CN1360498A - Carboxylic acid derivs. that inhibit binding of integrins to their receptors - Google Patents

Carboxylic acid derivs. that inhibit binding of integrins to their receptors Download PDF

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CN1360498A
CN1360498A CN00809935A CN00809935A CN1360498A CN 1360498 A CN1360498 A CN 1360498A CN 00809935 A CN00809935 A CN 00809935A CN 00809935 A CN00809935 A CN 00809935A CN 1360498 A CN1360498 A CN 1360498A
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amino
methyl
alkyl
carbonyl
oxo
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CN1292744C (en
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R·J·比迪格
Q·陈
G·W·霍兰德
J·M·卡斯尔
W·李
R·V·马克特
I·L·斯科特
C·吴
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Encysive Pharmaceuticals Inc
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Texas Biotechnology Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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  • Plural Heterocyclic Compounds (AREA)

Abstract

A method for the inhibition of the binding of alpha 4 beta 1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit this binding; pharmaceutically active compositions comprising such compounds; and to the use of such compounds either as above, or in formulations for the control or prevention of diseases states in which alpha 4 beta 1 is involved.

Description

The carboxylic acid derivates of inhibition of integrins and its receptors bind
Invention field
The present invention relates generally to α 4β 1Integrin and its receptor be VCAM-1 (vascular cell adhesion molecule-1) and the bonded inhibitory action of fibronectin for example.The invention still further relates to and suppress this bonded chemical compound; The medical active compositions that contains this chemical compound; And relate to described chemical compound and aspect above or in control or prevention, relate to α 4β 1The preparation of morbid state in application.
Background of invention
When tissue is subjected to microbiological attack or when impaired, leukocyte plays a major role in inflammatory reaction.One of most important aspect of inflammatory reaction relates to the cell adhesion process.In general, leukocyte circulates by blood flow.Yet when tissue infection or when impaired, leukocyte identification is subjected to invasion and attack tissue or damaged tissues, is attached to capillary wall, moves in the tissue of getting involved by blood capillary.These processes are by the protein family mediation that is called cell adhesion molecule.
There are 3 kinds of main types in leukocyte: granulocyte, mononuclear cell and lymphocyte.Beta 2 integrin alpha 4β 1(being also referred to as Vla-4-4, VLA-4) is the heterodimer albumen of mononuclear cell, lymphocyte and 2 kinds of hypotype granulocyte eosinophilic granulocytes and basophilic granulocyte surface expression.This albumen plays an important role in cell adhesion by its identification and in conjunction with the ability of blood capillary inwall endotheliocyte associated protein VCAM-1 and fibronectin.
The blood capillary surrounding tissue infect or impaired after, endotheliocyte is expressed a series of adhesion molecules, comprises VCAM-1, adhesion molecule is very crucial to infecting essential leukocyte in conjunction with opposing.Before VCAM-1 or fibronectin, leukocyte is attached on some adhesion molecule at first, it is flowed slow down and make leukocyte along activation endothelium " rolling ".Mononuclear cell, lymphocyte, basophilic granulocyte and eosinophilic granulocyte can pass through α then 4β 1Integrin combines with VCAM-1 or fibronectin on the blood vessel wall securely.Evidence suggests, this interaction also participate in these leukocyte cross cell wall move in the damaged tissues with and initial rolling process.
Although leucocyte migration helps opposing to infect and destroys exogenous material to damage location, leucocyte migration becomes uncontrollablely in many cases, and leukocyte pours in diseased region, causes extensive tissue injury.Therefore, the chemical compound that can block this process can be used as useful medicine.So exploitation prevents that the bonded inhibitor of leukocyte and VCAM-1 and fibronectin from should be useful.
Can be by suppressing α 4β 1The part disease of combined treatment includes but not limited to arteriosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel, graft-rejection, contact hypersensitivity and type i diabetes.α 4β 1Except seeing the part leukocyte, also see various cancerous cell, comprise leukaemia, melanoma cells, lymphoma cell and sarcoma cell.Proposed to relate to α 4β 1Cell adhesion may participate in some cancer metastasis.Therefore, α 4β 1Binding inhibitors also can be used for the treatment of the cancer of some type.
United States Patent (USP) the 5th, 510 discloses for No. 332 suppressing α 4β 1Separation and purification with protein bound peptide.WO 95/15973, EP 0 341 915, EP 0 422 938 A1, No. the 5th, 192,746, United States Patent (USP) and WO 96/06108 disclose and have suppressed bonded peptide.WO 96/22966, WO98/04247 and WO 98/04913 disclose the new compound that can be used for suppressing and preventing the pathology of cell adhesion and cell adhesion-mediated.
So one of the object of the invention provides and is α 4β 1The new compound of binding inhibitors and the Pharmaceutical composition that comprises this new compound.
The invention summary
The present invention relates to formula I chemical compound or its pharmaceutically acceptable salt:
Figure A0080993500131
Formula I wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S; Q is the integer of 3-10; A is selected from O, S, C (R 16) (R 17) and NR 6E is selected from CH 2, O, S and NR 7J is selected from O, S and NR 8T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3; M is selected from C (R 9) (R 10) and (CH 2) u, wherein u is the integer of 0-3; L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1; X is selected from CO 2B, PO 3H 2, SO 3H, SO 2NH 2, SO 2NHCOR 12, OPO 3H 2,
C (O) NHC (O) R 13, C (O) NHSO 2R 14, hydroxyl, tetrazole radical and hydrogen; W is selected from C, CR 15And N; With B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13,
R 14, R 15, R 16And R 17When occurring, independently be selected from every turn hydrogen, halogen, hydroxyl,
Alkyl, alkenyl, alkynyl group, alkoxyl, alkenyloxy, chain oxy-acetylene, alkane
Sulfenyl, hydroxyalkyl, aliphatic acyl ,-CF 3, nitro, amino, cyano group, carboxyl,
-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkyl) C (O)
NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl), alkyl amino, alkene
Base is amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3
Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2,
Haloalkyl, alkoxyl alkoxyl, carboxaldehyde radicals (carboxaldehyde), Methanamide
Base (carboxamide), cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkyl-alkyl,
Aryl, aroyl, aryloxy group, arylamino, biaryl, thioaryl, two
Arylamino, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl are mixed
Cyclic group, heterocyclic radical alkyl, sulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-
C 3Alkyl), sulfonamido, carbamate groups (carbamate), aryloxy group alkyl
The base, the carboxylic acid group and-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10,
R 11, R 12, R 13, R 14, R 15, R 16And R 17Be substituted radical not
Or by at least one group of replacing for electronics or electron withdraw group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
R wherein 9And R 10Can form a ring together;
Wherein working as A is NR 6With at least one Y be CR 1The time, R 1And R 6Together
Can form a ring;
Prerequisite be when A be C (R 16) (R 17) time, E is not NR 7
For formula I, preferred compound of the present invention can be that the chemical compound with following group: A is NR 6E is NR 7J is O; M is C (R 9) (R 10); Q is 4 or 5; T is (CH 2) b, wherein b is 0; L is (CH 2) n, wherein n is 0; X is CO 2B; W is C or CR 15R 4Be aryl, alkylaryl, aralkyl, heterocyclic radical, alkyl heterocyclic or heterocyclic radical alkyl; R 6, R 7, R 9, R 10And R 15Independent is hydrogen and low alkyl group.
More particularly, chemical compound of the present invention can be described with Formula Il or its pharmaceutically acceptable salt:
Formula II wherein Y when occurring, independently be selected from every turn C (O), N, CR1, C (R2) (R3), NR5, CH, O and S; Q is the integer of 3-7; T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3; L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1; W is selected from C, CR 15And N; B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 15Independently be selected from
Hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl group, alkoxyl, alkene oxygen
Base, chain oxy-acetylene, alkylthio group, hydroxyalkyl, aliphatic acyl ,-CF 3, nitro,
Amino, cyano group, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-
NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-
C 6Alkyl), alkyl amino, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-
(C 1-C 3Alkyl) ,-C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,
-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl alkoxyl,
Carboxaldehyde radicals, formamido, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkyl-alkyl,
Aryl, aroyl, aryloxy group, arylamino, biaryl, thioaryl, two
Arylamino, heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl are mixed
Cyclic group, heterocyclic radical alkyl, sulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3
Alkyl), sulfonamido, carbamate groups, aryloxy alkyl, carboxylic acid group and
-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 15
Replace for electronics or electron withdraw group for substituted radical not or by at least one
Group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together;
And wherein when A be NR 6With at least one Y be CR 1The time, R 1And R 6Together
Can form a ring.
For formula II, preferred compound of the present invention can be that the chemical compound with following group: q is 4 or 5; W is C or CR 15T is (CH 2) b, wherein b is 0; L is (CH 2) n, wherein n is 0; R 4Be aryl, alkylaryl, aralkyl, heterocyclic radical, alkyl heterocyclic or heterocyclic radical alkyl; R 6, R 7, R 9, R 10And R 15Independent is hydrogen and low alkyl group.
More particularly, chemical compound of the present invention can be described with Formula Il I or its pharmaceutically acceptable salt:
Formula III wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S; Q is the integer of 2-5; T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3; L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1; And B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10And R 11Independently be selected from hydrogen,
Halogen, hydroxyl, alkyl, alkenyl, alkynyl group, alkoxyl, alkenyloxy,
Chain oxy-acetylene, alkylthio group, hydroxyalkyl, aliphatic acyl ,-CF 3, nitro, amino,
Cyano group, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3
Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl), alkyl ammonia
Base, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-
C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH,
-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl alkoxyl, carboxaldehyde radicals, formyl
Amido, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkyl-alkyl, aryl, fragrant acyl
Base, aryloxy group, arylamino, biaryl, thioaryl, ammonia diaryl base,
Heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocycle
Base alkyl, sulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), Asia
Sulfonamido, carbamate groups, aryloxy alkyl, carboxylic acid group and-C (O) NH (benzyl
Base) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10And R 11For not
Substituted radical or by at least one base of replacing for electronics or electron withdraw group
Group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together;
And wherein when A be NR 6With at least one Y be CR 1The time, R 1And R 6Together
Can form a ring.
