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -3 - Quinoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(Cyclohexylmethyl-amino-carbonyl) amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - hexyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - Iodobenzene sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [5 - (3 - cyclopentylpropyl) - [1,2,4] - oxadiazol-3 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(] - Oxoheptyl) amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(1 - oxo-4 - phenylbutyl) amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(Propoxycarbonyl) amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [[[(Furan-2 - yl methyl) amino] carbonyl] amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [[[(2 - phenylethyl) amino] carbonyl] amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [[[(2 - indol-3 - yl-ethyl) amino] carbonyl] amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [[(Octyl amino) carbonyl] amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [(Hexyl-amino) carbonyl]-5 - dihydro-indol-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [(Octyl amino) carbonyl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [(N-methyl-N-octyl-amino) carbonyl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (1 - oxo-nonyl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - methyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - octyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - ethyl-5 - methyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - octyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (4,4,4 - trifluoro-butyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - phenyl-propyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (4,4,5,5,5 - pentafluoro-pentyl) -2 - imidazolin-one-1 - yl)] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (2 - cyclohexyl-ethyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - [3 - (4 - chlorophenyl) propyl] -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - pentyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - cyclopentyl-propyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (2 - cyclopentyl-ethyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - cyclohexyl-propyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (2,2 - dimethyl-hexyl)-2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - hexyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (4,4,4 - trifluoro-butyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - octyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - cyclopentyl-propyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - octyl-3 - oxo - [1,2,4] - triazol-4 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - hexyl-5 - tetrazol-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - Octyl-5 - tetrazol-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(3 - cyclopentylpropyl)-5 - tetrazol-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - pentyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - octyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (2 - cyclopentyl-ethyl)-oxazol-5 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (2 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(4 - ethyl-5 - methyl-thiazol-2 - yl) amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(4,5,6,7 - tetrahydro-benzothiazol-2 - yl) amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - hexyl-imidazol-4 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (1 - methyl - 2 - octyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [1 - methyl - 2 - (2 - cyclopentyl-ethyl)-imidazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [1 - methyl - 2 - [2 - (4 - fluorophenyl) ethyl] imidazole-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - pentyl - [1,2,4] - oxadiazol-3 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [5 - (2 - cyclopentyl-ethyl) - [1,2,4] - oxadiazol-3 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - heptyl - [1,2,4] - oxadiazol-3 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - octyl - [1,2,4] - oxadiazol-3 - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - hexylthio - [1,2,4] - triazol-3 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [[4 - (4 - propyl-piperidin-1 - yl) -1,1 - dioxo - [1,2,5] - thiadiazole - ³ -] amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [[4 - (4 - cyclohexylmethyl-amino) -1,1 - dioxo - [1,2,5] - thiadiazol-3 - Yl] amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [[4 - (N-heptyl group, N-methyl-amino) -1,1 - dioxo - [1,2,5] - thiadiazole Zol-3 - yl] amino] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (1 - octyl-2, 4 - dione-3-imidazolidine - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - nitrophenyl) - 5 - pyrazolone one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [4 - (1 - hydroxy-1 - hexyl heptyl)-5 - methyl - [1,2,3] - triazol - Yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [4 - (1 - hydroxy-heptyl)-5 - methyl - [1,2,3] - triazol-2 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] -2 - methyl-propyl Yl] phenyl] -4 - (3 - hexyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] -2 - methyl-propyl Yl] phenyl] -4 - iodo-benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] -2 - methyl-propyl Yl] phenyl] -4 - [[(hexyl-amino) carbonyl] amino] benzenesulfonamide N-[4 - [2 - [(2 - hydroxy-2 - phenylethyl) amino] ethyl] phenyl] -4 - iodo- Benzenesulfonamide N-[4 - [2 - [(2 - hydroxy-2 - phenylethyl) amino] ethyl] phenyl] -2 - naphthalenesulfonamide Amide N-[4 - [2 - [(2 - hydroxy-2 - phenylethyl) amino] ethyl] phenyl] -3 - quinoline Sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - chlorophenyl) ethyl] amino] ethyl] phenyl] -3 - Isopropyl benzene sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - chlorophenyl) ethyl] amino] ethyl] phenyl] -2 - Naphthalenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - chlorophenyl) ethyl] amino] ethyl] phenyl] -3 - Quinoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (4 - amino-3 ,5 - dichloro-phenyl) ethyl] amino Yl] ethyl] phenyl] -4 - (aminocarbonyl hexyl amino) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (4 - amino-3 ,5 - dichlorophenyl) ethyl] amino Yl] ethyl] phenyl] -1 - [(octyl amino) carbonyl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (4 - amino-3 ,5 - dichlorophenyl) ethyl] amino Yl] ethyl] phenyl] -4 - (3 - hexyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (4 - amino-3 ,5 - dichlorophenyl) ethyl] amino Yl] ethyl] phenyl] -4 - (3 - octyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (4 - hydroxyphenyl) ethyl] amino] ethyl] phenyl] -4 - Benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (4 - hydroxyphenyl) ethyl] amino] ethyl] phenyl] -4 - Iodobenzene sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - cyano-phenyl) ethyl] amino] ethyl] phenyl] -4 - (Aminocarbonyl hexyl amino) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - cyano-phenyl) ethyl] amino] ethyl] phenyl] -3 - Quinoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - hexyl - [1,2,4] - oxadiazol-3 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - heptyl-5 - methyl - [1,2,3] - triazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - hexyl-2, 4 - dione-imidazolin - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - octyl-2, 4 - dione-imidazolin - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - cyclopentyl-propyl) -2,4 - imidazolin-dione-- yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - pentyl - [1,2,4] - oxadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - hexyl - [1,2,4] - oxadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - heptyl - [1,2,4] - oxadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - octyl - [1,2,4] - oxadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (2 - cyclopentyl-ethyl) - [1,2,4] - oxadiazol-5 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - cyclopentylpropyl) - [1,2,4] - oxadiazol-5 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - pentyl - [1,2,4] - thiadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - hexyl - [1,2,4] - thiadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - heptyl - [1,2,4] - thiadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - octyl - [1,2,4] - thiadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (2 - cyclopentyl-ethyl) - [1,2,4] - thiadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - cyclopentylpropyl) - [1,2,4] - thiadiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - pentyl - [1,2,4] - thiadiazol-3 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - hexyl - [1,2,4] - thiadiazol-3 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - heptyl - [1,2,4] - thiadiazol-3 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - octyl - [1,2,4] - thiadiazol-3 - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [5 - (2 - cyclopentyl-ethyl) - [1,2,4] - thiadiazol-3 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [5 - (3 - cyclopentylpropyl) - [1,2,4] - thiadiazol-3 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - pentyl-3 - oxo - [1,2,4] - triazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - hexyl-3 - oxo - [1,2,4] - triazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - heptyl-3 - oxo - [1,2,4] - triazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - octyl-3 - oxo - [1,2,4] - triazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [4 - (2 - cyclopentyl-ethyl) -3 - oxo - [1,2,4] - triazol-2 - yl] benzene sulfonamide Amine N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [4 - (3 - cyclopentyl-propyl)-3 - oxo - [1,2,4] - triazol-2 - yl] benzene sulfonamide Amine N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - pentyl-oxazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridinyl) ethyl] amino] ethyl] phenyl] -4 - (5 - hexyl-oxazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - heptyl-oxazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - octyl-oxazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [5 - (2 - cyclopentyl-ethyl)-oxazol-2 - yl] methanesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [5 - (3 - cyclopentylpropyl) oxazol-2 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - pentyl-oxazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - hexyl-oxazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - heptyl-oxazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - octyl-oxazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [4 - (2 - cyclopentyl-ethyl)-oxazol-2 - yl] methanesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [4 - (3 - cyclopentylpropyl) oxazol-2 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - hexyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - heptyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (3 - cyclopentylpropyl) oxazol-5 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (4 - cyclopentyl-butyl)-5 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - [2 - (4 - fluorophenyl) ethyl]-5 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - pentyl-oxazol-4 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - hexyl-oxazol-4 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - heptyl-oxazol-4 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - octyl-oxazol-4 - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (2 - cyclopentyl-ethyl)-oxazole-4 - yl] methanesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (3 - cyclopentylpropyl) oxazol-4 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - pentyl-thiazol-2 - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - hexyl-thiazol-2 - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - heptyl-thiazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - octyl-thiazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [5 - (2 - cyclopentyl-ethyl)-thiazol-2 - yl] methanesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [5 - (3 - cyclopentylpropyl) thiazol-2 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - pentyl-thiazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - hexyl-thiazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - heptyl-thiazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - octyl-thiazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [4 - (2 - cyclopentyl-ethyl)-thiazol-2 - yl] methanesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [4 - (3 - cyclopentylpropyl) thiazol-2 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - pentyl-thiazol-4 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - hexyl-thiazol-4 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - heptyl-thiazol-4 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - octyl-thiazol-4 - yl) benzenesulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (2 - cyclopentyl-ethyl)-thiazol-4 - yl] methanesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (3 - cyclopentylpropyl) thiazol-4 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - pentyl-thiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - hexyl-thiazol-5 - yl) benzenesulfonamide N. - [4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - heptyl-thiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - octyl-thiazol-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (2 - cyclopentyl-ethyl)-thiazol-5 - yl] methanesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (3 - cyclopentylpropyl) thiazol-5 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - methyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - pentyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - hexyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - heptyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - octyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [5 - (2 - cyclopentyl-ethyl)-thiazol-2 - yl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [5 - (3 - cyclopentylpropyl) thiazol-2 - yl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - pentyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - hexyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - heptyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [4 - (2 - cyclopentyl-ethyl)-thiazol-2 - yl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [4 - (3 - cyclopentylpropyl) thiazol-2 - yl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - methyl-oxazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridinyl) ethyl] amino] ethyl] phenyl] -1 - (5 - pentyl-oxazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - hexyl-oxazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - heptyl-oxazol-2 - yl) -5 - indoline-sulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - octyl-oxazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [5 - (2 - cyclopentyl-ethyl)-oxazol-2 - yl] -5 - dihydro-indol-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [5 - (3 - cyclopentylpropyl) oxazol-2 - yl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - methyl-oxazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - pentyl-oxazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - hexyl-oxazol-2 - yl) -5 - dihydro-indol-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - heptyl-oxazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - octyl-oxazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [4 - (2 - cyclopentyl-ethyl)-oxazol-2 - yl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [4 - (3 - cyclopentylpropyl) oxazol-2 - yl] -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (3 - methyl - [1,2,4] - oxadiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (3 - pentyl - [1,2,4] - oxadiazol-5 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (3 - hexyl - [1,2,4] - oxadiazol-5 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (3 - heptyl - [1,2,4] - oxadiazol-5 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (3 - octyl - [1,2,4] - oxadiazol-5 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [3 - (2 - cyclopentyl-ethyl) - [1,2,4] - oxadiazol-5 - yl] -5 - dihydro-indol- Sulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [3 - (3 - cyclopentyl-propyl) - [1,2,4] - oxadiazol-5 - yl] -5 - dihydro-indol- Sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - methyl - [1,2,4] - oxadiazol-3 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - pentyl - [1,2,4] - oxadiazol-3 - yl) -5 - dihydro-indol-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - hexyl - [1,2,4] - oxadiazol-3 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - heptyl - [1,2,4] - oxadiazol-3 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (5 - octyl - [1,2,4] - oxadiazol-3 - yl) -5 - indoline-sulfonamide N_-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [5 - (2 - cyclopentyl-ethyl) - [1,2,4] - oxadiazol-3 - yl] -5 - dihydro-indol- Sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - [5 - (3 - cyclopentylpropyl) - [1,2,4] - oxadiazol-3 - yl] -5 - dihydro-indol- Sulfonamide ...
Compound of the present invention all has at least one center of asymmetry of representing with the asterisk among the structural formula I.According to the different substituents in the molecule, particularly R 2And R 3Character, in molecule, can have other symmetry centre.Each this type of center of asymmetry can produce two kinds of optically active isomers, this just means that all these class optically active isomers all comprise within the scope of the present invention, exists with isolating, pure or partially purified optically active isomer or its racemic mixture form no matter be.Shown in formula Ic, under the situation of the center of asymmetry of being represented by asterisk in formula I, hydroxyl substituent has more activity at the compound on the structural plan than the compound of hydroxyl substituent under the structural plan, thereby more preferably.
Following stereospecificity structure has been represented the preferred steric isomer of the present invention:
Figure A9519282100351
Wherein n, m, r, A, R 1, R 2, R 3, R 4, R 5, R 6, R 7With the X definition among the formula I as mentioned.
In this application, the connotation of following term is as follows:
Alkyl group mentioned above comprises the alkyl of the designated length of straight or branched.The example of this alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, sec.-propyl, hexyl, different ethyl or the like.
Alkoxy base mentioned above comprises the alkoxyl group of the designated length of straight or branched.The example of this alkoxyl group is methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, different hexyloxy or the like.
Term " halogen " comprises halogen atom fluorine, chlorine, bromine and iodine.
5 and 6-unit heterocycle and A, Z and R 1aThe example of annelated heterocycles comprise pyridyl, quinolyl, pyrimidyl, pyrryl, thienyl, imidazolyl, thiazolyl, benzimidazolyl-, thiadiazolyl group, diazosulfide base, indyl, indolinyl, benzo dioxane amyl group, benzodioxan base, benzothienyl, benzofuryl, benzoxazinyl, benzoisoxazole base, benzothiazolyl, tetralyl, dihydro benzo furyl, tetrahydric quinoline group, furo pyridine and thienopyridine.
Preferred A and Z are phenyl, and naphthyl and contains 1 to 4 heterocyclic fused phenyl ring of heteroatomic 5 or 6-unit that is selected from oxygen, sulphur and nitrogen, or contains 1 to 4 heteroatomic heterocycle that independently is selected from one of oxygen or sulphur and/or 1 to 4 nitrogen-atoms.
Preferred A is phenyl, pyridyl, quinolyl, pyrimidyl, pyrryl, thienyl, imidazolyl and thiazolyl.
Preferred Z is a phenyl, naphthyl, quinolyl, thienyl, benzimidazolyl-, thiadiazolyl group, the diazosulfide base, indyl, indolinyl, benzo dioxane amyl group, the benzodioxan base, benzothienyl, benzofuryl benzoxazinyl, the benzoisoxazole base, benzothiazolyl, tetralyl, dihydro benzo furyl, triazolyl, tetrazyl oxadiazole base, imidazolyl oxazolyl, thiazolyl, imidazolidyl, pyrazolyl isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydro benzothiazol base and tetrahydric quinoline group.As Z and-NSO 2(CH 2) r-when linking to each other, preferred phenyl, naphthyl or with contain 1 to 4 heterocyclic fused phenyl ring of heteroatomic 5-or 6-unit that is selected from oxygen, sulphur and nitrogen.When Z is R 8During the part of definition, preferred phenyl contains 1 to 4 heteroatomic 5 or 6-unit heterocycle that is selected from oxygen, sulphur and nitrogen, and contains 1 to 4 heterocyclic fused phenyl ring of heteroatomic 5 or 6-unit that is selected from oxygen, sulphur and nitrogen, or and C 3-C 8The naphthenic ring condensed contains 1 to 4 heteroatomic 5 or 6-unit heterocycle that is selected from oxygen, sulphur and nitrogen.