For formula III, preferred compound of the present invention can be the chemical compound with following group: R 5Be hydrogen, alkyl, aryl, cycloalkyl, alkyl heterocyclic, heterocyclic radical alkyl or heterocyclic radical; T is (CH 2) b, wherein b is 0; L is (CH 2) n, wherein n is 0; Y is CR 1And C (R 2) (R 3), and q is 2 or 3.
In formula III, the ingredient of described molecule
Figure A0080993500181
Can be
Figure A0080993500182
R wherein 18, R 19, R 20And R 21When occurring, independently be selected from every turn hydrogen, halogen, hydroxyl,
Alkyl, alkenyl, alkynyl group, alkoxyl, alkenyloxy, chain oxy-acetylene, alkane
Sulfenyl, hydroxyalkyl, aliphatic acyl ,-CF 3, nitro, amino, cyano group, carboxyl,
-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkane
Base) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl), alkyl ammonia
Base, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3Alkyl) ,-
C (O) NH-(C 1-C 3Alkyl) ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH,
-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl alkoxyl, carboxaldehyde radicals, formyl
Amido, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkyl-alkyl, aryl, fragrant acyl
Base, aryloxy group, arylamino, biaryl, thioaryl, ammonia diaryl base,
Heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocycle
Base alkyl, sulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), Asia
Sulfonamido, carbamate groups, aryloxy alkyl, carboxylic acid group and-C (O) NH (benzyl
Base) group;
C is the integer of 0-2;
D is the integer of 0-3;
E is the integer of 0-4; And
F is 0 or 1 integer.
In one embodiment, R 5Be alkylaryl; R 4Be aryl; T is (CH 2) b, wherein b is 0; L is that wherein n is 0 (CH 2) nAnd B, R 6, R 7, R 9And R 10Independent separately is hydrogen.
Preferred compound of the present invention comprises: (3S)-and 3-[({[2-methyl-4-(2-methyl-propyl)-6-oxo-1-(phenyl methyl)-1,6-dihydro-5-pyrimidine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-(1,3-benzo dioxole-5-yl)-3-[({[2-oxo-1-(phenyl methyl)-4-propyl group-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-propyl group-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-{[({6-methyl-2-oxo-1-(phenyl methyl)-4-[(phenyl methyl) the oxygen base]-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[4-(methoxyl group) phenyl] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(3, the 4-3,5-dimethylphenyl) propanoic acid, (3S)-3-{[({4-amino-1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-[({[1-[(2-chlorophenyl) methyl]-4-(1,4-oxazine alkane (oxazinan)-4-yl)-2-oxo-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-[({[1-[(2-chlorophenyl) methyl]-2-oxo-4-(propyl group amino)-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and 3-{[({1-[(2-bromo phenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[3-methyl-4-(methoxyl group) phenyl] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-[(2-{[2-(methoxyl group) ethyl] the oxygen base } ethyl) the oxygen base]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-6-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-[(1, the 1-dimethyl ethyl) amino]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-the 3-phenylpropionic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-[4-methyl tetrahydrochysene-1 (2H)-pyrazinyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[4-(methoxyl group) phenyl] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(3, the 5-3,5-dimethylphenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(3-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[3-(methoxyl group) phenyl] propanoic acid, (3S)-and 3-[3, two (methoxyl group) phenyl of 5-]-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino } propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-quinolyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (3S)-3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[3-(trifluoromethyl) phenyl] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[({ ethyl [(ethylamino) carbonyl] amino } carbonyl) amino]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-{[({4-(1-azetanyl)-1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(2-[(2-{[2-(methoxyl group) ethyl] and the oxygen base } ethyl) the oxygen base] ethyl } the oxygen base)-2-oxo-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-{[({1-[(2-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and 3-{[({1-[(2-chloro-6-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-(1,3-benzo dioxole-5-yl)-3-((((2-oxo-1-((4-(trifluoromethyl) phenyl) methyl)-1,2-dihydro-3-pyridine radicals) amino) carbonyl) amino) propanoic acid, (3S)-3-((((1-((2-chlorophenyl) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino carbonyl amino)))-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2-fluoro phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2-bromo phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino carbonyl amino)))-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2, the 4-Dichlorobenzene base) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2-chloro-6-fluoro phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino carbonyl amino)))-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2-chlorophenyl) methyl)-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals) amino) carbonyl) amino)-3-(4-trifluoromethyl) oxygen base) phenyl) propanoic acid and
Their pharmaceutically acceptable salt.
Derivant for example ester, carbamate, aminal, amide, optical isomer and prodrug have also been designed.
The invention still further relates to and comprise the Pharmaceutical composition that the physiology goes up acceptable diluent and at least a The compounds of this invention.
The invention still further relates to and suppress α 4β 1The bonded method of integrin and VCAM-1 makes express alpha under the The compounds of this invention that is included in effective inhibitory amount exists 4β 1The cell of integrin and the cells contacting of expressing VCAM-1.VCAM-1 is found in the surface of vascular endothelial cell, antigen presenting cell or other cell types.α 4β 1Be found in leukocyte such as mononuclear cell, lymphocyte, granulocyte; Stem cell; Or natural express alpha 4β 1Any other cell.
Detailed description of the Invention
The definition of term
The term that this paper is used alone or in combination " alkyl " is meant C 1-C 12Straight or branched, saturated hydrocarbons are removed replacement or the unsubstituted saturated chain base that a hydrogen atom produces, unless there is C term alkyl front x-C yIndicate.The representative instance of alkyl is particularly including methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group and the tert-butyl group.
The term that this paper is used alone or in combination " alkenyl " is meant the replacement that contains 2-10 carbon atom or substituted straight chain alkenyl or replace or do not replace branched alkenyl not.This examples of groups includes but not limited to vinyl, E-and Z-pentenyl, decene base etc.
The term that this paper is used alone or in combination " alkynyl group " is meant the replacement that contains 2-10 carbon atom or substituted straight chain alkynyl or replace or replace an alkynyl group not.This examples of groups includes but not limited to acetenyl, propinyl, propargyl, butynyl, hexin base, decynyl etc.
" alkyl ", " alkenyl " that term " rudimentary " is modified, the C that " alkynyl group " or " alkoxyl " is meant particular functionality 1-C 6The unit.For example low alkyl group is meant C 1-C 6Alkyl.
The term that this paper is used alone or in combination " aliphatic acyl " be meant the formula that alkanoic acid, chain-ene carboxylic acid or alkyne carboxylic acid produce: alkyl-C (O)-, alkenyl-C (O)-and alkynyl group-C (O)-group, wherein term " alkyl ", " alkenyl " and " alkynyl group " are with above definition.This aliphatic acyl examples of groups particularly including but be not limited to acetyl group, propiono, bytyry, valeryl, 4-methylpent acyl group, acryloyl group, crotyl, propioloyl and methyl propioloyl.
Term used herein " cycloalkyl " is meant the aliphatic ring system with 3-10 carbon atom and 1-3 ring, particularly including but be not limited to cyclopropyl, cyclopenta, cyclohexyl, norborny (norbornyl) and adamantyl (adanantyl).Cycloalkyl can not be substituted or independently is selected from 1,2 or 3 following substituent group and replaces: low alkyl group, haloalkyl, alkoxyl, alkylthio group, amino, alkyl amino, dialkyl amido, hydroxyl, halogen, sulfydryl, nitro, carboxaldehyde radicals, carboxyl, alkoxy carbonyl and formamido.
" cycloalkyl " comprises cis or trans cycloalkyl.In addition, described substituent group can be positioned at the position or the outer position of bridging bicyclic system.
The term that this paper is used alone or in combination " cycloalkenyl group " is meant the annular carbocyclic ring that contains 4-8 carbon atom and one or more pairs of keys.Such cycloalkenyl group example includes but not limited to cyclopentenyl, cyclohexenyl group, cyclopentadienyl group etc.
Term used herein " cycloalkyl-alkyl " is meant the cycloalkyl that is connected with low alkyl group, includes but not limited to cyclohexyl methyl.
Term used herein " halogen " or " halogen " are meant iodine, bromine, chlorine or fluorine.
Term used herein " haloalkyl " is meant the low alkyl group of subsidiary at least one halogenic substituent, for example chloromethyl, fluoro ethyl, trifluoromethyl and pentafluoroethyl group etc.
The term that this paper is used alone or in combination " alkoxyl " is meant alkyl ether groups, the same definition of term wherein " alkyl ".The example of suitable alkyl ether groups includes but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.
The term that this paper is used alone or in combination " alkenyloxy " is meant the group of formula: alkenyl-O-, and prerequisite is that this group is not an enol ether, the same definition of wherein said term " alkenyl ".The example of suitable alkenyloxy includes but not limited to allyloxy, E-and Z-3-methyl-2-propenyloxy group etc.
The term that this paper is used alone or in combination " chain oxy-acetylene " is meant the group of formula: alkynyl group-O-, and prerequisite is that this group can not be-alkynol ether (ynol ether).The example of suitable chain alkynyloxy group includes but not limited to alkynes propoxyl group, 2-butyne oxygen base etc.
Term used herein " carboxylic acid group " is meant carboxylic acid group-C (O) OH.
Term used herein " carboxyl " is meant-C (O) O-.
Term " alkylthio group " is meant the thioether group of formula: alkyl-S-, and wherein " alkyl " definition is the same.
Term used herein " carboxaldehyde radicals " be meant R wherein be hydrogen-C (O) R.
Term used herein " formamido " or " amide groups " are meant wherein R aAnd R bIndependence is hydrogen, alkyl or any other suitable substituent-C (O) NR separately aR b
Term used herein " alkoxyl alkoxyl " is meant R cO-R dO-, wherein R cFor defining the same low alkyl group R dBe alkylidene, wherein alkylidene is-(CH 2) N '-, wherein n ' is the integer of 1-6.The representative instance of alkoxyl alkoxyl comprises methoxymethoxy, ethyoxyl methoxy base, tert-butoxy methoxyl group etc.
Term used herein " alkyl amino " is meant R eNH-, wherein R eBe low alkyl group, for example ethylamino, butyl amino etc.
The term that this paper is used alone or in combination " alkenyl amino " is meant formula: alkenyl-NH-or (alkenyl) 2The group of N-, wherein term " alkenyl " definition is the same, and prerequisite is that this group is not the enamine base.An example of this alkenyl amino group is the allyl amino group.
The term that this paper is used alone or in combination " chain alkynyl amino " is meant formula: alkynyl group-NH-or (alkynyl group) 2The group of N-, wherein term " alkynyl group " definition is the same, and prerequisite is that this group is not an amido.An example of this chain alkynyl amino group is the propargyl amino group.
Term used herein " dialkyl amido " is meant R fR gN-, wherein R fAnd R gIndependently be selected from low alkyl group, for example diethylamino and methyl-propyl amino etc.
Term used herein " amino " is meant H 2N-.
Term used herein " alkoxy carbonyl " is meant the previously defined alkoxyl that is connected with parent molecular moiety by carbonyl.The alkoxy carbonyl example comprises methoxycarbonyl, ethoxy carbonyl and isopropoxy carbonyl etc.
The term that this paper is used alone or in combination " aryl " or " aromatic radical " be meant the replacement with about 6-12 carbon atom or do not replace the carbocyclic ring aromatic radical, for example phenyl, naphthyl, indenyl, 2,3-dihydro indenyl, azulenyl base, fluorenyl and anthryl; Perhaps be meant and contain at least one bridged ring nitrogen, the heterocyclic aromatic base of oxygen or sulphur atom, furyl for example, thienyl, pyridine radicals, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl, the 2-pyrazolinyl, pyrazolidinyl isoxazolyl, isothiazolyl, 1,2,3-oxadiazole base, 1,2, the 3-triazolyl, 1,3, the 4-thiadiazolyl group, pyridazinyl, pyrimidine radicals, pyrazinyl, 1,3, the 5-triazine radical, 1,3,5-trithiane base, the indolizine base, indyl, isoindolyl, the 3H-indyl, indolinyl, benzo [b] furyl, 2, the 3-dihydro benzo furyl, benzo [b] thio-phenyl, the 1H-indazolyl, benzimidazolyl, benzothiazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, the cinnolines base, 2, the 3-phthalazinyl, quinazolyl, quinoxalinyl, 1,8-naphthyridinyl (naphthridinyl), pteridyl, carbazyl, acridinyl, phenazinyl, phenothiazinyl, the phenoxy group azine, pyrazolo [1,5-c] triazine radical etc." aralkyl " and " alkylaryl " uses the term " alkyl " of above-mentioned definition.Ring can be polysubstituted ring.
The term that this paper is used alone or in combination " aralkyl " is meant the alkyl that aryl replaces, wherein the same definition of term " alkyl " and " aryl ".The example of suitable aralkyl includes but not limited to phenyl methyl, phenethyl, phenyl hexyl, diphenyl methyl, pyridylmethyl, tetrazole radical methyl, furyl methyl, imidazolyl methyl, indyl methyl, thienyl propyl group etc.
The term that this paper is used alone or in combination " aralkenyl " is meant the alkenyl that aryl replaces, wherein the same definition of term " aryl " and " alkenyl ".
The term that this paper is used alone or in combination " arylamino " is meant the group of formula: aryl-NH-, wherein " aryl " the same definition.The arylamino examples of groups includes but not limited to phenyl amino (phenylamino), naphthyl amino, 2-, 3-and 4-pyridinylamino etc.
The term that this paper is used alone or in combination " biaryl " is meant formula: the group of aryl-aryl, wherein the same definition of term " aryl ".
The term that this paper is used alone or in combination " thioaryl " is meant the group of formula: aryl-S-, wherein the same definition of term " aryl ".An example of thioaryl is a thio-phenyl.
The term that this paper is used alone or in combination " aroyl " is meant the group of formula: aryl-CO-, wherein the same definition of term " aryl ".The example of suitable aroyl includes but not limited to benzoyl group, 4-halogeno-benzene acyl group, 4-carboxyl benzoyl group, naphthoyl base, pyridine radicals carbonyl etc.
The term that this paper is used alone or in combination " heterocyclic radical " is meant the non-aromatic ring of 3-to 10-unit that contains at least one bridged ring N, O or S atom.Described heterocycle may optionally be the aryl condensed hetero ring.Described heterocycle also can be chosen wantonly by at least one substituent group and replace, and described substituent group independently is selected from hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl group, aryl, cyano group, carboxyl, alkoxy carbonyl group, carboxyalkyl, oxo base, aryl sulfonyl and aryl alkyl amino carbonyl etc.
Term used herein " alkyl heterocyclic " is meant the previously defined alkyl that is connected to parent molecular moiety by heterocyclic radical, includes but not limited to 2-methyl-5-thiazole base, 2-methyl isophthalic acid-pyrrole radicals and 5-ethyl-2-thienyl.
Term used herein " heterocyclic radical alkyl " is meant the previously defined heterocyclic radical that is connected to parent molecular moiety by alkyl, includes but not limited to 2-thienyl methyl, 2-pyridylmethyl and 2-(piperidino) ethyl.
Term used herein " aminal " is meant structure: R hC (NR iR j) (NR kR l)-hemiacetal, R wherein h, R i, R j, R kAnd R lIndependent separately is hydrogen, alkyl or any other suitable substituent.
Term used herein " ester " is meant-C (O) R m, R wherein mBe hydrogen, alkyl or any other suitable substituent.
Term used herein " carbamate " is meant based on carbamic acid NH 2The chemical compound of C (O) OH.
Using above-mentioned term means and comprises and replace part and non-replacement part.Replacement can be the replacement of one or more groups, for example alcohols; ethers; esters; amide-type; the sulfone class; sulfide-based; hydroxyl; nitro; cyano group; carboxyl; amine; hetero atom; low alkyl group; lower alkoxy; elementary alkoxy carbonyl; the alkoxyl alkoxyl; acyloxy; halogen; trifluoromethoxy; trifluoromethyl; alkyl; aralkyl; alkenyl; alkynyl group; aryl; cyano group; carboxyl; alkoxy carbonyl group; carboxyalkyl; cycloalkyl; cycloalkyl-alkyl; heterocyclic radical; alkyl heterocyclic; the heterocyclic radical alkyl; oxo; any substituent group in any substituent group of aryl sulfonyl and aryl alkyl amino carbonyl or above each section or the substituent group that directly is connected or connects by suitable joint.Joint is generally the short chain of 1-3 atom, comprise any combination-C-,-C (O)-,-NH-,-S-,-S (O)-,-O-,-C (O) O-or-S (O) O-.Ring can be substituted repeatedly.
Term " electrophilic " or " give electronics " are meant that substituent group can or be given electronics with respect to the hydrogen electrophilic if hydrogen is when occupying the same position of this molecule.These terms are well known to those skilled in the art, and J.March discusses in Advanced Organic Chemistry. 1985, the 16-18 pages or leaves, and the document is attached to herein by reference.Electron-withdrawing group comprises halogen, nitro, carboxylic acid group, low-grade alkenyl, alkynyl of low-grade chain, carboxaldehyde radicals, carboxyl acylamino-, aryl, quaternary ammonium, trifluoromethyl and aryl low-grade alkane acidyl etc.Donor residues comprises such as following group: hydroxyl, low alkyl group, amino, low-grade alkyl amino, two (low alkyl group) amino, aryloxy group, sulfydryl, lower alkylthio, low alkyl group sulfydryl and disulphide etc.One skilled in the art will appreciate that the above substituent group can have to electronics or electrophilic characteristic under the different chemical condition.The present invention has designed the substituent any combination that is selected from above-mentioned group.
Most preferred electronics or the electron-withdrawing substituent given has halogen, nitro, alkanoyl, carboxaldehyde radicals, aromatic yl silane terephthalamide yl, aryloxy group, carboxylic acid group, formamido, cyano group, sulfonyl, sulfoxide, heterocyclic radical, guanidine, quaternary ammonium, low-grade alkenyl, alkynyl of low-grade chain, sulfonium salt, hydroxyl, lower alkoxy, low alkyl group, amino, low-grade alkyl amino, two (low alkyl group) amino, amine low alkyl group sulfydryl, mercaptoalkyl, alkyl thio-base and alkyl dithio base.
Term used herein " compositions " comprises the product of the predetermined component that contains ormal weight and any product that is directly or indirectly obtained by the predetermined component combination of ormal weight.
The ring of Y definition can be monocyclic heterocycles or aromatic ring in formula I, II and III, maybe can be bicyclic ring.
The dotted line that uses in formula I, II and III represents that if Y and/or W are for example N, C or CH of substituent group, then for example the key between atom Y and the W can be singly-bound or two key.Therefore, the ring of Y definition can be saturated rings or unsaturated ring in the described formula, depends on the selection of W and/or Y.
The suitable substituent of the ring of the aryl among above-mentioned formula I and the II, alkyl, cycloalkyl, heterocyclic radical or Y definition, if present, comprise alcohols, amine, hetero atom or directly connect or aryl, alkoxyl, alkoxyl alkoxyl, alkyl, cycloalkyl or the heterocyclic radical of any combination by suitable joint connection.Joint is generally the short chain of 1-3 atom, comprises C, C=O, the CO of any combination 2, O, N, S, S=O, SO 2, for example ethers, amide-type, amine, ureas, sulfonamide, sulfonamides etc.
For example, with the R among following formula I, II and the III 1, R 2, R 3, R 5, R 6, R 7And R 8Can independently be (but being not limited to): hydrogen; alkyl; phenyl; thienyl methyl; isobutyl group; normal-butyl; the 2-thienyl methyl; 1,3-thiazoles-2-base-methyl; benzyl; thienyl; the 3-pyridylmethyl; 3-methyl isophthalic acid-benzothiophene-2-base; pi-allyl; the 3-methoxy-benzyl; propyl group; the 2-ethoxyethyl group; the cyclopropyl methyl; the dibenzylsulfide. alkyl methyl; benzyl sulfonyl methyl; phenyl sulfane ylmethyl; phenethyl sulfane ylmethyl; 3-phenyl propyl sulfane ylmethyl; 4-((2-toluidino carbonyl) amino) benzyl; 2-pyridine radicals ethyl; 2-(1H-indol-3-yl) ethyl; 1H-benzimidazolyl-2 radicals-Ji; the 4-piperidino methyl; 3-hydroxyl-4-methoxy-benzyl; the 4-leptodactyline; the 4-aminobenzyl; the phenyl sulfonyl methyl; 4-(acetylamino) phenyl; the 4-methoxyphenyl; the 4-aminophenyl; the 4-chlorphenyl; (4-(benzyl sulfonyl) amino) phenyl; (4-(methyl sulphonyl) amino) phenyl; the 2-aminophenyl; the 2-aminomethyl phenyl; isopropyl; 2-OXo-1-pyrrolidine base; 3-(methyl sulfane base) propyl group; (propylthio alkyl) methyl; octyl group sulfane ylmethyl; the 3-aminophenyl; 4-((2-toluidino carbonyl) amino) phenyl; 2-((methyl-benzyl) amino) benzyl; methyl sulfane base ethyl; hydroxyl; chlorine; fluorine; bromine; urea groups; amino; mesyl amino; acetylamino or ethyl sulfane ylmethyl.