Preferred R 1aHeterocycle is thienyl, thiadiazolyl group, triazolyl, tetrazyl, oxadiazole base, imidazolyl, oxazolyl, thiazolyl, imidazolidyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl and pyrazolyl.
Some term defined above can occur more than once in structural formula above, and according to this appearance, each term must define independently of each other with other, therefore NR for example 8R 8Can represent NH 2, NHCH 3, N (CH 3) CH 2CH 3Or the like.
Used following shortenings in this specification sheets:
Boc: tert-butoxycarbonyl
Cbz: carbobenzoxy-(Cbz)
DIP-Cl: diisopinocampheylchloroborane
DMF: dimethyl formamide
DMSO: dimethyl sulfoxide (DMSO)
HPLC: high pressure liquid chromatography
Me: methyl
MPLC: medium pressure liquid chromatography
MS: methylsulfonyl (mesyl)
The NBS:N-bromo-succinimide
The NCS:N-chlorosuccinimide
NHex: n-hexyl
The TBAF tetrabutylammonium fluoride
TBS (TBDMS): t-butyldimethylsilyl
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
Compound of the present invention (I) can be by suc as formula the epoxide intermediates of II with as the amine intermediate preparation of formula III.The preparation of these intermediates is described in hereinafter in the flow process.
Figure A9519282100371
Wherein n, m, r, A, R 1, R 2, R 3, R 4, R 5, R 6, R 7Define as mentioned with X.
Compound I I is known in the literature or can be simply by prepared in various methods well known to those skilled in the art.A kind of method commonly used is shown in flow process 1.In solvent as ether, utilize diazomethane to handle acyl chlorides 1, this acyl chlorides can be commercial or by utilizing as thionyl chloride or oxalyl chloride are handled and sourly be easy to make accordingly.Handle the diazo-ketones of gained again with hydrogenchloride, obtain chloro ketone 2 (X=Cl); Use reductive agent such as sodium borohydride reduction halogenated ketone 2 then; In backflow acetone, handle the product alcohol 3 that obtains again, obtain required epoxide II thus with alkali such as salt of wormwood.Can by the chiral reduction agent as (-) or (+)-DIP-Cl, (R) or (S)-Alpine borane or (R) or (S)-tetrahydrochysene-1-methyl-3,3-phenylbenzene-1H, 3H-pyrrolo-[1,2-c] [1,3,2] oxazaborole-borane ((R) or (S)-OABBH 3) carry out the asymmetric reduction of halogenated ketone 2 and easily obtain (R) of enantiomorph enrichment and (S) epoxide II.
Flow process 1
The other method that obtains halogenated ketone 2 is shown in flow process 2.Utilization well known to a person skilled in the art all ingredients, and methyl ketone is transformed into corresponding halogenated ketone, and described reagent is summarised in LarockComprehensive Organic Transformations; VCH:New York, 1989, among the 369-372.Simply, in acetate and other acid source such as hydrogenchloride or aluminum chloride, handle methyl ketone 4 with chlorine or N-chlorosuccinimide.For Synthetic 2 (X=Br), can use bromine, dibromobarbituric acid or NBS and hydrogen bromide or aluminum bromide.In some cases, chloro or bromo ketone 2 can be commercial.
Flow process 2
Figure A9519282100382
Many methyl ketone 4 can commercial or easily be prepared by the method for describing in the document that well known to a person skilled in the art.In following step, the R in acyl chlorides 1 or the methyl ketone 4 1Substituting group may need protected.The description of this class blocking group can obtain in following document: ProtectiveGroups in Organic Synthesis, 2nd Ed., T.w.Greene and P.G.M.Wuts, John Wiley and Sons, New York, 1991.
Compound III can be simply by prepared in various methods well known to those skilled in the art.Work as R 6During for hydrogen, the simple preparation route of compound is shown in flow process 3.Utilize as tert-Butyl dicarbonate or Carbobenzoxy Chloride, compound 5 is optionally protected into suitable carbamate derivatives 6.Be-20 to 50 ℃ in temperature then, under preferred 0 ℃, in anhydrous solvent such as methylene dichloride or chloroform, handled this compound 0.5 to 24 hour, obtain sulphonamide 8 with the preferred SULPHURYL CHLORIDE of sulfonic acid halide and alkali such as pyridine.Then utilize trifluoroacetic acid or remove protecting group, obtain required amine 9 for the Cbz catalytic hydrogenation for Boc.
Flow process 3
Figure A9519282100391
R 6The compound III that is not hydrogen can be prepared by the method shown in the flow process 4 simply.In the presence of alkali, utilize suitable alkylating reagent 10 to make as above sulphonamide 8 alkylations of preparation, obtain sulphonamide 11.Remove blocking group with above-described method and obtain required compound 9a.
Flow process 4
Utilize many methods well known to those skilled in the art easily to prepare SULPHURYL CHLORIDE 7, wherein many SULPHURYL CHLORIDE are commercial.According to S.N.Bhattacharya, et.al., J.Chem.Soc. (S), the method of describing among the 1265-1267 (1969), a kind of suitable method for preparing SULPHURYL CHLORIDE comprise the addition of organolithium reagent of SULPHURYL CHLORIDE or the addition of Grignard reagent, according to Y.J.Park, et.al., the method of describing among the Chemistry Letters, 1483-1486 (1992), the simple method of another preparation SULPHURYL CHLORIDE comprises utilizes sulfuryl chloride and metal nitrate disposal of mercaptans.Utilize PCl 5, PCl 3Or SOCl 2Handle, also can make sulfonic acid be transformed into corresponding SULPHURYL CHLORIDE (J.March, Advanced Organic Chemistry, 4th Ed. John Wiley and Sons, New York:1992, p1297 and the document of quoting thereof) simply.Aromatics and heteroaromatics can directly be handled by Vilsmeier reagent or chlorsulfonic acid and make its chlorosulfonylation (OrganicSynthesis, I, 8).
Diamines 5 can prepare by disclosed in the document or the method that well known to a person skilled in the art commercial or simply.According to J.D.Bloom, et.al., J.Med.Chem., 35, the method among the 3081-3084 (1992) prepares R by corresponding amino acid 2Or R 3Compound 5 for methyl.Just as shown in Scheme 5, for R 3Be methyl, handle that (R) amino acid/11 2 that esterification is suitable is handled with tert-Butyl dicarbonate then, obtains compound 13 with methanolic hydrochloric acid.Ester group is reduced by hydride source such as lithium borohydride, and product alcohol is transformed into leavings group such as methanesulfonate, removes the Boc protecting group and can obtain diamines 14.Under alkali such as sodium acetate existence condition,, obtain required Alpha-Methyl amine 15 with this compound for catalysis hydrogenation.Begin by corresponding (S) amino acid,, can obtain other enantiomorph according to similar step.
Flow process 5
Figure A9519282100411
Diamines 5 or X are-CH 2O-and m be 1 sulphonamide amine 9 also can be simply by disclosed in the document or well known to a person skilled in the art the method preparation.For example, shown in flow process 6, under the condition of backflow 2-butanone and alkali such as salt of wormwood, utilize 1-bromo-2-monochloroethane to make sodium salt 16 alkylations of 4-nitrophenols, obtain chlorinated derivative 17.Utilize Lithium Azide to handle, in aqueous tetrahydrofuran (THF), use as the triphenylphosphine reduction again, make muriate be transformed into corresponding amine.Utilize two dimethyl dicarbonate butyl esters that product amine is protected into its t-butyl carbamate, obtain derivative 18.Utilize as catalytic hydrogenation, make nitroreduction, obtain amine 19,, go protection with acid as trifluoroacetic acid again, obtain required intermediate 20 with SULPHURYL CHLORIDE 7 acidylate intermediates 19.
Flow process 6
Figure A9519282100421
In addition, utilizing trifluoroacetic acid to handle intermediate 19 also can make X and be-CH 2O-and m are 1 diamines 5.Diamines is modified by flow process 3 again.
Diamines 5 and X are-CH 2CH 2-and m be that 1 sulphonamide amine 9 also can be by disclosed in the document or well known to a person skilled in the art the method preparation.For example, shown in flow process 7, utilize sodium cyanide to handle br-derivatives 21 and obtain nitrile 22; Utilize hydrogen and catalytic palladium optionally to reduce nitro, obtain amine 23; Utilize SULPHURYL CHLORIDE 7 acylated amines 23, obtain corresponding sulphonamide 24; Utilize cobalt chloride and sodium borohydride reduction compound 24, obtain required amine 25.
Flow process 7
In addition, for example obtain wherein X and be-CH with the cyano group of cobalt chloride and sodium borohydride reduction intermediate 23 2CH 2-and m be 1 diamines 5, this diamines can be by flow process 3 described modifications then.
Shown in flow process 8, made their couplings obtain Compound I in 1-24 hour intermediate II and the III solution heating in polar solvent such as methyl alcohol, acetonitrile, tetrahydrofuran (THF), methyl-sulphoxide or N-Methyl pyrrolidone under the 30-150 ℃ of temperature.React in the methyl alcohol that suits under refluxing and carry out, in addition, also can use salt such as trifluoroacetate or the hydrochloride of amine III.In this case, should in reaction mixture, add alkali such as sodium bicarbonate or diethyl isopropylamine.At J.Org.Chem.43,2923 (1978) middle fast silica gel chromatogram method, medium pressure liquid chromatography method or the HPLC that describe remove unwanted by product with people such as recrystallization, development, preparative thin layer chromatography, W.C.Still, thus purified product.Compound by the HPLC purifying isolated in form of salt accordingly comes out, and purify intermediates can use the same method.
Flow process 8
Figure A9519282100441
In some cases, the coupling product I that obtains by flow process 8 described reactions can further be modified, for example by removing protecting group or handling particularly R 1And R 7On substituting group, these are handled including, but not limited to well known to a person skilled in the art reduction, oxidation, alkylation, acidylate and hydrolysis reaction.
The other method of synthetic compound I has been described in flow process 9.Method by above-mentioned coupling intermediate II and III (flow process 8) makes epoxide II and amine 5 couplings obtain anils 27.Secondary amine can selectively be protected, and for example handles obtaining carbamate 29 with tert-Butyl dicarbonate, thereby protects with the carboxylamine ester-formin.In addition, in coupled reaction, use nitra-amine 26 to obtain 28.After protecting as stated above, the reduction nitro for example carries out catalytic hydrogenation with palladium catalyst or Raney nickel and obtains intermediate 29.In some cases, also can reduce other group thereupon.For example, if the R in the intermediate 28 1Be halogen, it can be converted into the hydrogen in the intermediate 29 so.In the presence of alkali such as pyridine, handle with SULPHURYL CHLORIDE, then remove protecting group, for the t-butyl carbamate protecting group, can use sour hydrogenchloride to carry out deprotection, thereby obtain sulphonamide I as trifluoroacetic acid or methyl alcohol.
Flow process 9
In some cases, can further be modified, for example remove protecting group or handle particularly R by above-mentioned by the Compound I that flow process 9 described reactions steps obtain 1And R 7On substituting group.In addition, can handle the substituting group on arbitrary intermediate in flow process 9 described reactions steps, such example is shown in flow process 10.Use tin chloride (II) to reduce by the compound 30 of corresponding preparation of epoxides and obtain compound 31 by the method shown in the flow process 9.Substituent other example that can be reduced to the method for well known to a person skilled in the art on the Compound I of corresponding amine comprises nitro, cyano group and azido-.
Flow process 10
Shown in flow process 11, compound of the present invention (I) also can be by amine intermediate such as formula III compound and halogenated ketone intermediate suc as formula 2 compound, with halogenated derivative 2 alkylated amines III, the suitable alkali such as salt of wormwood or triethylamine used is handled the mixture of III and 2 in polar solvent such as acetonitrile, acetone or dimethyl formamide.The keto-amine 32 of gained for example obtains required amino alcohol I with the methanol solution reduction of sodium borohydride.
Flow process 11
In some cases, can further be modified, for example by removing protecting group or handling particularly R by the product that flow process 11 described reactions obtain 1And R 7On substituting group, these are handled including, but not limited to well known to a person skilled in the art reduction, oxidation, alkylation, acylations and hydrolysis reaction.
Another synthetic method of key intermediate 29 is shown in flow process 12.The alcohol of intermediate 3 can be protected, for example with its t-butyldimethylsilyl ether form protection, obtains TBS derivative 33.Be generally at solvent with amine 5 and alkali such as diisopropylethylamine then and handle compound 33 down at temperature 25-150 ℃ in polar aprotic solvent such as the acetonitrile and last 1-72 hour.Usually, can add propiodal such as sodium iodide and promote reaction, remove protecting group then, for silyl ether, available fluorine source such as tetrabutylammonium are handled the amine 34 of gained, obtain key intermediate 29 by protection secondary amine noted earlier.
Flow process 12
In some cases, Compound I also can need not to protect secondary amine by 27 direct synthesizing of intermediate.For example, work as R 2And R 3When being methyl, know that with SULPHURYL CHLORIDE 7 alkali such as pyridine are generally 0 ℃ of following anils 27 of handling in temperature-30 to 50 ℃ and obtain Compound I in solvent such as methylene dichloride.
In some cases, can further be modified, for example by removing protecting group or handling particularly R as stated above by the product that flow process 13 described reactions obtain 1And R 7On substituting group.
Flow process 13
Figure A9519282100491
Shown in flow process 14, R wherein 2And R 3For the The compounds of this invention (I) of hydrogen also can be by the sour intermediate of formula 36 and the amino alcohol preparation of formula 37.Handle corresponding ester 35 with SULPHURYL CHLORIDE 7 and alkali such as pyridine and be generally methyl esters or ethyl ester, then obtain sour 36 with aqueous acid or basic hydrolysis ester.(dimethylamino) Phosphonium hexafluorophosphate or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide methiodide makes acid 36 and amine 37 (compound known or the compound that can be easy to prepare by the method for well known to a person skilled in the art in the document) coupling obtain acid amides 38 to use coupler such as benzotriazole base-N-oxygen-three.Then be generally the borane processing and obtain required Compound I with reductive agent.
Flow process 14
By with suitable solvent such as methyl alcohol or ethyl acetate or its mixture fractional crystallization, the diastereomer that compound of Formula I is divided into enantiomorph is right.For example using optically active acid with ordinary method can be single steric isomer with a pair of Chiral Separation that obtains as resolution reagent.
In addition, use the optically pure starting raw material of configuration known by the single-minded synthetic arbitrary enantiomorph that can obtain compound of Formula I of solid.
The compounds of this invention can its pharmaceutically useful acid salt isolated in form come out the salt that for example uses mineral acid and organic acid to obtain.These sour examples are hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetate, trifluoroacetic acid, propionic acid, toxilic acid, succsinic acid, propanedioic acid etc.In addition, containing some compound of acidic functionality such as carboxyl or tetrazolium can its inorganic salt (wherein counter ion are selected from sodium, potassium, lithium, calcium, magnesium etc.) isolated in form and separated by organic bases.
As mentioned above, compound of the present invention has useful pharmacological properties.
The present invention also provides compound of Formula I or its pharmacologically acceptable salt as the active treatment material.
On the one hand, the invention provides compound of Formula I or its pharmaceutically acceptable ester or its pharmacologically acceptable salt of the obesity that is used for the treatment of people or non-human animal.
The present invention also provides compound of Formula I or its pharmaceutically acceptable ester or its pharmacologically acceptable salt of the hyperglycemia (diabetes) that is used for the treatment of people or non-human animal.
Diabetes are characterised in that and are producing and utilizing in the glucose that can cause keeping suitable glucose level metabolism damaged that these damaged results have improved blood glucose or made hyperglycemia.The research of treatment diabetes concentrates on attempts to make fasting and the horizontal normalizing of blood glucose after meal.Treatment comprises that non-enteron aisle takes outer Proinsulin, oral pharmaceutical and dietotherapy.
The diabetes of existing known two kinds of principal modes.Type i diabetes or the diabetes that rely on Regular Insulin are because Regular Insulin definitely damaged, and Regular Insulin is a kind of hormone of regulating glucose utilization.Type ii diabetes or the diabetes that do not rely on Regular Insulin usually be normal or even the situation of the insulin level that raises under take place, and to show be because tissue can not be replied the result of Regular Insulin suitably.Most of type ii diabetes also show obesity.
In addition, but The compounds of this invention triglyceride reducing level, cholesterol levels and can improve hdl level, so The compounds of this invention can be used for treating such reduction (and raising) and is considered to useful medical conditions.The compounds of this invention also can be used for treating the disease of hypertriglyceridemia, hypercholesterolemia and low HDL (high-density lipoprotein (HDL)) level, in addition, it is atherosis that they also can treat atheromatosis such as coronary atherosclerosis, cerebrovascular atherosclerosis and peripheral arterial, cardiovascular disorder and diseases associated.
Therefore, another aspect of the present invention has provided the method for triglyceride reducing and/or cholesterol levels and/or raising hdl level.This method comprises to the animal of needs treatment like this takes formula (I) compound or pharmaceutically acceptable salt thereof of treatment significant quantity.Another aspect of the present invention provides the method for treatment atheromatosis, and this method comprises to the animal of needs treatment like this takes formula (I) compound or pharmaceutically acceptable salt thereof of treatment significant quantity.Prepare and use composition by the general method that is used for the treatment of diabetes and obesity following detailed description, composition also can contain known other active ingredient that is used for the treatment of atheromatosis and diseases related, for example fibrates such as clofibrate, Bezalip Tablets and gemfibrozil; Cholesteral biosynthesis inhibitor such as HMG-CoA reductase inhibitor be lovastatin (lovastatin), simvastatin (simvastatin) and piperazine Liprevil (pravastain) for example; Cholesterol absorption inhibitor is β-Gu Zaichun and (acyl-CoA: inhibitor linolexamide for example cholesterol acyltransferase) for example; Anionite-exchange resin is the dialkyl aminoalkyl derivative of QUESTRAN, colestipol or sephadex for example; Nicotinic alcohol, nicotinic acid or its salt; Vitamin-E; And plan thyroid drug.
Compound of the present invention also has the effect of the motility that reduces intestines, therefore can be used for various gastrointestinal illnesss of assisting therapy such as the supersensitivity syndrome of defecating.The someone to propose the motility of non-sphincteral smooth muscle contraction be to pass through β 3The activity of adrenergic receptor is conducted, and β is slightly only arranged 1And β 2The β of receptor active 3The acquisition of specific agonist will help the pharmacology control of intestinal motility and not have cardiovascular effect simultaneously.The common similar dosed administration that is used for the treatment of diabetes and obesity as described below of The compounds of this invention.
Find unexpectedly that also The compounds of this invention can be used as β 3The agonist of adrenergic receptor, therefore can be used for treating gastrointestinal illness, particularly peptic ulcer, esophagitis, gastritis, duodenitis (comprising), intestinal ulcer (comprising inflammatory stool disease, ulcerative colitis, Crohn disease and rectitis) and gastroenteritic ulcer by Helicobacter pylori inductive enteritis.
In addition, β 3Acceptor has shown the release of the neuropeptide in some Sensory fibre of lung inhibited.Because comprising in the flu in tracheae neuron inflammation, sensory nerve plays an important role, therefore, and particular beta of the present invention 3Agonist can be used for treating neuron inflammation such as asthma and cardiorespiratory system is only had very little effect.
By stimulating the β in the brain 3Acceptor, β 3Adrenergic receptor also can produce the selectivity antidepressant effect, and therefore, the other desired use of The compounds of this invention is as antidepressive.
The drug composition oral administration that active compound of the present invention can form with inert diluent or absorbable edible carrier, active compound also can be packed in hard or the soft shell capsule, or they can be pressed in the tablet, or they can be with food directly in conjunction with administration.Comprise sublingual administration for oral therapeutic administration, these active compounds also can with mixed with excipients, and use with forms such as tablet, pill, capsule, ampulla, sachet agent, elixir, suspension agent, syrups.These compositions and preparation should contain at least 0.1% active compound.Certainly, the per-cent of active compound can change in these compositions, suits about 2% between about 60% unit weight.In these medicative compositions, the amount of active compound is the amount that will obtain effective dose.Active compound also can dropping liquid agent or spray form intranasal administration.
The variation of the effective dose of employed activeconstituents is depended on used particular compound, administering mode, the disease of being treated and the severity of the disease of being treated.
When treatment diabetes and/or hyperglycemia, if The compounds of this invention divides 2 times to 6 times with given divided dose or generally can obtain gratifying result with the sustained release form administration to the per daily dose of about 100mg/kg the weight of animals with about 0.1mg preferred every day.For most of Mammalss, total per daily dose is that about 1.0mg is to the extremely about 50mg of about 1000mg preferably approximately 1mg.For the 70kg adult, total per daily dose is generally about 7mg to about 350mg.Can reply to obtain best treatment by the conditioning agent weight range.
When treatment has the obesity of diabetes and/or hyperglycemia or only obesity is arranged, if The compounds of this invention divides 2 times to 6 times with given divided dose or generally can obtain gratifying result with the sustained release form administration to the per daily dose of about 1000mg/kg the weight of animals with 1mg preferred every day.For most of Mammalss, total per daily dose is about 10mg to about 10, and 000mg, preferably approximately 10mg be to about 500mg, and for the 70kg adult, total per daily dose is generally about 70mg to about 3500mg.Can reply to obtain best treatment by the conditioning agent weight range.
Tablet, pill, capsule etc. also can contain tackiness agent such as tragakanta, gum arabic, W-Gum or gelatin; Vehicle such as Lin Suanergai; Disintegrating agent such as W-Gum, yam starch, alginic acid; Lubricant such as Magnesium Stearate; Sweetener such as sucrose, lactose or asccharin.When unit dosage was capsule, except the material of mentioned kind, it can also contain liquid vehicle such as fatty oil.
Also can exist various other materials as dressing or change the physical form of unit dosage.For example, tablet can carry out dressing with shellac, sugar or both.Except activeconstituents, syrup or elixir can contain sucrose as sweetener, as methyl p-hydroxybenzoate and propyl ester, dyestuff and seasonings such as the cherry or the orange seasonings of sanitas.
These active compounds also can be through parenterai administration.The solution of these active compounds or suspension can with tensio-active agent such as the suitable blended water of hydroxypropylcellulose in prepare.Dispersion agent also can prepare in glycerine, liquid polypropylene glycol and the mixture in oil thereof.Under the normal condition of storing and using, these preparations can contain sanitas to prevent microbial growth.
The pharmaceutical dosage form that is suitable for injecting use comprises aseptic aqueous solution or dispersion liquid and the sterile powder that is used for temporarily preparing aseptic injectable solution or dispersion liquid.In all cases, formulation must be aseptic, and must to be liquid be present in the syringe being convenient to.Formulation must be stable under preparation and storage requirement, and should prevent the pollution of microorganism such as bacterium and fungi.Carrier can be solvent or separating medium, and it contains just like water, ethanol, polyvalent alcohol (for example glycerine, propylene glycol and liquid macrogol) and suitable mixture and vegetables oil.
The following example that is provided is in order to understand the present invention more fully, is any limitation of the invention and should not be considered as them.
Embodiment 1 (R)-and N-[2-[4-(aminophenyl)] ethyl]-2-hydroxyl-2-(tetrazolo [1,5-a] pyridine-6-base second] amine
With 1.62g (10mmol) (R)-2-(tetrazolo [1,5-a] pyridine-6-yl) oxyethane is (referring to Fisher ﹠amp; Wyvratt european patent application 0318092 A2, synthetic this compound) and the vlil of 4.1g (30mmol) 2-(4-aminophenyl) ethamine in 30ml methyl alcohol 5 hours, concentrated reaction mixture, resistates obtains 1.69g (56%) title compound with silica gel chromatography purifying (2% methyl alcohol/98% methylene dichloride): 1H NMR (400MHz, CD 3OD) δ 9.01 (d, 1H, J=1.3Hz), 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, 2 H, J=7.1Hz).
Embodiment 2
Figure A9519282100542
(R)-and N-[2-[4-(aminophenyl)] ethyl]-2-hydroxyl-2-(tetrazolo [1,5-a] pyridine-6-yl) ethyl carbamic acid 1,1-dimethyl ethyl ester
Under 0 ℃, 1.69g (56.7mmol) was derived from the amine of embodiment 1 and the solution stirring of 1.23g (56.7mmol) tert-Butyl dicarbonate in 10ml tetrahydrofuran (THF) (THF) 2 hours, concentrated reaction mixture, resistates obtains 2.2g (97%) title compound with silica gel chromatography purifying (4% methyl alcohol/96% methylene dichloride):
1H?NMR(400MHz，CD 3OD)δ8.96(s，1H)，8.05(m，2H)，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).
Embodiment 3 4-(hexyl amino carbonyl amino) benzene sulfonyl chloride
Under 0 ℃ with hexylamine (12.15ml 9.2mmol) is added drop-wise in THF (150ml) solution of 10ml (9.2mmol) phenylcarbimide, continue to stir 1 hour, solvent removed in vacuo, the hexyl phenylurea of gained can use and need not to be further purified.
(6g 2.7mmol) was added in the chlorsulfonic acid in 20 minutes, then 60 ℃ of heating 2 hours down to obtain product under 0 ℃ above with portion.After the cooling, mixture is added in ice/water (100ml), with EtOAc (3 * 100ml) aqueous phase extracted.The organic phase that merges is used MgSO with salt solution (50ml) washing 2Dry, concentrated.Obtain 6g (70%) title compound with purification by flash chromatography (silica gel, 75% hexane/25% ethyl acetate): 1H NMR (CDCl 3) δ 7.85 (d, 2H, J=9.6Hz), 7.54 (d, 2H, 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, 6H), 0.91-0.79 (m, 3H).
Embodiment 4
Figure A9519282100552
(R)-and N-[4-[2-[N-(1, the 1-dimethyl ethoxycarbonyl)-N-[2-hydroxyl-2-(tetrazolo [1,5-a] pyridine-6-yl)] ethyl] amino] ethyl] phenyl]-4-(hexyl amino carbonyl amino) benzsulfamide
In the 3ml dichloromethane solution of the Boc-compound of the 0.200g that is stirring (0.502mmol) embodiment 2, add 80mg (1.00mmol) pyridine.The SULPHURYL CHLORIDE that then adds 0.16g (0.75mmol) embodiment 3.Stir after 5 hours, concentrated reaction mixture, resistates obtains 0.303g (88%) title compound with silica gel chromatography purifying (10% methyl alcohol/90% methylene dichloride). 1H?NMR(400Hz，CD 3OD)δ8.95(s，1H)，8.0-8.08(m，1H)，7.75-7.87(m，1H)，7.40-7.62(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).
Embodiment 5 (R)-and N-[4-[2-[[2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino] ethyl] phenyl]-4-(hexyl amino carbonyl amino) benzsulfamide
With the tetrazine of 0.302g (0.44mmol) embodiment 4,0.20g (0.88mol) titanium chloride (II) dihydrate and the 0.3ml concentrated hydrochloric acid mixture heating up in 2ml methyl alcohol refluxed 5 hours.Concentrated reaction mixture, resistates obtains 0.32g (78%) title compound with anti-phase MPLC purifying (C8,47% methyl alcohol/530.1% trifluoroacetic acid damping fluid), and it is two (trifluoroacetic acid) salt: 1H NMR (400MHz, CD 3OD) δ 7.96 (dd, 1H, J=2.0,9.2Hz), 7.86 (d, 1H, J=2.0Hz), 7.59 (d, 2H, J=8.8Hz), 7.43 (d, 2H, J=8.8Hz), 7.14 (d, 2H, J=8.4Hz), 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, 4.0Hz), 1.49 (t, 2H, J=6.0Hz), 1.32 (m, 8H), 0.91 (t, 3H, J=6.0Hz); CI MS m/z 555 (M+1).
According to the described method of embodiment 1-5, the listed compound of preparation table 1.