With the R among following formula I, II and the III 4Substituent group can be (but being not limited to) 1,3-benzo dioxole-5-base, the 1-naphthyl, thienyl, the 4-isobutoxy phenyl, 2, the 6-3,5-dimethylphenyl, the allyloxy phenyl, 3-bromo-4-methoxyphenyl, the 4-butoxy phenyl, 1-benzofuran-2-base, the 2-thienyl methyl, phenyl, methyl sulfane base, phenyl sulfane base, phenethyl sulfane base, 4-bromo-2-thienyl, 3-methyl-2-thienyl, the 4-aminomethyl phenyl, 3,5-two (methoxyl group) phenyl, 4-(methoxyl group) phenyl, the 4-fluorophenyl, 3-(methoxyl group) phenyl, 3,4,5-trimethoxy phenyl, 2,3-dihydro-1-benzofuran-5-base, the 3-fluorophenyl, 4-(trifluoromethyl) phenyl, 4-fluoro-3-(trifluoromethyl) phenyl, 4-(1, the 1-dimethyl ethyl) phenyl, 3, the 5-3,5-dimethylphenyl, the 4-hydroxy phenyl, 3, the 4-3,5-dimethylphenyl, 3-methyl-4-(methoxyl group) phenyl, 4-hydroxy-3-methyl phenyl, the 3-aminomethyl phenyl, 2,3-dihydro-indenes-5-base, the 2-aminomethyl phenyl, 2,6-two (methoxyl group) phenyl, 2, the 6-dihydroxy phenyl, the 4-chlorphenyl, the 3-chlorphenyl, 3, the 4-Dichlorobenzene base, 4-((trifluoromethyl) oxygen base) phenyl, the 4-ethoxyl phenenyl, 4-(ethyoxyl) phenyl, methyl, 2-propyl group or 4,5-dihydro-1,3-oxazole-2-base.
Two R independently 1, R 2, R 3Or R 5Group can be connected to form ring together.
R 4And R 11Can be connected to form ring, for example 1-pyrrolidinyl (pyrrolidino), 1-piperidino (piperidino), 4-methyl isophthalic acid-piperazinyl (piperazino), 4-acetyl group-1-piperazinyl and 4-morpholino (morpholino) etc.
R 9And R 10Can be connected to form ring, for example cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl etc.
Abbreviation
The abbreviation of using in subsequent reaction flow process and embodiment has: BOC: tert-butoxycarbonyl; DMF: dimethyl formamide; THF: oxolane; DME: dimethoxy-ethane; DMSO: dimethyl sulfoxide; The NMM:N-methyl morpholine; DIPEA: diisopropyl ethyl amine; CDI:1,1 '-carbonyl dimidazoles; The TBS:TRIS-buffer saline; Ms: mesyl; TMEDA:N, N, N ', N '-tetramethylethylenediamine; DCE:1, the 2-dichloroethanes; The NCS:N-chlorosuccinimide; The NBS:N-bromo-succinimide; DPPA: diphenyl phosphoryl azide; DEAD: diethylazodicarboxylate; TFAA: trifluoroacetic anhydride; DCM: dichloromethane; LHMDS: two (trimethyl silyl) lithium amide; Cbz: benzyloxycarbonyl.Amino acid abbreviations is as follows: the C:L-cysteine; The D:L-aspartic acid; E:L-glutamic acid; G: glycine; The H:L-histidine; The I:L-isoleucine; The L:L-leucine; The N:L-agedoite; The P:L-proline; The Q:L-glutamine; The S:L-serine; The T:L-threonine; The V:L-valine; The W:L-tryptophan.
Following flow process shows the method embodiment of the chemical compound that can be used for synthetic said structure formula.Following examples are described representative compounds of the present invention in detail.
Figure A0080993500311
The method that flow process 1 above flow process 1 explanation embodiment 1 introduces.The flow process 2 that embodiment 2 methods are described is as follows.
The flow process 3 of flow process 2 explanation embodiment 3 methods is as follows.
Figure A0080993500331
The flow process 4 of flow process 3 explanation embodiment 4 methods is as follows.
Figure A0080993500332
The flow process 5 of flow process 4 explanation embodiment 5 methods is as follows.
The flow process 6 of flow process 5 explanation embodiment 6 methods is as follows.
Figure A0080993500342
The flow process 7 of flow process 6 explanation embodiment 7 methods is as follows.
Figure A0080993500343
The flow process 8 of flow process 7 explanation embodiment 8 methods is as follows.
The flow process 9 of flow process 8 explanation embodiment 9 methods is as follows.
Figure A0080993500352
The flow process 10 of flow process 9 explanation embodiment 10 methods is as follows.
Figure A0080993500361
The flow process 11 of flow process 10 explanation embodiment 11 methods is as follows.
Figure A0080993500362
The flow process 12 of flow process 11 explanation embodiment 12 methods is as follows.
Figure A0080993500371
The flow process 13 of flow process 12 explanation embodiment 13 methods is as follows.
The flow process 14 of flow process 13 explanation embodiment 14 methods is as follows.
Figure A0080993500381
The flow process 15 of flow process 14 explanation embodiment 15 methods is as follows.
Figure A0080993500391
The flow process 16 of flow process 15 explanation embodiment 16 methods is as follows.
The flow process 17 of flow process 16 explanation embodiment 17 methods is as follows.
Figure A0080993500401
The flow process 18 of flow process 17 explanation embodiment 18 methods is as follows.
The flow process 19 of flow process 18 explanation embodiment 19 methods is as follows.
Figure A0080993500411
The flow process 20 of flow process 19 explanation embodiment 20 methods is as follows.
Figure A0080993500412
The flow process 21 of flow process 20 explanation embodiment 21 methods is as follows.
Figure A0080993500413
The flow process 22 of flow process 21 explanation embodiment 22 methods is as follows.
Figure A0080993500421
The flow process 23 of flow process 22 explanation embodiment 23 methods is as follows.
Figure A0080993500422
The flow process 24 of flow process 23 explanation embodiment 24 methods is as follows.
Flow process 24
Can use the The compounds of this invention of the pharmaceutically acceptable salt form that produces with mineral acid or organic acid.Term " pharmaceutically acceptable salt " is meant such salt: be applicable to contact tissue and lower animal tissue and do not have over-drastic toxicity, zest, allergy etc. in rational medical determination range, and have rational interests/risk ratio.Pharmaceutically acceptable salt is well known in the art.For example S.M.Berge etc. is at J.Pharmaceutical Sciences, and 1977, describe pharmaceutically acceptable salt among the 66:1 etc. in detail.Described salt can original position make or independently make free alkali functional group and suitable organic acid reaction to make in the last separation of The compounds of this invention and purification.Typical acid-addition salts includes but not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, caproate, fumarate, hydrochlorate, hydrobromate, hydriodate, the 2-isethionate (different thiosulfate, isothionate), lactate, maleate, mesylate, nicotinate, the 2-naphthalene sulfonate, oxalates, palmitate, pectinic acid salt (pectinate), persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, tartrate, rhodanate, phosphate, glutamate, Glu, bicarbonate, tosilate and undecylate.In addition, the group that contains basic nitrogen can be quaternized with following material, for example low alkyl group halogen such as methyl, ethyl, propyl group and butyl chloride, bromine and iodine; Dialkyl sulfate such as dimethyl, diethyl, dibutyl and diamyl sulfate; Long-chain halogenide such as decyl, dodecyl, myristyl and stearyl chloride, bromine and iodine; Aralkyl halogen such as benzyl bromide a-bromotoluene and phenethyl bromide etc.Therefore obtain water solublity or oil-soluble or dispersibility product.The example that can be used in the acid that forms pharmaceutically-acceptable acid addition comprises mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and organic acid such as oxalic acid, maleic acid, succinic acid and citric acid.
By make the part that contains carboxylic acid and suitable alkali for example pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate reaction or with ammonia or organic primary amine, secondary amine or reactive tertiary amine, in the end separate and the purification The compounds of this invention during, can the in-situ preparing base addition salts.Pharmaceutically acceptable salt is including, but not limited to the cation of alkali metal or alkaline-earth metal, for example lithium, sodium, potassium, calcium, magnesium and aluminum salt etc., and nontoxic quaternary ammonium and amine cation, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other the typical organic amine that is used to form base addition salts comprises ethylenediamine, ethanolamine, diethanolamine, piperidines, piperazine etc.
The dosage form that is used for the topical administration The compounds of this invention comprises powder, spray, unguentum and inhalant.Described reactive compound is mixed with the antiseptic of pharmaceutically acceptable carrier and any needs, the propellant that buffer agent maybe may need.Ophthalmic preparation, Eye ointments, powder and solution are also considered within the scope of the present invention.
Can change active component actual dose level in the Pharmaceutical composition of the present invention to obtain the reactive compound of effective dose, realize the therapeutical effect that needs of concrete patient, compositions and mode of administration.Selected dosage level depend on particular compound activity, route of administration, the sanatory order of severity and the patient's that treats the state of an illness and medical history.Yet this area routine operation is that the initial dose of described chemical compound is lower than the dosage that needs of realizing the therapeutic interest effect, and increases dosage then gradually up to the therapeutical effect of needing realizing.