Table 1
Figure A9519282100571
Embodiment R Select 1H?NMR(CD 3OD) data
6 Ph, trifluoroacetate 7.74(m，2H)，7.53(m，1H)，7.45 (m，2H).
7 2-naphthyl trifluoroacetate 7.93(m，4H)，7.75(d，1H，J＝1.7 Hz)，7.61(m，2H)
8 3-quinolyl trifluoroacetate 9.00(d，1H，J＝2.3Hz)，8.06(m， 2H)，7.94(m，2H)，7.72(t，1H，J＝ 7.2Hz)
9 1,2-benzoisoxazole [5-base trifluoroacetate 9.02(s，1H)，8.30(d，1H，J＝1.3 Hz)，7.90(m，1H)，7.77(m，1H)
10 4-iodophenyl trifluoroacetate 7.83(d，2H，J＝8.6Hz)，7.46(d， 2H，J＝8.6Hz)
11 The 4-[(N-hexyl, N-methylamino carbonyl) amino] phenyl, trifluoroacetate, 7.62(d，2H，J＝4.6Hz)，7.48(d， 2H，J＝4.6Hz)，2.99(s，3H)
12 4-[(N, N-dimethylamino carbonyl) amino] phenyl, trifluoroacetate 3.0(s，6H)
13 4-(3-hexyl-2-imidazolone-1-yl) phenyl, trifluoroacetate 3.88-3.83(m，2H)，3.57-3.50(m， 2H)，2.89-2.95(m，2H)，1.61-1.52 (m，2H)，1.37-1.30(m，6H)，and 0.93-0.88(m，3H)
Embodiment 14
Figure A9519282100581
3-(2-chloracetyl) pyridine hydrochloride
To 12g (11ml, 100mmol) hydrogenchloride of adding 100ml 1M ether in the 100ml diethyl ether solution of 3-acetylpyridine.Filter the precipitation of gained, collect and obtain 15.0g (95.2mmol), put into the 500ml round-bottomed flask that magnetic stirring bar is housed then.To the acetic acid solution that wherein adds 95ml 1M hydrogenchloride.Stir the mixture after all solids dissolving, disposable adding 12.7g (95.2mmol) N-chloro-succinimide (NCS), the solution becomes yellowly, NCS dissolves gradually.After 4 hours, form white precipitate, mixture was stirred 2.5 days, filter then.The solid of collecting obtains the title compound of 15.2g (83%) white solid with 10ml acetate and the washing of 200ml ether: 1H NMR (200MHz, d 6-DMSO) δ 9.22 (t, 1H, J=1Hz), 8.29 (dd, 1H, J=1.6,5.1Hz), 8.55 (td, 1H, J=2,8.1Hz), 7.82 (ddd, 1H, J=0.8,5.1,8.1Hz), 5.27 (s, 2H).
Embodiment 15
Figure A9519282100582
(R)-α-chloromethyl-3-piconol
At the 5ml THF pulpous state liquid that in the 11ml THF solution of the 3.67g that is stirring (11.5mmol) (-)-B-chlorine two different loose amphene base boranes [(-)-DIP-Cl], adds the product of 1.00g (5.21mmol) embodiment 14 under-25 ℃ by sleeve pipe.After adding 0.80ml (5.79mmol) triethylamine ,-25 ℃ of following stirred reaction mixtures 4 days, in mixture, add 10ml water, be heated to room temperature then, in mixture, add the 20ml ethyl acetate, isolate organic phase, the saturated NaHCO of water 3The solution neutralization is used ethyl acetate extraction 6 times then.The organic phase that vacuum concentration merges obtains yellow oil, and purification by flash chromatography (silica gel, 75-100% ethyl acetate-hexane) obtains 561mg (68%) title compound, is light yellow oil: 1H NMR (400MHz, CD 3OD) δ 8.58 (d, 1H, J=1.8Hz), 8.46 (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).
Embodiment 16
Figure A9519282100591
(R)-(pyridin-3-yl) oxyethane
In the 16ml acetone soln of the product of 557mg (3.55mmol) embodiment 15, add 1.80g salt of wormwood, mixture heating up was refluxed 20 hours, be cooled to room temperature then, filtering mixt, vacuum-evaporation filtrate, purification by flash chromatography (silica gel, 2% methyl alcohol-methylene dichloride) obtains 262mg (61%) title compound, is light yellow oil:
1H?NMR(200MHz，CDCl 3)δ8.54(m，2H)，7.52(m，1H)，7.24(m，1H)，3.86(dd，1H，J＝4.0，2.5Hz)，3.17(dd，1H，J＝5.4，4.0Hz)，2.80(dd，1H，J＝5.4，2.5Hz).
Embodiment 17
Figure A9519282100592
(R)-and N-[2-[4-(aminophenyl)] ethyl]-2-hydroxyl-2-(pyridin-3-yl) ethamine
The 15ml methanol solution that adds the product of 300mg (2.48mmol) embodiment 16 to the 10ml methanol solution of the 377mg that is stirring (2.44mmol) 4-amino-benzene ethamine.Mixture heating up was refluxed 16 hours, be cooled to room temperature then, vacuum is removed methyl alcohol, resistates obtains 101mg (16%) title compound and 279mg mixture through chromatogram purification (silica gel, 6-8% methyl alcohol, 1% ammoniacal liquor-methylene dichloride), with mixture chromatogram purification (5% methyl alcohol again, 1% ammoniacal liquor-methylene dichloride), obtain 54mg (9%) title compound in addition, be pale solid:
1H?NMR(500MHz，CD 3OD)δ8.52(d，1H，J＝1.8Hz)，8.43(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)，2.90-2.65(m，6H).
Embodiment 18
Figure A9519282100601
(R)-and N-[2-[4-(aminophenyl)] ethyl]-2-hydroxyl-2-(pyridin-3-yl) ethyl carbamic acid 1,1-dimethyl ethyl ester
The 3.5ml THF solution that in being cooled to 0 ℃ the 3.6ml THF pulpous state liquid of product of the 456mg that is stirring (1.77mmol) embodiment 17, adds 386mg (1.77mmol) tert-Butyl dicarbonate by sleeve pipe.Yellow solution was stirred 3 hours down at 0 ℃, and vacuum is removed THF then, and purification by flash chromatography (silica gel, 10% methyl alcohol, 1% ammoniacal liquor-methylene dichloride) obtains 549mg (87%) title compound, is pale solid: 1H NMR (500MHzCD 3OD, mixture of rotomers) δ 8.45 (m, 2H), 7.83 (d, 0.6H, J=7.4Hz), 7.78 (d, 0.4H, J=6.9Hz), 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, 1H), 3.42-3.21 (m, 4H), 2.67 (m, 2H), 1.39 (s, 5.4H), 136 (s, 3.6H).
Described in another synthetic method such as embodiment 19-23 of anils among the embodiment 18:
Embodiment 19 2-chloro-5-(2-acetyl bromide) pyridine hydrochloride
Be added in the 10ml THF solution of 1.44g dibromobarbituric acid (DBBA) by the 10ml THF solution of sleeve pipe with 784mg 2-chloro-5-acetylpyridine, the solution of gained heated 12 hours down at 50-55 ℃, added other 0.72g DBBA then.After stirring under 50-55 ℃ more than 2.5 hours, add 0.36g DBBA, mixture to be stirred 2 hours, this moment, the NMR analysis revealed transformation efficiency of aliquots containig was 87%.Reaction mixture is with the ethyl acetate dilution, with two parts of saturated sodium bicarbonate aqueous solutions, water and salt water washing, with dried over mgso and concentrated.Obtain the title compound of 0.86g (73%) white solid with purification by flash chromatography (silica gel, 15% ethyl acetate/hexane): 1H NMR (400MHz, CDCl 3) δ 8.96 (d, 1H, J=2.6Hz), 8.21 (dd, 1H, J=2.5,8.3Hz), 7.46 (d, 1H, J=8.4Hz), 4.37 (s, 2H).NMR also shows has corresponding 2-br-derivatives to exist.Synthetic obtain about 4: 1 mixture by this.
Embodiment 20
Figure A9519282100611
(R)-α-brooethyl-3-(6-chloropyridine) methyl alcohol
The 1.5mlTHF solution of the ketone by the 200mg embodiment 19 under adding-25 ℃ in the 0.5ml THF solution of 602mg (1.88mmol) (-)-DIP-Cl of sleeve pipe under-25 ℃.Reaction mixture stirred 17 hours down at-25 ℃, added the entry termination reaction then, used extracted with diethyl ether.Ether with two parts of saturated sodium bicarbonate aqueous solutions, water and salt water washing, with dried over mgso and concentrated, obtains l70mg (84%) title compound with purification by flash chromatography (silica gel, 15 and 25% ethyl acetate/hexane) with the ethyl acetate dilution: 1H NMR (400MHz, CDCl 3) δ 8.38 (d, 1H), 7.70 (dd, 1H), 7.32 (d, 1H), 4.97 (m, 1H), 3.61 (dd, 1H), 3.50 (dd, 1H), 2.85 (d, 1H).
Embodiment 21 (R)-(2-chloropyridine-5-yl) oxyethane
1: 1 THF of 2ml to the bromohydrin of 100mg embodiment 20: add the 1ml5N aqueous sodium hydroxide solution in the solution of water.Mixture was stirred 10 minutes, use three parts of dichloromethane extractions then.The organic phase that merges obtains 98mg (93%) title compound with two parts of water and salt water washing with dried over mgso is also concentrated, need not to be further purified then and can use: 1H NMR (400MHz, CDCl 3) δ 8.34 (d, 1H), 7.48 (dd, 1H), 7.29 (d, 1H), 3.86 (dd, 1H), 3.18 (dd, 1H), 2.78 (dd, 1H).
Embodiment 22
Figure A9519282100622
(R)-and N-[2-[4-(nitrophenyl)] ethyl]-2-hydroxyl-2-(2-chloropyridine-5-yl) ethyl carbamic acid 1,1-dimethyl ethyl ester
According to embodiment 17 and 18 described methods, prepare title compound by epoxide and the 4-nitrophenyl ethamine of embodiment 21: 1H NMR (400MHz, CDCl 3) δ 8.32 (d, 1H, J=1.3Hz), 8.13 (d, 2H, J=8.6Hz), 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).
Embodiment 23
Figure A9519282100631
(R)-and N-[2-[4-(aminophenyl)] ethyl]-2-hydroxyl-2-(pyridin-3-yl) ethyl carbamic acid 1,1-dimethyl ethyl ester
In the 2ml ethanolic soln of the nitro-compound of 80mg (0.19mmol) embodiment 22, add 0.114ml (0.57mmol) 5N aqueous sodium hydroxide solution and 20mg Raney nickel.Reaction mixture is vibrated 16 hours under room temperature 45psi hydrogen, mixture neutralizes with the saturated monosodium phosphate aqueous solution, with three parts of ethyl acetate extractions.The organic phase water and the salt water washing that merge, dry (sal epsom) also concentrates and obtains 40mg (59%) title compound, and the prepared sample of this compound and embodiment 18 is identical.
Embodiment 24
Figure A9519282100632
4-(3-hexyl-2-imidazolone-1-yl) phenyl SULPHURYL CHLORIDE
Under 0 ℃ with hexyl iodide (50mmol, 7.38ml) be added to 2-aminoacetaldehyde dimethylacetal (100mmol, 11ml) and salt of wormwood (50mmol, 6.9g) the mixture of DMF (10ml) in, before with ethyl acetate (200ml) dilution, continue to stir 16 hours, use the plug of celite filtering solution.Vacuum concentration is then with column chromatography purifying (eluent: ethyl acetate) obtain N-hexyl 2-aminoacetaldehyde dimethylacetal (7.39g, 78%), be colorless oil.
Under 0 ℃ to amine (38.6mmol; 7.3g) methylene dichloride (100ml) solution in add 4-(chlorosulfonyl) phenyl isocyanate (38.6mmol; 8.4g), reaction mixture is stirred 20 minutes until forming clear soln, add l: 1 water: trifluoroacetic acid (amounting to 100ml).Continued vigorous stirring 16 hours, separate each layer, organic layer dilutes with ethyl acetate (500ml), with saturated sodium bicarbonate solution (4 * 50ml), salt solution (50ml) washing, use anhydrous magnesium sulfate drying, vacuum concentration is with column chromatography purifying (eluent: 3 hexanes/1 ethyl acetate) obtain title compound, be pale yellow crystals (8.8g, 67%).
Embodiment 25 (R)-and N-[4-[2-[[2-hydroxyl-2-(pyridin-3-yl) ethyl] amino] ethyl] phenyl]-4-(hexyl amino carbonyl amino) benzsulfamide
4-(hexyl amino carbonyl amino) benzene sulfonyl chloride that in the 10ml dichloromethane solution of the product of 302mg (0.845mmol) embodiment 18 and 137ml (1.69mmol) pyridine, adds 296mg (0.928mmol) embodiment 3; reaction mixture was stirred 12 hours; solvent removed in vacuo then; purification by flash chromatography (silica gel; 6% methyl alcohol, 0.5% ammoniacal liquor-methylene dichloride) obtain the title compound of 468mg (87%) BOC protection.
The 5ml methylene dichloride and the 5ml trifluoroacetic acid solution of the protected title compound of 468mg (0.731mmol) BOC-were stirred 30 minutes; vacuum is removed the volatilization composition then; resistates is with twice of 10% methanol/toluene azeotropic; with twice of methanol azeotropic; vacuum-drying obtains 521mg (93%) title compound then, and it is its trifluoroacetate: 1H NMR (400MHz, CD 3OD) 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=8.6,2.1Hz), 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).
Embodiment 26
Figure A9519282100651
(N)-[4-[2-[(phenyl methoxycarbonyl) amino] ethyl] phenyl]-4-cyano group benzsulfamide
According to embodiment 4 described methods, prepare title compound by 2-(4-aminophenyl) ethyl carbamic acid phenyl methyl ester (referring to people such as Fisher, european patent application 0611003 A1,1994) and 4-cyano group benzene sulfonyl chloride: 1H NMR (400MHz, CD 3OD) δ 1H NMR (400MHz, CDCl 3) δ 7.8 1 (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=8.4Hz), 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).
Embodiment 27
Figure A9519282100652
(N)-[4-[2-[(phenyl methoxycarbonyl) amino] ethyl] phenyl]-4-amino isonitroso methyl) benzsulfamide
With the nitrile of embodiment 26 (2.71g, 6.23mmol), dehydrated alcohol (65ml), fine powdered K 2CO 3(5.17g, 37.4mmol) and hydroxylamine hydrochloride (2.17g, 31.2mmol) mixture refluxed 6 hours, remove ethanol under the decompression, the solid of gained is dissolved in the ethyl acetate, wash with water 3 times, the vacuum concentration organic phase, obtain the title compound of 2.87g (98%) white powder, product has enough purity, and it can be used in the next step:
1H?NMR(400MHz，CD 3OD)δ?7.71(s，4H)，7.31(m，5H))，7.04(d，2H，J＝8.4Hz)，6.99(d，2H，J＝8.4Hz)，5.02(s，2H)，3.25(t，2H，J＝6.8Hz)，2.67(t，2H，J＝6.7Hz).
Embodiment 28 (N)-[4-[2-[(phenyl methoxycarbonyl) amino] ethyl] phenyl]-4-[5-(3-cyclopentyl propyl group)-[1,2,4] oxadiazole-3-yl] benzsulfamide
(0.468g, (0.175g, 1.00mmol), mixture refluxed 3.5 hours to add 4-cyclopentyl butyryl chloride in anhydrous pyridine 1.00mmol) (5.0ml) solution to the compound of embodiment 27.Pyridine is removed in decompression, and the gained resistates obtains 0.152g (26%) title compound with silica gel chromatography purifying (hexane solution of 35% ethyl acetate): 1H NMR (400MHz, CDCL 3) δ 8.12 (d, 2H, J=8.7Hz), 7.81 (d, 2H, J=8.7Hz), 7.31 (m, 5H), 7.03 (d, 2H, J=8.1Hz), 6.97 (d, 2H, J=8.4Hz), 6.67 (s, 1H), 5.05 (s, 2H), (4.70 t, br 1H), 3.37 (q, 2H, J=6.5Hz), 2.91 (t, 2H, J=7.6Hz), 2.72 (t, 2H, J=7.0), 1.90-1.70 (m, 5H), 1.65-1.30 (m, 6H), 1.06 (m, 2H).
Embodiment 29
Figure A9519282100671
(N)-[4-(2-amino-ethyl) phenyl]-4-[5-(3-cyclopentyl propyl group)-[1,2,4] oxadiazole-3-yl] benzsulfamide
Cbz amine (0.145g with embodiment 28,0.246mmol), the mixture hydrogenation of palladium hydroxide/carbon (0.02g) and Glacial acetic acid (5.0ml) 2 hours, the decompression under remove acetate, resistates with the silica gel chromatography purifying (methanol solution of 1: 9 10% ammonium hydroxide: methylene dichloride) obtain 0.058g (52%) title compound: 1HNMR (400MHz, CD 3OD) δ 8.11 (d, 2H, J=8.6Hz), 7.87 (d, 2H, J=8.5Hz), 7.06 (d, 2H, J=8.6Hz), 7.02 (d, 2H, 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), 1.70-1.40 (m, 6H), 1.12 (m, 2H).
Embodiment 30
Figure A9519282100672
(R)-and N-[4-[2-[[2-hydroxyl-2-(pyridin-3-yl) ethyl] amino] ethyl] phenyl]-4-[5-(3-cyclopentyl propyl group)-[1,2,4] oxadiazole-3-yl] benzsulfamide
To the amine of embodiment 29 (0.053g, add in anhydrous methanol 0.117mmol) (30.0ml) solution embodiment 16 3-pyridine ring oxide compound (0.021g, 0.175mmol).The backflow of gained solution is spent the night, and after concentrating, resistates obtains 0.01g (15%) title compound with silica gel chromatography purifying (dichloromethane solution of 13% methyl alcohol): 1H NMR (400MHz, CD 3OD) δ 8.52 (d, 1H, J=1.9Hz), 8.42 (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), 7.03 (d, 2H, J=8.6Hz), 4.81 (dd, 1H, J=4.9,8.1Hz), 2.96 (t, 2H, J=7.5Hz), 2.93-2.70 (m, 6H), 1.90-1.72 (m, 5H), 1.68-2.48 (m, 4H), 1.42 (m, 2H), 1.11 (m, 2H).
Embodiment 31 (R)-and N-[4-[2-[[2-hydroxyl-2-(pyridin-3-yl) ethyl] amino] ethyl] phenyl]-4-[4-(1-hydroxyl-1-hexyl heptyl)-5-methyl-[1,2,3]-and triazole-2-yl] benzsulfamide and (R)-N-[4-[2-[[2-hydroxyl-2-(pyridin-3-yl) ethyl] amino] ethyl] phenyl]-4-[4-(1-(R, S)-the hydroxyl heptyl)-5-methyl-[1,2,3]-and triazole-2-yl] benzsulfamide
Under 0 ℃ of argon atmospher to 180mg (R)-N-[4-[2-[[2-hydroxyl-2-(pyridin-3-yl) ethyl] amino] ethyl] phenyl]-4-[4-methoxycarbonyl-5-methyl-[1,2,3] triazole-2-yl) be added dropwise to the diethyl ether solution of 2ml 2.0M n-hexyl magnesium bromide in the distilled THF solution of 2ml of benzsulfamide (by the preparation of the described method of embodiment 14-19), after 5 minutes, the careful 5ml aqueous ammonium chloride solution termination reaction that adds, then use the ethyl acetate extraction water layer, the organic extract liquid dried over sodium sulfate that merges, filter, vacuum concentration obtains crude product, preparation of lamina chromatogram (PLC) purifying with the thick silica-gel plate of 2 * 0.5mm, with 9: 1 (v/v) methylene dichloride: methanol-eluted fractions obtained two bands of a spectrum A (20mg) and B (60mg).
1H NMR (500MHz, CD 3OD) of A: δ 8.51 (d, 1H, J=2Hz), 8.41 (dd, 1H, J=1.5,5Hz), 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 3OH), 4.79 (dd, 1H, J=7.5,8Hz), (m, 6H), 2.44 (s, 3H), 1.85 (m, 4H), (m, 16H), 0.83 (t, 6H J=7Hz) are indicated as dihexyl tertiary alcohol affixture to 1.40-1.15 to 2.9-2.7, and the mass spectrum desired value is 677, and measured value is 677.
1H NMR (500MHz, CD 3OD) of B:8.51 (d, 1H, J=2Hz), 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), 7.07; 7.02 (ABq, 4H, Jab=8Hz), 4.86 (s, CD 3OH), 4.80 (m, 2H), 2.9-2.7 (m, 6H), 2.38 (s, 3H), 1.87 (m, 2H), 1.44 (m, 1H), and 1.4-1.2 (m, 7H), 0.87 (t, 3H J=7Hz) are indicated as a hexyl affixture, the mass spectrum desired value is 591 (for hexyl ketones), and measured value is 593 (hexanol reduces intermediate ketone with Grignard reagent on the spot).
According to the described method of embodiment 14-31, listed compound in the preparation table 2:
Table 2
Figure A9519282100701
Embodiment R Select 1H?NMR(CD 3OD) data
??32 The 4-isopropyl phenyl 7.64(d，2H，J＝8.0Hz)，7.33(d， 2H，J＝8.0Hz)，4.80(m，1H)，2.95- 2.70(m，7H)，1.22(d，6H，J＝6.7 Hz)
??33 The 4-iodophenyl, two (trifluoroacetic acid) salt 7.84(d，2H，J＝8.6Hz)，7.47(d， 2H，J＝8.6Hz)，5.19(dd，1H，J＝ 10.1，3.0Hz)，3.40-3.20(m，4H)， 2.96(m，2H)
??34 The 2-naphthyl 8.28(s，1H)，7.94(m，3H)，7.72 (dd，1H，J＝8.7，1.9Hz)，7.60(m， 2H)
??35 The 3-quinolyl, two (trifluoroacetic acid) salt 9.01(d，1H，J＝2.3Hz)，8.76(d， 1H，1.8Hz)，8.08(d，1H，J＝8.7 Hz)，8.04(d，1H，J＝8.0Hz)，7.93 (m，1H)，7.73(m，1H)
36 The 4-[(N-hexyl, N-methylamino carbonyl) amino] phenyl, two (trifluoroacetic acid) salt 5.12(d，1H，J＝8.7Hz)，3.40-3.10 (m，6H)，2.99(s，3H)，2.95(m，2H)， 1.56(m，2H)，1.31(m，6H)，0.88 (m，3H)
37 4-(3-hexyl-2-imidazolone-1-yl) phenyl, two (trifluoroacetic acid) salt 5.15(m，1H)，3.85(m，2H)，3.53 (m，2H)，3.40-3.15(m，6H)，2.94 (m，2H)，1.55(m，2H)，1.32(m， 6H)，0.89(m，3H).
38 4-[(1-oxo heptyl) amino] phenyl, two (trifluoroacetic acid) salt 2.35 (tr, 2H, J=7.5Hz), 1.65 (quintets, 2H, J=7.1Hz), 1.32 (m, 6H), 0.892 (tr, 3H, J=6.8Hz).
39 4-[(1-oxo-4-phenyl butyl) amino] phenyl, two (trifluoroacetic acid) salt 7.34-7.25(m，4H)，7.15-7.05(m， 5H)，2.71(tr，2H，J＝7.7Hz)，2.36 (tr，2H，J-7.4Hz)，1.96(m，2H).
40 The 4-[(third oxygen carbonyl) amino] phenyl 4.07 (tr, 2H, J=6.6Hz), 1.67 (sextet, 2H, J=7.0Hz) .0.968 (tr, 3H, J=7.4Hz).
41 4-[[[furans-2-ylmethyl) amino] carbonyl] amino] phenyl two (trifluoroacetic acid) salt 7.40(d，1H，J＝0.9Hz)，6.32(dd， 1H，J＝2.9，1.8Hz)，6.23(d，1H，J ＝2.9Hz)，4.34(s，2H)
42 The 4-[[[(2-phenylethyl) amino] carbonyl] amino] phenyl, two (trifluoroacetic acid) salt 7.38-7.02(m，9H)，3.50-3.15(m， 6H)，2.80(m，2H)
43 4-[[[(2-draws diindyl-3-base ethyl) amino] carbonyl] amino] phenyl 7.58-7.53(m，3H)，7.42-7.30(m，4 H)，7.08-6.94(m，7H)，3.48(tr，2 H，J＝6.9Hz)2.94(tr，2H，J＝6.8 Hz).
44 4-[[(octyl group amino) carbonyl] amino] phenyl, two (trifluoroacetic acid) salt 2.94(m，2H)，1.51(tr，2H，J＝6.8 Hz)，1.30(m，10H)，0.884(tr，3H， J＝6.9Hz).
45 1-[(hexyl amino) carbonyl] dihydro draws diindyl-5-base 7.83 (d, 2H, J=9.2Hz), 7.48 (m, 2H), 3.92 (t, 2H, J=8.8Hz), 3.1-3.2 (two eclipsed pulse signal t, 4H), 1.54 (m, 2H), 1.30 (m, 6H), 0.90 (t, 3H, J=6.8Hz).
46 1-[(octyl group amino) carbonyl] indoline-5-base 7.83 (d, 2H, J=9.2Hz), 7.48 (m, 2H), 3.92 (t, 2H, J=8.8Hz), 3.1-3.2 (third eclipsed pulse signal t, 4H), 1.63 (m, 2H), 1.30 (m, 10H), 0.89 (t, 3H, J=6.9Hz).
47 1-[(N-methyl-N-octyl group amino) carbonyl] dihydro draws diindyl-5-base 7.53(m，2H)，6.90(d，1H，J＝8.3 Hz)，3.89(t，2H，J＝8.4Hz)，3.26 (t，2H，J＝7.6Hz)，3.04(t，2H，J＝ 8.4Hz)，2.91(s，3H)，1.60(m，2H)， 1.27(m，10H)，0.87(t，3H，J＝6.8).
48 1-(1-oxo nonyl) indolinyl-5-base 7.49(m，2H)，8.09(d，1H，J＝9.1)， 4.04(t，2H，J＝8.5)，3.07(t，2H， J＝8.5)，2.41(t，2H，J＝7.5)，1.62(m， 2H)，1.30(m，10H)，0.88(t，3H， J＝6.8)
49 1-(4-methylthiazol-2-yl) dihydro draws diindyl-5-base 7.87(d，1H，J＝8.6Hz)，7.58(1H， dd，J＝2.0，8.6Hz)，7.52(d，1H，J ＝2.0Hz)，6.48(s，1H)，4.08(t，2H， J＝8.7Hz)，3.25(t，2H，J＝8.7Hz)， 2.30(s，3H).
50 1-(4-octyl group thiazol-2-yl) indoline-5-base 7.97(d，1H，J＝8.6Hz)，7.57(1H， dd，J＝2.0，8.6Hz)，7.53(d，1H，J ＝2.0Hz)，6.49(s，1H)，4.06(t，2H， J＝8.8Hz)，3.24(t，2H，J＝8.8?Hz)， 2.62(t，2H，J＝7.5Hz)，1.68(m， 2H)，1.2-1.4(m，10H)，0.88(t，3H， J＝7.0Hz).
51 1-(4-ethyl-5-methylthiazol-2-yl) dihydro draws diindyl-5-base 7.87(d，1H，J＝8.5Hz)，7.54(1H， dd，J＝2.0，8.5Hz)，7.50(d，1H，J ＝2.0Hz)，4.02(t，2H，J＝8.7Hz)， 3.20(t，2H，J＝8.7Hz)，2.56(q， 2H，J＝7.7Hz)，2.26(s，3H)，1.20 (t，3H，J＝7.7Hz).
52 4-(3-octyl group-2-imidazolone-1-yl) phenyl 4.78(m，1H)，3.83(m，2H)，3.52 (m，2H)，3.24(t，2H，8Hz)，1.60- 1.51(m，2H)，1.35-1.25(m，10H)， 0.88(t，2H，8Hz).
53 4-[3-(4,4,4-trifluoro butyl)-2-imidazolone-1-yl] phenyl, two (trifluoroacetic acid) salt 3.86(m，2H)，3.54(m，2H)，3.40- 3.20(m，6H)，2.19(m，2H)，1.82 (quin，J＝7.9Hz，2H)
54 4-[3-(3-phenyl propyl)-2-imidazolone-1-yl] phenyl, two (trifluoroacetic acid) salt 7.20(m，4H)，7.10(m，1H)，5.15 (dd，1H，9.6，4Hz)，3.75(m，2H)， 3.46(m，2H)，3.36-3.20(m，6H)， 2.95-2.91(m，2H)，2.65(t，2H， 8Hz)，1.90(qu，2H，8Hz).
55 4-[3-(4,4,5,5,5-five fluorine amyl groups)-and 2-imidazolone-1-yl] phenyl, two (trifluoroacetic acid) salt 3.87(m，2H)，3.56(m，2H)，3.40- 3.20(m，6H)，2.14(m，2H)，1.86 (quin，J＝7.8Hz，2H)
56 4-[3-(2-cyclohexyl ethyl)-2-imidazolone-1-yl] phenyl, two (trifluoroacetic acid) salt 3.82 (m, 2H), 3.50 (m, 2H), and 2.87-2.70 (m, 6H), 1.78-1.63 (m, 5H), 1.41 (quartets, 2H, J=7.2Hz), and 1.30-1.18 (m, 4H), 0.949 (m, 2H).
57 4-[3-[3-(4-chloro-phenyl-) propyl group]-2-imidazolone-1-yl] phenyl 7.19(s，4H)，4.79(m，1H)，3.74(m， 2H)，3.47(m，2H)，3.30(m，2H)， 2.63(t，2H，7.6Hz)，1.91-1.83(m， 2H).
58 4-(3-amyl group 2-imidazolone-1-yl) phenyl, two (trifluoroacetic acid) salt 3.82 (m, 2H), 3.53 (m, 2H), 2.94 (m, 2H), 1.57 (quintet, 2H, J=7.4 Hz), 1.39-1.28 (m, 4H), 0.916, (tr, 3H.J=7.1Hz).
59 4-[3-(3-cyclopentyl propyl group)-2-imidazolone-1-yl] phenyl 3.81(m，2H)，3.51(m，2H)，3.23(t， J＝7.3Hz，2H)，1.78(m，3H)，1.57 (m，6H)，1.33(m，2H)，1.17(m， 2H)
60 4-[3-(2-cyclopentyl ethyl)-2-imidazolone-1-yl] phenyl, two (trifluoroacetic acid) salt 3.83(m.2H)，3.53(m，2H)，2.94 (m，2H)，1.81(m，4H)，1.65-1.53 (m，5H)，1.16(m，2H).