When being used for above or other when treatment, can use the The compounds of this invention of a kind of following form of treatment effective dose: respective pure form or (existing under the situation of such form) pharmaceutically acceptable salt, ester or prodrug form.Perhaps described chemical compound can comprise the Pharmaceutical composition administration of purpose chemical compound and one or more pharmaceutically acceptable excipient." the treatment effective dose " of term The compounds of this invention means with suitable interests/risk of being applicable to any therapeutic treatment q.s than sanatory described chemical compound.Yet people know that the total daily dosage of The compounds of this invention and compositions is determined through rational medical judgment by the attending doctor.Any concrete patient's concrete treatment effective dose level depends on various factors, comprises the similar factor that the medicine of excretion rate, treatment persistent period, use in conjunction of concrete compositions, patient's age, body weight, general health situation, sex and diet, administration time, route of administration and employed particular compound of particular compound activity, use of the order of severity, the use of the disease of being treated and disease or the medicine that uses simultaneously with used particular compound and medical domain are known.For example the initial dose of described chemical compound well known in the art is lower than the dosage that needs of realizing the therapeutic interest effect, and increases dosage then gradually up to the therapeutical effect of needing realizing.
Administration of human or the total daily dose of zootic The compounds of this invention can be about 0.0001 to about 1000mg/kg/ day.For oral administration, more preferably dosage can be about 0.001 to about 5mg/kg/ day.If desired, effectively daily dose can be divided into a plurality of dosed administrations; Therefore unit-dose composition can comprise the divided dose of effective daily dose or its formation daily dose.
The present invention also provides the Pharmaceutical composition that comprises the The compounds of this invention of preparing with one or more pharmaceutically acceptable non-toxic carriers.Described Pharmaceutical composition can be formulated as solid form or liquid form especially, is used for injection of oral administration or parenteral or rectally.
Pharmaceutical composition of the present invention can by in oral, rectum, parenteral, the brain pond, intravaginal, intraperitoneal, part (as with powder, unguentum or drop), cheek film or mouthspray or nose spraying administration of human and other mammals.Term used herein " parenteral " refer to comprise vein, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the mode of administration of joint cavity injection and infusion.
On the other hand, the invention provides the Pharmaceutical composition that comprises the diluent that can tolerate on composition of the present invention and the physiology.The present invention includes one or more above-claimed cpds can tolerance on one or more nontoxic physiologys or the compositions that is mixed with of acceptable diluent, carrier, adjuvant or solvent (this paper is generically and collectively referred to as diluent), said composition is solid form or liquid form, is used for parenteral injection, intranasal administration, oral administration or is used for rectally or topical etc.
Described compositions also can be by crown inner tubular structure fixed die (intracoronary stent) (tubular unit of being made up of the fine rule net) or by biological degradation polyalcohol, through the conduit topical administration to target site.Described chemical compound also can with aglucon for example antibodies be used for target administration.
The compositions that is applicable to parenteral injection can comprise that the physiology goes up acceptable aseptic aqueous solution or non-aqueous solution agent, dispersant, suspensoid or Emulsion and is used to copy as the sterile powder of aseptic injectable solution or dispersion liquid.The suitable aqueous or the example of non-aqueous carrier, diluent, solvent or solvent comprise water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.), vegetable oil (for example olive oil), injection organic ester for example ethyl oleate and their suitable mixture.
These compositionss also can comprise adjuvant, for example antiseptic, wetting agent, emulsifying agent and dispersant.For example following various antibacterial and antifungal can guarantee to prevent action of microorganisms: for example parabens, chlorobutanol, phenol, sorbic acid etc.Also may need to comprise isotonic agent for example sugar, sodium chloride etc.Use to postpone for example aluminum monostearate and the gelatin absorption that can postpone to inject pharmaceutical dosage form of absorbent.
Except that described reactive compound, suspensoid can comprise suspending agent, for example ethoxylation isooctadecanol, polyoxyethylene sorbitan ester and polyoxyethylene sorbitol acid anhydride ester, microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, bentonite, agar and tragacanth or these materials partially.
In some cases, for the effect of prolong drug, need slow down the drug absorption of subcutaneous injection or intramuscular injection.This can realize by the crystallization of use poorly water-soluble or the liquid suspension of amorphous substance.The absorption rate of medicine depends on its dissolution rate so, and dissolution rate may depend on crystal size and crystal type.Perhaps, described medicine dissolution or be suspended in the oily solvent, postpone the absorption that parenteral gives pharmaceutical dosage form.
By making described medicine for example form the microencapsulation skeleton in polyactide-poly-Acetic acid, hydroxy-, bimol. cyclic ester at biological degradation polyalcohol, the reservoir devices dosage form is injected in preparation.According to the ratio of medicine and polymer and the character of employed concrete polymer, may command drug release rate.The example of other biological degradation polyalcohol comprises poly-(ortho esters) and poly-(anhydride).Also pharmaceutical pack can be embedded in the liposome or microemulsion that mates with body tissue preparation reservoir devices ejection preparation.
For example by the membrane filtration of detention antibacterial or in facing, mix antibacterial, can make ejection preparation aseptic with preceding available sterilized water or other aseptic injection medium dissolves or dispersive aseptic solid composite.
The solid dosage forms that is used for oral administration comprises capsule, tablet, pill, powder and granule.In such solid dosage forms, reactive compound can with at least a pharmaceutically acceptable inert excipient or carrier for example sodium citrate or dicalcium phosphate and/or following any material mix: a) filler or extender, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; B) binding agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; C) wetting agent, for example glycerol; D) disintegrating agent, for example agar, calcium carbonate, potato starch or tapioca, alginic acid, some silicate and sodium carbonate; E) liquid blocker, for example paraffin; F) absorption enhancer, for example quaternary ammonium compound; G) wetting agent, for example monostearate hexadecane alcohol ester and glyceryl monostearate; H) absorbent, for example Kaolin and POLARGEL NF, and i) lubricant, for example Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.If be capsule, tablet and pill, described dosage form also can comprise buffer agent.
The excipient of utilization such as lactose or toffee and high molecular weight polyethylene glycol etc., the solid composite of similar type also can be used as the filler of soft-filled gelatin capsule and hard-filled gelatin capsule.
Available coating and housing for example other coating materials of knowing of enteric coating and medicine formulation art prepare tablet, dragee, capsule, pill and granule solid dosage forms.They can be chosen wantonly and comprise opacifier, and can be such compositions: they optional with delayed mode only or preferably discharge described active component at certain partial enteral.The example of spendable embedding composition comprises polymer material and wax.
Described reactive compound also can be the microencapsulation form, if suitable, can contain one or more above-mentioned excipient.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable Emulsion, solution, suspensoid, syrup and elixir.Except that described reactive compound, liquid dosage form also can contain the conventional inert diluent that uses in this area, for example water or other solvent, solubilizing agent and emulsifying agent, for example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, the fatty acid ester of 3-butanediol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl carbinol, Polyethylene Glycol and sorbitan, and their mixture.
Except that inert diluent, Orally administered composition also can comprise adjuvant, for example wetting agent, emulsifying agent and suspending agent, sweeting agent, flavoring agent and flavouring agent.
The compositions that is used for rectum or vagina administration is preferably suppository, for example cocoa butter, Polyethylene Glycol or suppository wax are mixed with described suppository can to make The compounds of this invention and the non-irritating excipient that suits or carrier, described excipient or carrier at room temperature are solid, but under body temperature liquid, therefore fusion and discharge described reactive compound in rectum or vaginal canal.
The compounds of this invention also can the liposome form administration.Known in the art, generally prepare liposome with phospholipid or other lipid matter.By being dispersed in list in the aqueous medium-or brilliant liposome that forms of many-layer aqua liquid.Can use can form liposome any nontoxic, the physiology is last accepts and metabolizable lipid.Except that The compounds of this invention, the present composition of liposome form can comprise stabilizing agent, antiseptic, excipient etc.Preferred lipid is natural and synthetic phospholipid and the phosphatidylcholine (lecithin) that uses or use together separately.
The method for preparing liposome is known in the art.Edit Method in Cell Biology, XIV volume, Academic Press, New York, N.Y. (1976), the 33rd page and following document etc. referring to for example Prescott.
Term used herein " pharmaceutically acceptable prodrug " is the prodrug of The compounds of this invention, it is applicable to contact tissue and lower animal tissue and does not have excessive toxicity, zest, allergic effect reaction etc. in rational medical judgment scope, has corresponding rational interests/risk ratio, and be effective to its intended purpose, and be the zwitterionic form of (under possible situation) The compounds of this invention.For example, by hydrolysis in blood, prodrug of the present invention can be converted into the parent compound of following formula in vivo rapidly.At T.Higuchi and V.Stella, prodrug as novel drug delivery system, edit in the 14th volume of American Chemical Society's series symposium (A.C.S.Symposium Series) and at Edward B.Roche, among bioreversible carrier in the drug design (Bioreversible Carriers in Drug Design) the .AmericanPharmaceutical Association and Pergamon Press (1987) its comprehensive argumentation is arranged, described document is attached to herein by reference.
The The compounds of this invention that forms by the different chemical compounds of conversion in the body when giving mammal is included in the scope of the present invention.
The compounds of this invention can be used as the stereoisomer that wherein has asymmetric or chiral centre and exists.According to the substituent group configuration around the chiral carbon atom, these stereoisomers are " R " or " S " configuration.The present invention has designed various stereoisomers and their mixture.Stereoisomer comprises the mixture of enantiomer and diastereomer and enantiomer or diastereomer.The available available from the market raw material that contains asymmetric or chiral centre synthesizes or by the preparation racemic mixture, then by resolving racemic mixtures well known to those skilled in the art, prepares the various stereoisomers of The compounds of this invention.These method for splitting have for instance: (1) is attached on the chirality adjuvant mixture of enantiomers, separate the non-enantiomer mixture that generates by recrystallization or chromatography, discharge optically pure product or (2) direct optical antimer mixture that separates on the chirality chromatographic column from adjuvant then.
The compounds of this invention can the non-solvent form and is comprised hydrate forms such as the solvation form of semihydrate exists.In general, pharmaceutically acceptable solvent for example the solvation form of water and ethanol etc. right and wrong solvation form is equal to for the object of the invention.