61 4-[3-(3-cyclohexyl propyl group)-2-imidazolone-1-yl] phenyl 3.83(m，2H)，3.51(m，2H)，3.22(t， J＝7.3Hz，2H)，1.71(m，5H)，1.56 (m，2H)，1.20(m，6H)，0.88(m， 2H)
62 4-[3-(2,2-dimethyl hexyl)-2-imidazolone-1-yl] phenyl 3.82(m，2H)，3.60(m，2H)，3.03(s， 2H)，1.28(m，6H)，0.93(m，3H)， 0.91(s，6H)
63 4-(3-hexyl 2-imidazolone-1-yl) phenyl 6.93(d，1H，4Hz)，6.70(d，1H， 4Hz)，4.79(m，1H)，3.64(t，2H， 8Hz)，1.71-1.64(m，2H)，1.35-1.28 (m，6H)，0.91-0.86(m，3H).
64 4-[3-(4,4,4-trifluoro butyl)-2-imidazolone-1-yl] phenyl 6.97(d，1H，3Hz)，6.73(d，1H， 3Hz)，3.73(t，2H，7Hz)，2.23-2.19 (m，2H)，1.98-1.92(m，2H).
65 4-(3-octyl group-2-imidazolone-1-yl) phenyl 6.93(d，1H，4Hz)，6.69(d，1H， 4Hz)，3.64(t，2H，7Hz)，1.70-1.63 (m，2H)，1.33-1.23(m，10H)，0.90- 0.85(m，3H).
66 4-[3-(3-cyclopentyl propyl group)-2--imidazolone-1-yl] phenyl 6.93(d，1H，3Hz)，6.69(d，1H， 3Hz)，3.63(t，2H，7Hz)，1.80-1.47 (m，11H)，1.35-1.29(m，2H)，1.13- 1.02(m，2H).
67 4-(2-octyl group-3-oxo-[1,2,4]-triazole-4-yl) phenyl 8.25(s，1H)，3.79(t，2H，7Hz)， 1.80-1.70(m，2H)，1.36-1.25(m， 10H)，0.91-0.86(m，3H).
68 4-(4-hexyl 5-tetrazole ketone-1-yl) phenyl 3.98(t，2H，J＝7.1Hz)，2.9-2.7(m， 6H)，1.82(q，2H，J＝7Hz)，1.4-1.27 (m，6H)，0.89(t，3H，J＝7Hz)
69 4-(4-octyl group-5-tetrazole ketone-1-yl) phenyl 3.98(t，2H，J＝7.1Hz)，2.9-2.7(m， 6H)，1.83(m，2H)，1.4-1.2(m， 10H)，0.87(t，3H，J＝7Hz)
70 4-[(3-cyclopentyl propyl group)-and 5-tetrazole ketone-1-yl] phenyl 3.97(t，2H，J＝7.1Hz)，2.9-2.7(m， 9H)，1.9-1.7(m，5H)，1.6(m，1H)， 1.5(m，1H)，1.37(m，2H)，1.07(m， 1H)
71 4-(2-Wu Ji oxazole-5-yl) phenyl 7.48(s，1H)，4.82(m，1H)，2.92- 2.70(m，8H)，1.80(m，2H)，1.39 (m，4H)，0.92(m，4H)
72 4-(2-Xin Ji oxazole-5-yl) phenyl 7.52(s，1H)，5.09(m，1H)，3.01- 2.82(m，8H)，1.77(m，2H)，1.37- 1.27(m，10H)，0.87(m，1H)
73 4-[2-(2-cyclopentyl ethyl) oxazole-5-yl] phenyl 7.52(s，1H)，4.80(m，1H)，2.94- 2.70(m，8H)，1.79(m，5H)，1.62 (m，2H)，1.54(m，2H)，1.12(m， 2H)
74 4-[(4-ethyl-5-methylthiazol-2-yl) amino] phenyl 7.62(d，2H，J＝9Hz)，7.58(d，2H， J＝9Hz)，2.53(q，2H，J＝7.5Hz)， 2.23(s，3H)，1.18(t，3H，J＝7.5 Hz)
75 4-[(4,5,6,7-tetrahydro benzothiazol-2-yl) amino] phenyl 7.54(d，2H，J＝9Hz)，7.48(d，2H， J＝9Hz)，2.54(m，2H)，2.50(m， 2H)，1.75(m，4H)
76 4-(2-hexyl imidazol-4 yl) phenyl 7.75(s，1H)，5.04(m，1H)，3.29- 3.20(m，4H)，2.97-2.90(m，4H)， 1.82(m，2H)，1.40-1.30(m，6H)， 0.9(m，3H)
77 4-(1-methyl-2-octyl group imidazoles-5-yl) phenyl 7.92(s，1H)，5.30(m，1H)，4.84(s， 3H)，3.48-3.25(m，4H)，3.05-2.95 (m，4H)，1.80(m，2H)，1.50-1.26 (m，10H)，0.89(m，3H)
78 4-[1-methyl-2-(2-cyclopentyl ethyl) imidazoles-5-yl] phenyl 7.41(s，1H)，3.64(s，3H)，2.96-2.68 (m，8H)，1.90-1.79(m，9H)，1.16 (m，2H)
79 4-[1-methyl-2-[2-(4-fluorophenyl) ethyl] imidazoles-5-yl] phenyl 7.40(s，1H)，7.10-6.95(m，4H)， 4.91(m，1H)，3.39(s，3H)，3.0(bs， 4H)
80 4-(5-amyl group-[1,2,4]-oxadiazole-3-yl) phenyl 2.96(t，2H，J＝7.6Hz)，1.84(t，2H， J＝7.4Hz)，1.39(m，4H)，0.92(t，3H， J＝7.1)
81 4-[5-(2-cyclopentyl ethyl)-[1,2,4]-oxadiazoles-3-yl] phenyl 2.98(t，2H，J＝7.5Hz)，1.84(m，5H)， 1.70-1.50(m，4H)，1.16(m，2H)
82 4-(5-hexyl-[1,2,4]-oxadiazole-3-yl) phenyl 2.96(t，2H，J＝7.5Hz)，1.84(quin， 2H，J＝7.4Hz)，1.48-1.28(m，6H)， 0.90(t，3H，J＝7.0Hz)
83 4-(5-heptyl-[1,2,4]-oxadiazoles-3-yl) phenyl 2.96(t，2H，J＝7.5Hz)，1.84(quin， 2H，J＝7.0Hz)，1.46-1.26(m，8H)， 0.89(t，3H，J＝6.9Hz)
84 4-(the own sulfenyl of 5-[1,2,4]-triazole-3-yl) phenyl 3.11(t，2H，J＝7.3Hz)，2.98-2.84 (m，4H)，2.76(t，2H，J＝7.3Hz)，1.65 (q，2H，J＝7.3Hz)，1.37 (q，2H，J＝7.1Hz)，1.28-1.23(m，4H)， 0.84(t，3H，J＝6.9Hz)
85 4-[[4-(4-propyl group piperidines-1-yl)-1,1-dioxo-[1,2,5]-and thiadiazoles-3-yl] amino] phenyl 8.84(s，1H)，8.75(d，1H，J＝5.07 Hz)，8.46(d，1H，J＝8Hz)，7.15& 7.08each(d，2H，J＝8Hz)，0.92(t， 3H，J＝7Hz)
86 4-[[4-(hexyl methyl amino)-1,1-dioxo-[1,2,5]-thiadiazoles-3-yl] amino] phenyl 7.15(d，2H，J＝8.5Hz)，7.12(d，2H， J＝8.5Hz)，5.19(dd，1H，3.1Hz，9Hz)， 2.93(m，2H)，0.90(t，3H，6.8Hz)
87 4-[[4-(heptyl methylamino)-1,1-dioxo-[1,2,5]-thiadiazoles-3-yl] amino] phenyl 7.16(d，2H，J＝8.8Hz)，7.11(d，2H， J＝8.8Hz)，5.01(dd，J＝3.2Hz， 9.9Hz)，2.92(m，2H)，1.68(m，2H)
88 4-(1-octyl group-2.4-imidazolinedione-3-yl) phenyl 4.09(s，2H)，3.41(t，2H，7hz)， 1.65-1.56(m，2H)，1.30-1.25(m， 10H)，0.91-0.86(m，3H).
89 4-[3-(3-nitrophenyl)-5-pyrazolone-1-yl] phenyl 8.55(t，1H，J＝1.9Hz)，8.47(d， 1H，J＝2.0Hz)，8.37(dd，1H， J＝3.2Hz)，8.14(d，2H，J＝8.9Hz)，8.08 (t，2H，J＝8.5Hz)，7.74(d， 3H，J＝8.9Hz)，7.56(t，1H，J＝8.0Hz)， 7.33(dd，1H，J＝4.8Hz)，7.04 (dd，4H，J＝6.6Hz)，4.75(t， 1H，J＝2.1Hz)，2.83-2.69(m，6H)
As starting raw material,, prepare listed compound in the table 3 by commercially available (R)-epoxidation of styrene thing according to embodiment 17,18 and 25 described methods.
Table 3
Figure A9519282100781
Embodiment R Select 1H?NMR(CD 3OD) data
90 4-iodophenyl trifluoroacetate 7.84(d，2H，J＝8.6Hz)，7.45(d， 2H，J＝8.5Hz)
91 The 2-naphthyl, trifluoroacetate 8.31(s，1H)，7.96-7.90(m，3H)， 7.74(dd，1H，J＝1.8，8.7Hz)，7.63 (t.1H)，7.58(t，1H)
92 The 3-quinolyl, trifluoroacetate 9.01(d，1H，J＝2.2Hz)，8.75(d， 1H，J＝2.1Hz)，8.07(d，1H，J＝8.4 Hz)，8.03(d，1H，J＝8.3Hz)，7.92 (t，1H，J＝7.0Hz)，7.72(t，1H，J＝ 7.1Hz)
Embodiment 93 (R)-and N-[4-[2-[[2-hydroxyl-2-(pyridin-3-yl) ethyl] amino]-the 2-methyl-propyl] phenyl]-4-(3-hexyl-2-imidazolone-1-yl) benzsulfamide
Pyridine ring oxide compound (160mg with embodiment 16,1.32mmol) and 4-amino-a, (1.2g, 7.3mmol press J.Biol.Chem.1981 to the a-phenpromethamine, 256, the described preparation of 11944-50) methyl alcohol (8ml) vlil 16 hours, after the cooling, concentrated reaction mixture, with purification by flash chromatography (silica gel, 95: 5 CH 2Cl 2: 10% NH 4OH/CH 3OH) obtain 23mg (0.080mmol) oily product.
(18mg 0.063mmol) is dissolved in CH with above-mentioned product 2Cl 2(1ml) and in the pyridine (0.05ml), gained solution is cooled to 0 ℃, and (22mg 0.063mmol) handles, and mixture stirred 20 hours down at 0 ℃, used purification by flash chromatography (silica gel, 95: 5 CH then with 4-(3-hexyl-2-imidazolone-1-yl) benzene sulfonyl chloride 2Cl 2: 10% NH 4OH/CH 3OH) obtain required oily product (21mg, 0.035mmol): 1HNMR (CD 3OD) δ 8.53 (s, 1H), 8.44 (d, 1H, J=5.0), 7.83 (d, 1H, J=7.9), 7.63 (m, 4H), 7.40 (dd, 1H, 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, 6H), 1.01 (s, 3H), 0.99 (s, 3H), 0.89 (m, 3H).
According to method recited above, the compound in the preparation table 4.
Table 4
Embodiment R Select 1H?NMR(CD 3OD) data
94 The 4-iodophenyl 7.82(d，2H，J＝8.6)，7.42(d，2H， J＝8.6)
95 4-[[(hexyl amino) carbonyl] amino] phenyl 7.55(d，2H，J＝8.8)，7.42(d，2H， J＝8.8)，3.11(t，2H，J＝7.0)，1.49(m， 2H)，1.30(m，6H)，.089(m，3H)
Embodiment 96
Figure A9519282100801
(R)-and 4-amino-α-(brooethyl)-3,5-Dichlorbenzyl Alcohol dimethyl 1,1-dimethylethylsilyl ether
Under ice-water-bath cooling, with tert-butyldimethylsilyl chloride (1.67g, 11.1mmol) DMF (15ml) solution slowly be added to (R)-4-amino-α-(brooethyl)-3 of stirring, 5-Dichlorbenzyl Alcohol (2.1g, 7.4mmol, referring to people such as Judkins, european patent application 0460924) and imidazoles (0.75g, 11.1mmol) DMF (6ml) solution in, stir under the room temperature after 3 hours, in reaction mixture impouring water (300ml), the product extracted with diethyl ether, organic phase saturated sodium bicarbonate aqueous solution, salt water washing, dry (MgSO 4), be evaporated to driedly, obtain title compound (2.73g, 93%) with silica gel purification (95/5 hexane/ethyl acetate) crude product: 1H NMR (400MHz, 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, 6H)
Embodiment 97 (R)-and N-[2-[4-(aminophenyl)] ethyl]-2-[(dimethyl-1, the 1-dimethylethylsilyl) the oxygen base]-2-(4-amino-3,5-two aminophenyls) ethamine
(2.73g 6.86mmol) is dissolved in CH with the O-TBDMS bromine compounds of embodiment 96 3Among the CN (50ml), add 4-amino-benzene ethamine (1.86g, 13.72mmol), then add N, N '-diisopropylethylamine (3.58ml, 20.6mmol) and sodium iodide (1.03g, 6.86mmol), reflux is after 48 hours, concentrated reaction mixture, resistates obtains title compound (2.3g, 75%) with silica gel chromatography purifying (50/50 ethyl acetate/hexane): 1H NMR (400MHz, CDCl 3) δ 7.08 (s, 2H), 6.94 (AA ', 2H, J=8.4Hz), 6.60 (BB ', 2H, J=8.4Hz), 4.63 (m, 1H), 4.37 (s, 2H), 3.53 (br s, 2H), 2.87-2.60 (m, 6H), 0.80 (s, 9H) ,-0.03 (s, 6H)
Embodiment 98
Figure A9519282100811
(R)-and N-[2-[4-(aminophenyl)] ethyl]-2-hydroxyl-2-(4-amino-3,5-dichlorophenyl) ethamine
At room temperature to silyl compound (2.2g, the disposable adding tetrabutylammonium in THF 4.8mmol) (20ml) solution (10ml, the THF solution of 1.0M) of the embodiment 97 that is stirring.After at room temperature stirring 2 hours, concentrated reaction mixture is with silica gel chromatography purifying (10/90 CH 3OH/CH 2Cl 2) obtain title compound (1.59g, 97%): 1H NMR (400MHz, CD 3OD) δ 7.15 (s, 2H), 6.92 (AA ', 2H, J=8.3Hz), 6.60 (BB ', 2H, 8.3Hz), 4.58 (m, 1H), 2.83-2.65 (m, 6H)
Embodiment 99 (R)-and N-[4-[2-[[2-hydroxyl-2-(4-amino-3,5-dichlorophenyl) ethyl] amino] ethyl] phenyl]-4-(hexyl amino carbonyl amino) benzsulfamide
According to embodiment 18 and 25 described methods, prepare title compound by the anils of embodiment 98.