On the other hand, the present invention has designed inhibition α 4β 1The bonded method of integrin and VCAM-1.The inventive method can be used in external or body.According to the inventive method, in the presence of the The compounds of this invention of effective inhibitory amount, make express alpha 4β 1The cellular exposure of integrin is in the cell of expressing VCAM-1.
Express alpha 4β 1The cell of integrin can be natural leukocyte, mastocyte or in the natural express alpha of cell surface 4β 1Other cell type or with comprising coding for alpha 4β 1The expression vector cells transfected of the polynucleotide of integrin (for example genomic DNA or cDNA).In an especially preferred embodiment, α 4β 1Integrin is present in for example surface of mononuclear cell, lymphocyte or granulocyte (for example eosinophilic granulocyte or basophilic granulocyte) of leukocyte.
The cell of expressing VCAM-1 can be n cell (for example endotheliocyte) or with the expression vector cells transfected of the polynucleotide that comprise the VCAM-1 that encodes.The method that is used to produce the transfectional cell of expressing VCAM-1 is a method well known in the art.
When VCAM-1 is present in cell surface, preferably pass through inflammatory cytokine for example tumor necrosis factor-alpha, interleukin 4 and interleukin-1 ' beta ' abduction delivering VCAM-1.
Work as express alpha 4β 1The cell of integrin and VCAM-1 is in Living organism the time, gives described Living organism with the The compounds of this invention of effective dose.Described chemical compound is preferably Pharmaceutical composition of the present invention.The inventive method is specially adapted to treatment and migrates to the damaged tissue diseases associated uncontrollably with leukocyte.Such disease is including, but not limited to asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus erythematosus, inflammatory bowel, graft-rejection, contact hypersensitivity, type i diabetes, leukemia and the brain cancer.Preferably by interior, subcutaneous, the intranasal of blood vessel, percutaneous or oral delivery realization administration.
The present invention also provides selectivity to suppress α 4β 1Under existing, the The compounds of this invention that the method for integrin and protein bound, this method are included in effective inhibitory amount make integrin be exposed to described protein.In a preferred embodiment, α 4β 1Integrin is in express alpha 4β 1The n cell of integrin or transformant surface expression.
α 4β 1The bonded protein of integrin can be present in cell surface or be the extracellular matrix ingredient.Particularly preferred protein is fibronectin or hyaluronidase.
Describe The compounds of this invention hereinafter among the embodiment in detail and suppress bonded ability.These embodiment are in order to describing the preferred embodiments of the invention and practicality, rather than limit the present invention with it, unless explanation is arranged in accompanying Claim in addition.
Embodiment 1
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (10) synthetic
Step 1: (20.8g 135mmol) is dissolved in the methanol (270mL), adds palladium on carbon (with 10% palladium dry weight basis, Degussa E101 NE/W type ,～50% water content, 5.75g, 2.7mmol Pd) with chemical compound 1.Replace atmosphere (between vacuum and balloon hydrogen, switching 5 times) with hydrogen, stir the mixture and spend the night, filter then.Vacuum concentrated filtrate is with 1: 1 hexane: ethyl acetate mixture dissolving residue, water and saturated NaHCO 3, saturated NaHCO 3With mixture washing in brinish 4: 1.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the chemical compound 2 (12.43g, 74%) into white solid.This material need not purification and can use.
Step 2: (2.64g 21.3mmol) is dissolved in the dichloromethane (50mL) and is cooled to 0 ℃ with chemical compound 2.With triethylamine (3.6mL, 25.6mmol) and trimethyl-aceyl chloride (2.90mL 23.4mmol) handles cold solution continuously.At room temperature agitating solution is 6 hours, refluxes then and spends the night.Mixture is distributed between dichloromethane and the NaOH aqueous solution (2N).With salt water washing organic layer, through MgSO 4Dry also filtration, concentrated filtrate obtains chemical compound 3 (3.33g, 75%).
Step 3: under dry nitrogen atmosphere, with chemical compound 3 (0.50g 2.4mmol) is dissolved in anhydrous THF, (9.6mL) and TMEDA (1.1mL, 7.2mmol) in.The solution that generates is cooled between-20 ℃ and-10 ℃, drips n-BuLi (the hexane solution 2.25mL of 1.6M) and tert-butyl lithium (pentane solution of 1.7M, 2.1mL) processing continuously with syringe.After 30 minutes, make bathe temperature go back up to-5 to 0 ℃ and by syringe (0.77mL 9.6mmol) handles with iodoethane.0 ℃ of following agitating solution 2 hours, at room temperature stir then and spend the night.With the methanol chilled mixture and be concentrated into dried.By filtered through silica gel purification residue, with 3: 1 hexanes: eluent ethyl acetate, recrystallization obtains chemical compound 4 (0.32g, 56%) from hexane then.
Step 4: (0.32g 1.3mmol) is dissolved in the glacial acetic acid (4.5mL), and (0.65g 3.9mmol) handles with potassium iodide with chemical compound 4.The mixture that heating generates in being adjusted in 115 ℃ oil bath 1.0 hours.Cooling mixture, dilute with water also uses 2NNaOH and 2NHCl is adjusted to pH6.With chloroform extraction mixture (4 times).With the extracting solution of sodium thiosulfate solution washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains the chemical compound 5 (0.25g, 86%) into white solid.This material need not be further purified and can use.
Step 5: under 0 ℃, (0.25g 1.1mmol) is dissolved among the THF (45mL), and (toluene solution of 0.5M 2.7mL) drips processing with two (trimethyl silyl) amide potassium solutions with chemical compound 5.(0.16mL 1.2mmol) handles the solution that generates, and makes solution be warmed to ambient temperature overnight with 2-chloro benzyl bromide a-bromotoluene.Mixture is distributed between 2N HCl and the ethyl acetate.With salt water washing organic layer, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate is through chromatography (SiO 2, gradient elution is converted to 2: 1 hexanes at 4: 1: ethyl acetate) purification residue obtains chemical compound 6 (0.16g, 41%).
Step 6: (0.16g 0.46mmol) is suspended in 1: 1 water: among the dense HCl (4.6mL) with chemical compound 6.Made suspension returning 4 hours, compound dissolution during the backflow.Cooling mixture, dilute with water is used ether extraction.After with excessive saturated sodium bicarbonate solution water layer being adjusted to alkalescence, use the ethyl acetate extraction mixture.Merge extractive liquid, is used the salt water washing, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains chemical compound 7 (0.081g, 67%).
Step 7: with chemical compound 7 (0.080g 0.30mmol) is dissolved in 1,2-dichloroethanes (1.2mL) and DIPEA (0.115mL, 0.66mmol) in and be cooled to 0 ℃.With phosgene solution (toluene solution of 1.93M, 0.170mL, 0.33mmol) the cold solution of fast processing.After 30 minutes, by syringe add fast chemical compound 8 (0.068g, 0.33mmol) 1,2-dichloroethane solution (0.5mL).The mixture heated to 55 that generates ℃ 1 hour.Mixture is distributed between dichloromethane and the 2N HCl.Use saturated NaHCO 3Aqueous solution and salt water washing organic layer are through MgSO 4Dry after-filtration.Concentrated filtrate obtains chemical compound 9 (0.110g, 74%).
Step 8: (0.11g 0.22mmol) is dissolved in 2: 1 THF: H with chemical compound 9 2Handle among the O (0.88mL) and with 2N NaOH solution (0.33mL).Drip methanol, up to obtaining homogeneous solution.Stirred the mixture 20 minutes, dilute with water washs with ether then.Behind 2NHCl acidify water layer, use ethyl acetate extraction.With salt water washing ethyl acetate layer, through MgSO 4Dry after-filtration.Concentrated filtrate obtains (3S)-3-{[({1-[(2-chlorophenyl) methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (10,0.095g, 92%).
Embodiment 2
(3S)-and 3-{[({6-methyl-2-oxo-1-(phenyl methyl)-4-[(phenyl methyl) the oxygen base]-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (15) synthetic
Step 1: to chemical compound 11 (1.0g, 5.9mmol) and K 2CO 3(2.40g, 17.6mmol) add in the acetone suspension (50mL) benzyl bromide a-bromotoluene (2.31g, 13.5mmol).After backflow is spent the night, the cooling reactant, mixture is distributed in ethyl acetate and saturated NaHCO 3Between.With rare HCl and salt water washing organic layer, through MgSO 4Dry after-filtration, concentrated filtrate obtains chemical compound 12 (1.60g, 80%).
Step 2: with chemical compound 12 (0.30g, 0.86mmol), zinc powder (0.30g, 4.6mmol) and saturated NH 4Cl aqueous solution (0.30mL) is mixed among the MeOH (18mL).This mixture was stirred 1 hour, add then other zinc powder (0.30g, 4.6mmol).The heterogeneous mixture backflow that generates is spent the night.After filtering the mixture and concentrating under reduced pressure filtrate of heat, residue is dissolved in the ethyl acetate, uses saturated NaHCO 3Aqueous solution and salt water washing.Through MgSO 4Dry organic layer after-filtration, concentrating under reduced pressure filtrate obtains chemical compound 13 (0.18g, 66%).
Step 3: with chemical compound 13 (0.30g, 0.94mmol.) and DIPEA (0.40mL 2.3mmol.) is dissolved in CH 2Cl 2In, mixture is cooled to 0 ℃.In solution, drip phosgene (toluene solution of 1.9M, 0.55mL, 1.0mmol).0 ℃ of following stirred reaction mixture 15 minutes, add chemical compound 8 (0.19g, CH 0.94mmol) then 2Cl 2Solution (2mL).At room temperature the solution stirring that generates is spent the night, be poured into then in the ethyl acetate, use saturated NaHCO 3Aqueous solution, 1N HCl and salt water washing.Through MgSO 4Dry organic layer after-filtration, concentrating under reduced pressure filtrate.Through flash chromatography on silica gel method purification residue, with the hexane that increases to 1: 2 at 1: 1: eluent ethyl acetate obtains chemical compound 14 (0.33g, 64%).
Step 4: (0.33g, 0.6mmol) solution in THF (6mL) is handled with 2N NaOH (2mL) with chemical compound 14.Add MeOH, up to obtaining uniform solution.At room temperature stirred reaction mixture is 30 minutes, and it is poured into H 2Among the O (50mL).Wash water layer (twice) with ether, use 1N HCl acidify then.With ethyl acetate extraction water layer (twice).With the acetic acid ethyl acetate extract (twice) of salt water washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains (3S)-3-{[({6-methyl-2-oxo-1-(the phenyl methyl)-4-[(phenyl methyl into pale solid) the oxygen base]-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (15,0.26g, 90%).Fusing point: 124-126 ℃.
Embodiment 3
(3S)-and 3-{[({4-amino-1-[(2-chlorophenyl) methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (22) synthetic
Step 1: under 0 ℃, to chemical compound 11 (10.00g, add in anhydrous DMF solution 58.8mmol) (120mL) NaH (60% mineral oil dispersion liquid, 5.40g, 135mmol).Under 0 ℃, stirred the mixture 15 minutes, add then 2-chloro benzyl chloride (12.3g, 76.4mmol).After 55 ℃ stirring is spent the night down, mixture is poured in the frozen water, use Et 2The O washed twice.The acidify water layer also filters the precipitation that generates, and obtains chemical compound 16 (14.7g, 85%).
Step 2: under dry nitrogen atmosphere, chemical compound 16 will be housed, and (8.00g, flask 28.6mmol) adds POCl with diaphragm of rubber and balloon sealing by syringe in room temperature 3(30.0ml, 322mmol).Remove the nitrogen feed-line, spend the night, be poured into ice (300ml) then and go up and stirred 30 minutes at 70 ℃ of following stirred reaction mixtures.Extract the mixture that generates with dichloromethane (300ml), through MgSO 4Anhydrous organic facies after-filtration.Concentrating under reduced pressure filtrate obtains the chemical compound 17 (7.3g, 86%) into dark brown solid.
Step 3: at room temperature, to condenser is equipped with and be equipped with add in the 250ml flask of rubber separator of balloon chemical compound 17 (2.1g, 7.05mmol), methanol (55ml) and ammonium hydroxide aqueous solution (28-30%, 70.0ml, solution 1.14mol).Reactant mixture is heated to 65 ℃ of reactions 60 hours, only open balloon.Filtering mixt, concentrating under reduced pressure filtrate obtain the chemical compound 18 (1.5g, 76%) into brown solid.
Step 4: at room temperature, to chemical compound 18 (0.3g, add continuously in methanol solution 1.02mmol) (50ml) saturated aqueous ammonium chloride (2ml) and zinc powder (0.30g, 4.6mmol).After at room temperature stirring 30 minutes, (0.30g 4.6mmol) and reaction mixture refluxed spends the night to add other zinc powder.With the reactant mixture heat filtering, concentrating under reduced pressure filtrate.Residue is distributed between ethyl acetate and the 1N NaOH.Filtering solution is used the ethyl acetate extraction water.Through MgSO 4The dry organic facies that merges is also filtered.Concentrating under reduced pressure filtrate obtains the chemical compound 19 (0.21g, 78%) into brown solid.
Step 5: with chemical compound 19 (0.10g, 0.38mmol), (0.040mL, 0.38mmol) (0.14g, anhydrous DMF solution 0.38mmol) (5mL) are heated to 50 ℃ and spend the night NMM with chemical compound 20.Cooling mixture is also used ethyl acetate (60mL) dilution.With 0.5N NaOH (3 * 30mL) and salt water washing organic layer, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate is through flash chromatography on silica gel method purification residue, with the CHCl that increases to 17: 3 at 9: 1 3: the MeOH eluting obtains the chemical compound 21 (0.120g, 65%) into yellow foam thing.
Step 6: (0.120g, THF solution (6mL) 0.25mmol) is handled with 2NNaOH (2mL) with chemical compound 21.Add methanol, up to obtaining uniform solution.At room temperature stirred reaction mixture was poured into H after 30 minutes 2On the O (50mL).Wash water layer (twice) with ether, use 1N HCl acidify then.With ethyl acetate extraction water layer (twice).With the acetic acid ethyl acetate extract (twice) of salt water washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains (the 3S)-3-{[({4-amino-1-[(2-chlorophenyl into pale solid) methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (22,0.100g, 89%).Fusing point: 145-147 ℃.
Embodiment 4
(3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(methoxyl group)-2-oxo-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: the chemical compound 23 under 0 ℃ (adding NaH among the 10.00g, anhydrous DMF solution 64.0mmol) (130mL) (60% mineral oil dispersion liquid, 5.90g, 147mmol).Under 0 ℃, stirred the mixture 15 minutes, add then 2-chloro benzyl chloride (13.4g, 83.3mmol).After 55 ℃ stirring is spent the night down, mixture is poured in the frozen water, use Et 2O washs (twice).The acidify water layer filters the precipitation that generates and obtains chemical compound 24 (13.5g, 75%).
Step 2: with chemical compound 24 (1.0g, 3.6mmol), K 2CO 3(0.85g, 6.2mmol) and MeI (1.18g, 8.3mmol) acetone suspension (20mL) reflux and spend the night.Use the ethyl acetate diluted reaction mixture, use saturated NaHCO 3Aqueous solution, 1N HCl and salt water washing.Through MgSO 4Dry organic layer after-filtration, concentrating under reduced pressure filtrate obtains chemical compound 25 (0.74g, 70%).
Method according to embodiment 3 describes prepares (3S)-3-[({[1-[(2-chlorophenyls with chemical compound 25) methyl]-4-(methoxyl group)-2-oxo-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid.MS: value of calculation: (M+H) +=469.93; Measured value: (M+H) +=470.01.
Embodiment 5
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: under dry nitrogen atmosphere, with chemical compound 3 (0.65g, 3.1mmol) be dissolved in anhydrous THF (12.4mL) and TMEDA (0.90mL, 6mmol) in.The solution that generates is cooled between-15 and-10 ℃ and by syringe drip n-BuLi (hexane solution of 1.6M, 7.75mL, 12.4mmol).1.5 after hour, in cold solution, add N-fluorobenzene sulfimide (1.07g, THF solution (5mL) 3.4mmol) rapidly by syringe.0 ℃ of following agitating solution 1 hour, at room temperature stirred then 3 hours.The water chilled mixture is also used chloroform extraction (4 times).With organic extracting solution of salt water washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate is through purification by chromatography residue (SiO 2, the plunger gel uses to be converted to 3: 1 hexanes at 4: 1: ethyl acetate), obtain chemical compound 26 (0.177g, 25%).
According to the method for describing among the embodiment 1, with chemical compound 26 preparation (3S)-3-{[({1-[(2-chlorophenyls) methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid.MS: value of calculation: (M+H) +=458.12; Measured value: (M+H) +=458.01.Embodiment 6
(3S)-and 4-chloro-3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: with chemical compound 3 (0.65g, 3.1mmol) be dissolved in THF (21mL) and TMEDA (1.20mL, 7.75mmol) in, make it be cooled to-15 ℃.With n-BuLi (hexane solution of 1.6M, 4.8mL, 7.8mmol) Treatment Solution.Mixture was kept 1 hour between-20 and-10 ℃, be cooled to-78 ℃ then.(0.45g, 3.4mmol), device is under the positive nitrogen current simultaneously to add the solid N-chlorosuccinimide.Making reactant be warmed to room temperature gradually stirs then and spends the night.After the water chilled mixture, with chloroform extraction (4 times).Merge organic layer, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate, the recrystallization residue obtains chemical compound 27 (0.25g, 33%) from hexane.
According to the method for describing among the embodiment 1, with chemical compound 27 preparation (3S)-4-chloro-3-{[({1-[(2-chlorophenyls) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid.
Embodiment 7
(3S)-and 4-bromo-3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: under dry nitrogen atmosphere, with chemical compound 3 (2.00g, 9.6mmol) be dissolved in anhydrous THF (32mL) and TMEDA (2.20mL, 14.4mmol) in.The solution that generates is cooled between-20 and-10 ℃, by syringe drip n-BuLi (hexane solution of 1.60M, 18.0mL, 28.8mmol).After adding, solution is cooled to-78 ℃, by the syringe dripping bromine (0.49mL, 10.5mmol).Make solution slowly be warmed to ambient temperature overnight, then water quenching and use chloroform extraction.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.The recrystallization residue obtains the chemical compound 28 (1.32g, 48%) into brown white solid from hexane.
According to the method for describing among the embodiment 1, with chemical compound 28 preparation (3S)-4-bromo-3-{[({1-[(2-chlorophenyls) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid.Embodiment 8
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (32) synthetic
Step 1: the chemical compound 24 under room temperature (1.5g, and continuous adding saturated ammonium chloride (1.5mL) and zinc powder in methanol solution 5.3mmol) (50ml) (1.5g, 23mmol).After at room temperature stirring 30 minutes, (1.5g 23mmol), spends the night reaction mixture refluxed to add other zinc powder.The filtered while hot reactant mixture, concentrating under reduced pressure filtrate.Adding HCl (1N) in the residue that obtains is about 4 up to pH, filters and collects the precipitation that generates, and obtains the chemical compound 29 (0.80g, 57%) into brown solid.
Step 2: with chemical compound 29 (0.26g, 1.0mmol) and CDI (0.25g, DMF solution (10ml) 1.6mmol) is heated to 70 ℃ and spends the night.After being cooled to room temperature, with ethyl acetate diluted mixture thing, with 1N HCl (3 times) and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the chemical compound 30 (0.14g, 50%) into brown solid.
Step 3: (0.1g, 0.36mmol) (0.082g, anhydrous DMF solution 0.40mmol) (5ml) are heated to 70 ℃ and spend the night with chemical compound 8 with chemical compound 30.Cooling mixture is with the ethyl acetate dilution, with 1N HCl (3 times) and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Through flash chromatography method (SiO 2) the purification residue, with 9: 1CHCl 3: the MeOH eluting obtains chemical compound 31 (0.17g, 97%).