NMR(400MHz，CD 3OD)7.57(AA′，2H，J＝2.7Hz)，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＝6.7Hz).ESIMS?m/z622(M).
According to the described method of embodiment 96-99, the compound in the preparation table 5.
Table 5
Figure A9519282100821
Embodiment R Select 1H?NMR(CD 3OD) data
100 1-[(octyl group amino) carbonyl] indoline-5-base 7.82(d，1H，J＝9.2Hz)，7.47(m， 2H)，3.93(t，2H，J＝9.0Hz)，3.18 (m，4H)，1.53(m，2H)，1.31(m， 10H)，0.88(t，3H，J＝7.1Hz)
101 4-(3-hexyl-2-imidazolone-1-yl) phenyl 7.68-7.60(AA′BB′，4H)，3.82(t， 2H，J＝6.2Hz)，3.52(t，2H，J＝6.2 Hz)，3.30(t，2H，J＝6.0Hz)，1.54 (m，2H)，1.31(m，6H)，0.89(t，3H J＝6.0Hz)
102 4-(3-octyl group 2-imidazolone-1-yl) phenyl 7.65-7.60(AA′BB′，4H)，3.82(t， 2H，J＝6.2Hz)，3.52(t，2H，J＝6.2 Hz)，3.29(t，2H，J＝6.0Hz)，154 (m，2H)，1.30(m，10H)，0.87(t，3H， J＝6.1HZ)
Embodiment 103 (R)-and N-[4-[2-[[2-hydroxyl-2-(4-hydroxy phenyl) ethyl] amino] ethyl] phenyl] benzsulfamide
At room temperature use one night of 50ml DMF solution of 5.5g tert-butyldimethylsilyl chloride (TBDMS-Cl) and 2.5g imidazoles silylanizing 5g 4-amino-benzene ethyl alcohol.Extraction product, then handle and obtain 6.6g O-TBDMS ether with aqueous ammonium chloride solution, then this anils and the benzene sulfonyl chloride coupling in pyridine-methylene dichloride are obtained sulphonamide, productive rate is greater than 80% behind the chromatogram purification, at room temperature remove the TBDMS group of sulphonamide, last 30 minutes with the HCl of methyl alcohol.The thick alcohol of acetone soln oxidation with Jones reagent obtains corresponding carboxylic acid (room temperature 30 minutes, ethyl acetate extraction).
In the 7ml DMF solution of the 4-N-phenylsulfonamido toluylic acid of 180mg (R)-octopamine and 300mg gained, add 0.5ml triethylamine and 490mg benzotriazole base-N-oxygen base-three (dimethylamino) Phosphonium hexafluorophosphate.Reaction mixture at room temperature stirred 2 hours, used the flash chromatography on silica gel purifying, with 95: 5 chloroform-methanol wash-outs, obtained the pure acid amides of 322mg.
The 13ml 1.0M borane-THF solution of the above-mentioned acid amides of 220mg was refluxed 2 hours under argon atmospher, then add 3ml N, the N-dimethylaminoethanol, refluxed again 1 hour, solvent removed in vacuo and excessive volatile matter, the solid of remnants is dissolved in the acetone, with silica gel PLC purifying (9: 1 ethyl acetate: methyl alcohol) obtain the 61mg title compound: 1HNMR (500MHz, CD 3OD) δ 7.73 (dt, 2H, J=2.1,8.2Hz), 7.53 (tt, 1H, J=1.4,7.6Hz), 7.44 (t, 2H, J=8Hz), 7.18 (d, 2H, J=8.4Hz), 7.05 (ABq, 4H, Jab=8.5Hz), 6.76 (d, 2H, J=8.4Hz), 4.75 (dd, 1H, J=7.5,7.6Hz), 3.05-2.90 (m, 4H), 2.81 (t, 2H, J=7.6Hz). mass spectrum: calculated value .412.5 measured value 413.2.
Embodiment 104
Figure A9519282100841
(R)-and N-[4-[2-[[2-hydroxyl-2-(4-hydroxy phenyl) ethyl] amino] ethyl] phenyl]-4-iodobenzene sulphonamide
According to embodiment 103 described methods, the preparation title compound:
1H NMR (500MHz, CD 3OD) δ 7.77 (d, 2H, J=8.5Hz), 7.43 (d, 2H, J=8.5Hz), 7.15 (d, 2H, J=8.5Hz), 7.02 (ABq, 4H, Jab=8.7Hz), 6.75 (d, 2H, J=8.5Hz), 4.67 (dd, 1H, J=4.4,6.6Hz), 2.90-2.66 (m, 6H). mass spectrum: calculated value .538.4 measured value 538.9.
Embodiment 105
Figure A9519282100842
3-(2-acetyl bromide) benzonitrile
In the 70ml ether of 1.02g (7.04mmol) 3-ethanoyl benzonitrile, add 1.02g (3.52mmol, 0.5eq.) dibromo barbituric acid.Mixture at room temperature stirs and spends the night, and filters the white pulpous state liquid of gained, and concentrated filtrate obtains 1.28g (81%) white solid title compound with purification by flash chromatography (silica gel, 20% ethyl acetate/hexane): 1H NMR (400MHz, CDCl 3) δ .8.26 (t, 1H, J=1.4Hz), 8.20 (td, 1H, J=1.5,8.0Hz), 7.87 (dd, 1H, J=1.3,7.8Hz), 7.64 (t, 1H, J=7.9Hz), 4.40 (s, 2H).
Embodiment 106
Figure A9519282100851
(R)-α-brooethyl-3-cyano-phenyl methyl alcohol
Under 0 ℃ to 181mg (0.623mmol) (R)-tetrahydrochysene-1-methyl-3,3-phenylbenzene-1H, 3H-pyrrolo-[1,2c] [1,32] be added dropwise to the THF solution of 6.24ml (6.24mmol) 1M borane in the 6ml THF suspension of oxazaborole-borane (R-OAB catalyzer), the settled solution of gained stirred 5 minutes, the 6ml THF solution that in 1 hour, slowly adds the bromoketone of 1.27g (5.67mmol) embodiment 1O5 then, after reaction mixture stirs more than 30 minute, be added dropwise to 6ml methyl alcohol termination reaction and concentrated reaction mixture, purification by flash chromatography (silica gel, the 20-25% ethyl acetate/hexane), obtain 944mg (74%) title compound after the crystallization, be clarifying oily matter: 1H NMR (400MHz, CDCl 3) δ 7.7O (d, 1H, J=1.5Hz), 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).
Embodiment 107 (R)-(3-cyano-phenyl) oxyethane
In the 8ml methanol solution of the bromohydrin of 937mg (4.14mmol) embodiment 106, add 601mg (4.35mmol, 1.05eq.) salt of wormwood.Reaction mixture at room temperature stirred 7 hours, with the ethyl acetate dilution, washed with water then, used dried over mgso, and concentrated, and obtained 573mg (95%) title compound with purification by flash chromatography (silica gel, 20% ethyl acetate/hexane): 1HNMR (400MHz, 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).
Embodiment 108 (R)-and N-[2-[4-(aminophenyl)] ethyl]-2-hydroxyl-2-(3-cyano-phenyl) ethyl carbamic acid 1,1-dimethyl ethyl ester
According to embodiment 17 and 18 described methods, by the preparation of epoxides title compound of embodiment 107: 1H NMR (400MHz, CDCl 3) δ 7.58-7.52 (br m, 3H), 7.41 (t, 1H, J=7.5Hz), 6.89 (br d, 2H, J=7.6Hz), 6.65 (br d, 2H, J=7.8Hz), 4.82 (br dd, 1H, J=2.7,7.9Hz), 3.42-3.05 (br m, 4H), 2.75-2.55 (br m, 2H).
Embodiment 109 (R)-and N-[4-[2-[[2-hydroxyl-2-(3-cyano-phenyl) ethyl] amino] ethyl] phenyl]-4-(hexyl amino carbonyl amino) benzsulfamide
According to embodiment 25 described methods, prepare title compound by the Boc anils of embodiment 108:
1H?NMR(400MHz，CD 3OD)δ7.70(s，1H)，7.63-7.57(m，4H)，7.48(t，1H，J＝7.7Hz)，7.43(d，2H，J＝8.9Hz)，7.06(d，2H，J＝8.5Hz)，6.99(d，2H，J＝8.5Hz)，4.77(dd，1H，J＝3.9，8.5Hz)，3.15(t，2H，J＝7.0Hz)，2.86-2.69(m，6H)，1.49(brm，2H)，1.31(brm，6H)，0.90(brt，3H).
Embodiment 110
Figure A9519282100871
(R)-and N-[4-[2-[[2-hydroxyl-2-(3-cyano-phenyl) ethyl] amino] ethyl] phenyl]-3-quinoline sulphonamide
According to embodiment 25 described methods, prepare title compound by Boc anils and the 3-quinoline sulfuryl chloride of embodiment 108: 1H NMR (400MHz, CD 3OD) δ 9.02 (d, 1H, J=2.3Hz), 8.68 (d, 1H, J=1.9Hz), 8.06 (d, 1H, J=8.3Hz), 8.02 (d, 1H, J=7.9Hz), 7.90 (ddd, 1H, J=1.4,7.0,8.4Hz), 7.72-7.69 (m, 2H), 7.62-7.58 (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=4.0,8.5Hz), 2.85-2.68 (m, 6H).
According to the described method of embodiment 14-31, listed compound in the preparation table 6.
Table 6
Figure A9519282100881
Embodiment R Select 1H?NMR(CD 3OD) data
111 4-(3-hexyl-2,4-imidazolinedione-1-yl) phenyl 4.40(s，2H)，3.54(m，2H)，1.68- 1.59(m，2H)，1.37-1.28(m，6H)， 0.91(m，3H).
112 4-(3-octyl group-2,4-imidazolinedione-1-yl) phenyl 4.40(s，2H)，3.52(m，2H)，1.68- 1.59(m，2H)，1.38-1.23(m，10H)， 0.89(m，3H).
113 4-[2-(4-cyclohexyl butyl)-oxazole-5-yl] phenyl, tri hydrochloride 7.66(s，1H)，5.35(m，1H)，3.22- 3.32(m，5H)，2.95(m，2H)，2.90(t， J＝6.5Hz，2H)，1.8(m，2H)，1.69(m， 5H)，1.45(m，2H)，1.24(m，6H)， 0.89(m.2H)
114 4-[2-[2-(4-fluorophenyl) ethyl]-oxazole 5-yls] phenyl 7.49(s，1H)，7.2(m，2H)，6.99(m， 2H)，4.90(m，1H)，3.05(m，4H)， 2.70-2.85(m，6H)
115 4-[2-(3-cyclopentyl propyl group)-oxazole-5-yl] phenyl 7.51(s，1H)，4.90(m，1H)，2.65- 2.90(m，8H)，1.80(m，5H)，1.46- 1.62(m，4H)，1.05(m，2H)
116 4-(4-hexyl-3-oxo-[1,2,4]-triazole-2-yl) phenyl 8.04(s，1H)，3.69(m，2H)，1.78- 1.69(m，2H)，1.39-1.28(m，6H)， 0.90(m，3H).
117 4-(4-octyl group-3-oxo-[1,2,4]-triazole-2-yl) phenyl 8.03(s，1H)，3.69(m，2H)，1.77- 1.69(m，2H)，1.38-1.25(m，10H)， 0.89(m，3H).
118 4-(4-heptyl-5-methyl-[1,2,3]-triazole-2-yl) phenyl 2.28(s，3H)，1.67(t，2H，J＝6.9Hz)， 1.36-1.34(m，4H)，1.31-1.29(m， 2H)，1.18(d，4H，J＝2.5Hz)，0.88(t， 3H，J＝7.0Hz)

Claims (17)

1. the compound or pharmaceutically acceptable salt thereof that has formula I: Wherein n is 0 to 5; M is 0 or 1; R is 0 to 3; A contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen for (1),
(2) with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen,
(3) encircle heterocyclic fused 1 to 4 the heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen that contains with containing 1 to 4 heteroatomic 5 or 6 yuan of being selected from oxygen, sulphur and nitrogen,
(4) phenyl, or
(5) and C 3-C 8Naphthenic ring condensed phenyl ring; R 1Be (1) hydroxyl
(2) oxo,
(3) halogen,
(4) cyano group,
(5)NR 8R 8，
(6)SR 8，
(7) trifluoromethyl,
(8) C 1-C 10Alkyl,
(9)OR 8，
(10)SO 2R 9，
(11)OCOR 9，
(12)NR 8COR 9，
(13)COR 9，
(14)NR 8SO 2R 9，
(15) NR 8CO 2R 8, or
(16) by hydroxyl, halogen, cyano group, NR 8R 8, SR 8, trifluoromethyl, OR 8, C 3-C 8Cycloalkyl, phenyl, NR 8COR 9, COR 9, SO 2R 9, OCOR 9, NR 8SO 2R 9Or NR 8CO 2R 8The C that replaces 1-C 10Alkyl; R 2And R 3Be independently
(1) hydrogen,
(2) C 1-C 10Alkyl, or
(3) contain 1 to 4 and be selected from hydroxyl, C 1-C 10The C of alkyl and halogen 1-C 10Alkyl; X is (1)-CH 2-,
(2)-CH 2-CH 2-，
(3)-CH=CH-, or
(4)-CH 2O-; R 4And R 5Be independently
(1) hydrogen,
(2) C 1-C 10Alkyl,
(3) halogen,
(4)NHR 8，
(5)OR 8，
(6) SO 2R 9, or
(7) NHSO 2R 9R 6Be (1) hydrogen, or
(2) C 1-C 10Alkyl; R 7Be Z-(R 1a) nR 1aBe (1) R 1, be when A is phenyl, R 1aNot C 1-C 10Alkyl,
(2) C 3-C 8Cycloalkyl,
(3) be independently selected from R by 4 of as many as 8, NR 8R 8, OR 8, SR 8With any phenyl that replaces of the group of halogen,
(4) be independently selected from oxo, R by 4 of as many as 8, NR 8R 8, OR 8, SR 8Contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen with the group of halogen replaces arbitrarily; Z is (1) phenyl,
(2) naphthyl,
(3) contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen,
(4) and C 3-C 8Naphthenic ring condensed phenyl ring,
(5) with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen,
(6) with contain 1 to 4 heteroatomic 5 or 6 yuan of being selected from oxygen, sulphur and nitrogen and heterocyclic fused contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen, or
(7) and C 3-C 8The naphthenic ring condensed contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; R 8Be (1) hydrogen,
(2) C 1-C 10Alkyl,
(3) C 3-C 8Cycloalkyl,
(4) can choose wantonly and have 1 to 4 and be selected from halogen, nitro, oxo, NR 10R 10, C 1-C 10Alkyl, C 1-C 10Alkoxyl group, C 1-C 10Alkylthio and contain 1 to 4 and be selected from hydroxyl, halogen, CO 2H, CO 2-C 1-C 10Alkyl, SO 2-C 1-C 10Alkyl, C 3-C 8Cycloalkyl, C 1-C 10The substituent C of alkoxyl group 1-C 10The substituent Z of alkyl, and can choose wantonly by 1 to 3 halogen, C 1-C 10Alkyl or C 1-C 10The Z that alkoxy base replaces, or
(5) have 1 to 4 and be selected from hydroxyl, halogen, CO 2H, CO 2-C 1-C 10Alkyl, SO 2-C 1-C 10Alkyl, C 3-C 8Cycloalkyl, C 1-C 10Alkoxyl group, C 1-C 10The substituent C of alkyl 1-C 10Alkyl, and arbitrarily by 1 to 4 halogen, C 1-C 10Alkyl or C 1-C 10The Z that alkoxy base replaces; R 9Be (1) R 8, or
(2) NR 8R 8R 10Be (1) C 1-C 10Alkyl, or
(2) connect into and to choose wantonly by C with N 1-C 10Two R of 5 or 6 yuan of rings that alkyl replaces 10Group.
2. the compound of claim 1, wherein n is 0 to 3; M is 1; R is 0 to 2; A is phenyl or 5-that contains 1 to 4 nitrogen-atoms or 6-unit heterocycle, and X is-CH 2-; R 1Be (1) hydroxyl
(2) halogen,
(3) cyano group,
(4) trifluoromethyl,
(5)NR 8R 8，
(6)NR 8SO 2R 9，
(7)NR 8COR 9，
(8)NR 8CO 2R 8，
(9) by the optional C that replaces of hydroxyl 1-C 10Alkyl; R 2And R 3Be independently
(1) hydrogen, or
(2) methyl; R 4, R 5And R 6The hydrogen of respectively doing for oneself; R 7Be Z-(R 1a) nAnd R 8, R 9, Z and R 1aAs the definition in the claim 1, work as R 1Be R 1aThe definition part the time, have the definition in the claim 1.
3. the compound that has the claim 1 of formula Ia: Wherein n is 0 to 3; M is 1; R 1Be (1) halogen, or
(2) NR 8R 8R 2And R 3Be hydrogen or methyl independently; R 1aBe (1) halogen,
(2) C 1-C 10Alkyl,
(3)NR 8R 8；
(4)NR 8COR 9，
(5)NR 8CO 2R 8，
(6)COR 9，
(7) OCOR 9, or
(8) be independently selected from oxo, halogen, R by 4 of as many as 8, NR 8R 8, OR 8And SR 8Group replace arbitrarily contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; Z is (1) phenyl,
(2) naphthyl,
(3) contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen,
(4) with contain 1 to 3 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen, or
(5) and C 3-C 8The naphthenic ring condensed contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; X is-CH 2-; And R 8And R 9As the definition in the claim 1.
4. the compound of claim 3, wherein R 2And R 3The hydrogen of respectively doing for oneself.
5. the compound that has the claim 1 of formula Ib:
Figure A9519282100061
Wherein n is 0 to 3; M is 1; R 1Be (1) hydroxyl,
(2) cyano group,
(3) NR 8R 8, or
(4) halogen; R 1aBe (1) halogen,
(2)NR 8R 8；
(3)NR 8COR 9，
(4)NR 8CO 2R 8，
(5) OCOR 9, or
(6) be independently selected from oxo, halogen, R by 3 of as many as 8, NR 8R 8, OR 8And SR 8Group replace arbitrarily contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; Z is (1) phenyl,
(2) naphthyl, or
(3) with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen; X is-CH 2-; And R 2And R 3Be hydrogen or methyl independently.
6. the compound that has the claim 1 of formula Id: N is 0 or 1; R 1Be NR 8R 8R 2And R 3Be independently
(1) hydrogen, or
(2) methyl; B is (1) hydrogen,
(2) benzene and phenyl ring condense the naphthyl of formation, or
(3) contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen with the phenyl ring condensed; R 1aBe (1) halogen,
(2) C 1-C 10Alkyl,
(3)NR 8R 8；
(4)NR 8COR 9，
(5)NR 8CO 2R 8，
(6) COR 9, or
(7) be independently selected from oxo, R by 4 of as many as 8, SR 8, OR 8And N 8R 8Group replace arbitrarily contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen; When B and phenyl ring formation condensed ring system, R 1aLink to each other with one of them ring; R 8Be (1) hydrogen,
(2) C 1-C 10Alkyl,
(3) optional have 1 to 4 and be selected from nitro, oxo and NR 10R 10Substituent Z; Or
(5) contain 1 to 4 and be selected from hydroxyl, halogen, C 1-C 10Alkyl, C 3-C 8The C of naphthenic substituent 1-C 10Alkyl and quilt are by 1 to 4 halogen, C 1-C 10Alkyl or C 1-C 10The Z that alkoxy base replaces arbitrarily; R 9Be (1) R 8, or
(2) NR 8R 8R 10Be (1) C 1-C 10Alkyl, or
(2) connect into by C with N 1-C 10Two R of 5 or 6 yuan of rings that alkyl replaces arbitrarily 10Group; Or Z is (1) phenyl,
(2) contain 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen,
(3) with contain 1 to 4 heteroatomic 5 or 6 yuan of heterocyclic fused phenyl ring that are selected from oxygen, sulphur and nitrogen, or
(4) and C 3-C 8The naphthenic ring condensed contains 1 to 4 heteroatomic 5 or 6 yuan of heterocycle that are selected from oxygen, sulphur and nitrogen.
7. the compound of claim 1, it is selected from: amino N-[4-[2-[(2-hydroxyl-2-phenylethyl)] ethyl] phenyl]-the 4-iodobenzene sulfamide; N-[4-[2-[(2-hydroxyl-2-phenylethyl) amino] ethyl] phenyl]-the 2-naphthalene sulfonylamide; With N-[4-[2-[(2-hydroxyl-2-phenylethyl) amino] ethyl] phenyl]-3-quinoline sulphonamide N-[4-[2-[[2-hydroxyl-2-(4-amino-3, the 5-dichlorophenyl) ethyl] amino] ethyl] phenyl]-4-(hexyl amino carbonyl amino) benzsulfamide N-[4-[2-[[2-hydroxyl-2-(4-amino-3, the 5-dichlorophenyl) ethyl] amino] ethyl] phenyl]-1-[(octyl group amino) carbonylamino]-5-indoline sulphonamide N-[4-[2-[[2-hydroxyl-2-(4-amino-3, the 5-dichlorophenyl) ethyl] amino] ethyl] phenyl]-4-(3-hexyl-2-imidazolone-1-yl) benzsulfamide N-[4-[2-[[2-hydroxyl-2-(4-amino-3, the 5-dichlorophenyl) ethyl] amino] ethyl] phenyl]-4-(3-octyl group-2-imidazolone-1-yl) benzsulfamide N-[4-[2-[[2-hydroxyl-2-(4-hydroxy phenyl) ethyl] amino] ethyl] phenyl] benzsulfamide N-[4-[2-[[2-hydroxyl-2-(4-hydroxy phenyl) ethyl] amino] ethyl] phenyl]-4-iodobenzene sulfamide N-[4-[2-[[2-hydroxyl-2-(3-cyano-phenyl) ethyl] amino] ethyl] phenyl]-4-(hexyl amino carbonyl amino) benzsulfamide and N-[4-[2-[[2-hydroxyl-2-(3-cyano-phenyl) ethyl] amino] ethyl] phenyl]-3-quinoline sulphonamide
8. The compound of claim 1, it is selected from: N-[4 - [2 - [[2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino] ethyl] phenyl] -4 - ( hexyl amino carbonyl amino) benzsulfamide; N-[4 - [2 - [[2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino] ethyl] phenyl]-the 4-iodobenzene sulfamide; N-[ 4 - [2 - [[2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino] ethyl] phenyl] benzsulfamide; N-[4 - [2 - [[2-hydroxyl-2-(6 -aminopyridine-3-yl) ethyl] amino] ethyl] phenyl]-the 2-naphthalene sulfonylamide; N-[4 - [2 - [[2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino ] ethyl] phenyl]-3-quinoline sulphonamide; N-[4 - [2 - [[2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino] ethyl] phenyl]-5-benzoisoxazole sulphonamide; N-[4 - [2 - [[2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino] ethyl] phenyl] -4 - [(hexyl methyl aminocarboxyl) amino] benzsulfamide; N-[4 - [2 - [[2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino] ethyl] phenyl] -4 - (dimethylamino carbonyl) amino] benzsulfamide; N-[4 - [2 - [[ 2-hydroxyl-2-(6-aminopyridine-3-yl) ethyl] amino] ethyl] phenyl] -4 - (3-hexyl-2-imidazolone-1-yl) benzsulfamide; N-[4 - [2 - [ [2-hydroxyl-2-(3-pyridyl) ethyl] amino] ethyl] phenyl] -4 - (hexyl amino carbonyl amino) benzsulfamide; N-[4 - [2 - [[2-hydroxyl-2-(3 - pyridyl) ethyl] amino] ethyl] phenyl]-4-isopropyl benzene sulphonamide; N-[4 - [2 - [[2-hydroxyl-2-(3-pyridyl) ethyl] amino] ethyl] phenyl]-the 2 - naphthalene sulfonylamide; N-[4 - [2 - [[2-hydroxyl-2-(3-pyridyl) ethyl] amino] ethyl] phenyl]-3-quinoline sulphonamide; N-[4 - [2 - [[2 - hydroxyl-2-(3-pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(hexyl methyl aminocarboxyl) amino] benzsulfamide; N-[4 - [2 - [[2-hydroxyl-2-(3-pyridyl ) ethyl] amino] ethyl] phenyl] -4 - (3-hexyl-2-imidazolone-1-yl) benzsulfamide; N-[4 - [2 - [[2-hydroxyl-2-(3-pyridyl) ethyl] amino] ethyl] phenyl]-the 4-iodobenzene sulfamide; N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [ 3 - (3 - cyclopentyl-propyl) -2 - imidazol-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino ] ethyl] phenyl] -4 - (3 - octyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl ) ethyl] amino] ethyl] phenyl] -4 - (3 - hexyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - ( 3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (3 - octyl-2 - imidazolin-one-1 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy -2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [3 - (3 - cyclopentyl-propyl) -2 - imidazolin-one-1 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -1 - (4 - octyl-thiazol-2 - yl) -5 - indoline-sulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (5 - pentyl - [1 ; 2; 4]-oxadiazoles-3-yl) benzsulfamide N-[4 - [2 - [[2-Qiang base-2-(3-Bi Ding yl) Yi yl] amino] the Yi yl] phenyl] -4 - (5-hexyl-[1; 2; 4]-oxadiazoles-3-yl) benzsulfamide N-[4 - [2 - [[2-Qiang base-2-(3-Bi Ding yl) Yi yl] amino] the Yi yl] phenyl] -4 - (5-heptyl-[1; 2; 4]-oxadiazole-3-yl) benzsulfamide N-[4 - [2 - [[2-Qiang base-2-(3-Bi Ding yl) Yi yl] amino] the Yi yl] phenyl] -4 - (5-Xin Ji-[1; 2; 4]-oxadiazoles-3-yl) benzsulfamide N-[4 - [2 - [[2 - Qiang base-2-(3-Bi Ding yl) Yi yl] amino] the Yi yl] phenyl] -4 - [5 - (2-cyclopenta Yi yl) - [1; 2; 4]-oxadiazoles-3-yl ] benzsulfamide N-[4 - [2 - [[2-Qiang base-2-(3-Bi Ding yl) the Yi yl] amino] the Yi yl] phenyl] -4 - [5 - (3-cyclopenta propyl group ) - [1; 2,4] - oxadiazol-3 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl ] phenyl] -4 - (2 - pentyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl yl] phenyl] -4 - (2 - hexyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl yl] phenyl] -4 - (2 - heptyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (2 - octyl-5 - yl) benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino ] ethyl] phenyl] -4 - [2 - (2 - cyclopentyl-ethyl)-oxazol-5 - yl] benzenesulfonamide N-[4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [2 - (3 - cyclopentylpropyl) oxazol-5 - yl] benzenesulfonamide N-[4 - [2 - [[ 2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - hexyl-5 - tetrazol-one-1 - yl) benzenesulfonamide N-[4 - [ 2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - (4 - Octyl-5 - tetrazol-one-1 - yl) benzenesulfonamide N - [4 - [2 - [[2 - hydroxy-2 - (3 - pyridyl) ethyl] amino] ethyl] phenyl] -4 - [(3 - cyclopentylpropyl) -5 - tetrazole one-1 - yl] benzenesulfonamide....
9. the compound that has the claim of structural formula Ic:
Figure A9519282100121
Wherein n, m, r, A, R 1, R 2, R 3, R 4, R 5, R 6, R 7With the definition in X such as the claim 1.
10. method for the treatment of diabetes, it comprises the compound of using the claim 1 of significant quantity to the diabetic subject.
11. the method for a treatment of obesity, it comprises the compound of using the claim 1 of significant quantity to the obesity patient.
12. the method for a triglyceride reducing level and cholesterol levels or high density lipoprotein increasing level, it comprises the compound of using the claim 1 of significant quantity to the patient who needs triglyceride reducing level and cholesterol levels or high density lipoprotein increasing level.
13. a method that reduces intestinal motive force, it comprises that the patient to needs reduction intestinal motive force uses the compound of the claim 1 of significant quantity.
14. a method that reduces the airway neurogenic inflammation, it comprises that the patient to needs reduction airway neurogenic inflammation uses the compound of the claim 1 of significant quantity.
15. one kind is reduced depressed method, it comprises the compound of using the claim 1 of significant quantity to depressive patient.
16. a method for the treatment of gastrointestinal illness, it comprises the compound of using the claim 1 of significant quantity to the patient with gastrointestinal illness.
17. one kind is used for the treatment of diabetes or obesity or is used for the triglyceride reducing level or cholesterol level or be used for the high density lipoprotein increasing level or be used to reduce intestinal motive force or be used to reduce neurogenic inflammation or be used for the treatment of depression or be used for the treatment of the composition of gastrointestinal illness, said composition contains the compound of the claim 1 of inert support and significant quantity.
CN95192821A 1994-04-26 1995-04-21 Substituted sulfonamides as selective beta3 agonists for treatment of diabetes and obesity Pending CN1149869A (en)

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