Step 4: handle chemical compound 31 (0.170g, THF solution (3ml) 0.35mmol) with 2N NaOH (1ml).Add methanol up to obtaining uniform solution.At room temperature stirred reaction mixture is 30 minutes, is poured into H 2Among the O (50ml).Wash water layer (twice) with ether, use 1N HCl acidify then.With ethyl acetate extraction water layer (twice).With the acetic acid ethyl acetate extract (twice) of salt water washing merging, through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains (the 3S)-3-{[({1-[(2-chlorophenyl into pale solid) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (32,0.150g, 94%).Fusing point: 113-115 ℃.Embodiment 9
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: (method according to describing in embodiment 1 makes with chemical compound 28, and 0.20g 0.50mmol) is dissolved in DMF (1.8ml) and the water (0.7ml), uses K with chemical compound 33 3PO 4(0.39g, 1.86mmol) and phenylboric acid (0.113g 0.93mmol) handles.With the mixture deoxidation (between vacuum and nitrogen, switching 5 times) that generates, add then tetrakis triphenylphosphine palladium (0) (8.7mg, 0.050mmol).Ditto make the mixture deoxidation and 90 ℃ of following heated overnight.Cooling mixture, dilute with water is with ethyl acetate extraction (twice).With the extracting solution of salt water washing merging, through MgSO 4Dry back is by filtered through silica gel, concentrating under reduced pressure.Residue is suspended in 1: 1 water: in dense HCl (2ml) and the acetonitrile (0.5ml).Made suspension returning 1 hour, cooling is distributed in ethyl acetate and saturated NaHCO then 3Between the aqueous solution.With salt water washing ethyl acetate layer, through MgSO 4Drying is filtered concentrating under reduced pressure.Through flash chromatography method (SiO 2, 3: 1 hexane/ethyl acetate) and the purification residue, obtain chemical compound 34 (0.115g, 94%).This material need not purification and can use.
According to the method for in embodiment 1, describing, with chemical compound 34 preparation (3S)-3-{[({1-[(2-chlorophenyls) methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid. 1H?NMR(400MHz，CD 3OD)：δ2.25(s，3H)，2.50(m，2H)，4.89(t，J＝5.9Hz，1H)，5.34(s，2H)，6.40(d，J＝7.0Hz，1H)，7.0(d，J＝8.0Hz，2H)，7.10(d，J＝8.0Hz，2H)，7.18(m，1H)，7.28(m，2H)，7.35(m，3H)，7.43(m，1H)，7.49(m，3H)。
Embodiment 10
(3S)-and 3-[({[2-methyl-4-(2-methyl-propyl)-6-oxo-1-(phenyl methyl)-1,6-dihydro-5-pyrimidine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid (43) synthetic
Step 1: (2.00g 18.2mmol) is dissolved in the absolute methanol of 30mL with chemical compound 35.To wherein add benzylamine (1.97g, 18.2mmol) and triethylamine (2.0g, 20.0mmol).50 ℃ of following stirred reaction mixtures 3 hours, concentrating under reduced pressure then.Residue is distributed in H 2O and CH 2Cl 2Between.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains chemical compound 36 (2.3g, 82%).
Step 2: to chemical compound 37 (3.50g, add in ethanol 26.5mmol) (10mL) and pyridine (5mL) solution isovaleral (2.8mL, 27mmol) and piperidines (1mL).Reactant mixture be heated to refluxed 3 hours after concentrating under reduced pressure.Residue is distributed between 2N HCl (15mL) and the ethyl acetate (30mL).Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.With residue through the silica gel chromatography purification, with 2: 1 hexanes: eluent ethyl acetate obtains chemical compound 38 (3.6g, 67%).
Step 3: (2.5g, 12.48mmol) (2.52g, absolute methanol solution 13.7mmol) (25mL) was heated to vigorous reflux 3 hours, cooling back concentrating under reduced pressure with chemical compound 36 with chemical compound 38.With residue chromatography on silica gel, with 2: 1 hexanes: eluent ethyl acetate obtains chemical compound 39 (2.75g, 69%).
Step 4: to chemical compound 39 (2.5g, CCl 7.9mmol) 4Add in the solution (15mL) NBS (1.4g, 8.0mmoL), K 2CO 3(11.0g, 80.0mmol) and benzoyl peroxide (50mg, 0.20mmol).Reactant mixture is heated to backflow 1 hour, is cooled to room temperature, use H 2Use CH after the O dilution 2Cl 2Extract.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.With residue chromatography on silica gel, with 3: 1 hexanes: eluent ethyl acetate obtains chemical compound 40 (0.62g, 25%).
Step 5: usefulness 2N NaOH (5mL) and THF (3mL) processing chemical compound 40 (0.60g, 1.9mmol).The mixture that stirring at room temperature generates 2 hours is with using ethyl acetate extraction after the 2N HCl acidify.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains chemical compound 41 (560mg, 98%).
Step 6: to chemical compound 41 (0.56g, add in the anhydrous benzene solution (10mL) 1.86mmol) diphenylphosphine acyl azide thing (0.56g, 2.0mmol) and triethylamine (2.02g, 2.0mmol).Reactant mixture be heated to 90 ℃ 1 hour, add chemical compound 8 (0.39g, 1.9mmol) solution in benzene (2mL) then.Under 90 ℃, reactant restir 1 hour, be cooled to room temperature, with using ethyl acetate extraction after the dilution of 10% aqueous ammonium chloride solution.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.With residue chromatography on silica gel, with 7: 3 ethyl acetate: the hexane eluting obtains chemical compound 42 (0.38g, 40%).
Step 7: to chemical compound 42 (0.35g, THF 0.7mmol): MeOH1: add 2N NaOH (8mL) in 1 mixture solution (8mL).At room temperature reaction stirred is 3 hours, with extracting with ethyl acetate (20mL) after 2NHCl (10mL) acidify.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains (3S)-3-[({[2-methyl-4-(2-methyl-propyl)-6-oxo-1-(phenyl methyl)-1,6-dihydro-5-pyrimidine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid (43,250mg, 75%).MS: value of calculation: (M+H) +=477.25m/z; Measured value: (M+H) +=477.17m/z.
Embodiment 11
(3S)-and 3-[({[2-methyl-6-oxo-1-(phenyl methyl)-1,6-dihydro-5-pyrimidine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: (2.3g, 15.5mmol) (3.36g, ethanol solution 15.5mmol) (35mL) refluxed 3 hours and concentrated with chemical compound 44 with chemical compound 36.With residue chromatography on silica gel, with 1: 1 ethyl acetate: the hexane eluting obtains chemical compound 45 (1.87g, 55% yield).
According to the method for in embodiment 10, describing, with chemical compound 45 preparation (3S)-3-[({[2-methyl-6-oxo-1-(phenyl methyl)-1,6-dihydro-5-pyrimidine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid. 1H?NMR(400MHz，CD 3OD)：δ2.28(s，3H)，2.35(s，3H)，2.57(m，2H)，5.16(m，1H)，5.30(s，2H)，7.13(m，4H)，7.30(m，5H)，8.50(s，1H)。
Embodiment 12
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[({ ethyl [(ethylamino) carbonyl] amino } carbonyl) amino }-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: to the chemical compound under 0 ℃ 46 (make according to the method for in embodiment 3, describing, add among the 0.50g, THF solution (10mL) 1.8mmol) NaH (60% mineral oil dispersion liquid, 0.23g, 5.1mmol).Under 0 ℃, stirred the mixture 10 minutes, add then ethyl isocyanate (0.65g, 9.15mmol).At room temperature, mixture is stirred a weekend, with the 1NHCl quenching and use ethyl acetate extraction.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains chemical compound 47 (0.60g).This material need not purification and can use.
According to the method for in embodiment 3, describing, with chemical compound 47 preparation (3S)-3-{[({1-[(2-chlorophenyls) methyl]-4-[({ ethyl [(ethylamino) carbonyl] amino } carbonyl) amino }-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid.Fusing point: 128-130 ℃.
Embodiment 13
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-quinolyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: the chemical compound 48 under 0 ℃ (adding NaH among the 2.00g, anhydrous DMF solution 9.70mmol) (25mL) (60% mineral oil dispersion liquid, 0.89g, 22mmol).Under 0 ℃, stirred the mixture 15 minutes, add then 2-chloro benzyl chloride (2.03g, 12.6mmol).After 55 ℃ stirring is spent the night down, mixture is poured in the frozen water, use Et 2O washs (twice).The acidify water layer filters the precipitation that generates and obtains chemical compound 49 (3.45g).This material need not purification and can use.
According to the method for in embodiment 8, describing, with chemical compound 49 preparation (3S)-3-{[({1-[(2-chlorophenyls) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-quinolyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid.Fusing point: 134-136 ℃.
Embodiment 14
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid (56) synthetic
Step 1: in room temperature under dry nitrogen atmosphere, to chemical compound 51 (1.67g, add continuously in the DMF suspension (33mL) 9.81mmol) the 2-chloro-benzylamine (1.30mL, 10.8mmol) and EDCI (2.35g, 12.3mmol).At room temperature the mixture that generates of vigorous stirring is 5 hours, with the ethyl acetate dilution and with 2N HCl, H 2O (three times), saturated NaHCO 3Aqueous solution and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the chemical compound 52 (2.55g, 100%) into light yellow solid.
Step 2: (555mg, 2.17mmol) (738mg, dehydrated alcohol 6.5mmol) (4.3mL) and glacial acetic acid (0.22mL) solution are heated to reflux and spend the night with 3-dimethylamino-methacrolein with chemical compound 52.The mixture that generates is cooled to room temperature, after the ethyl acetate dilution, with 2N HCl (twice), H 2O and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.With residue through the silica gel chromatography purification, with increasing to 1: 1 hexane at 7: 3: ethyl acetate, use 19: 19: 2 hexanes at last: ethyl acetate: methanol-eluted fractions obtains the chemical compound 53 (182mg, 27%) into yellow oil.
Step 3: (add 2N NaOH (1mL) and methanol (2mL) among the 167mg, THF solution (3mL) 0.55mmol) to chemical compound 53.The mixture that stirring generates 15 minutes is used H 2After the O dilution, use ether extraction.Behind 2N HCl acidify water layer, use ethyl acetate extraction.Use H 2O and salt water washing ethyl acetate layer are through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains the chemical compound 54 (139mg, 91%) into white solid.
Step 4: in room temperature under dry nitrogen atmosphere, by syringe to chemical compound 54 (175mg, THF 0.63mmol) (6.7mL) and DIPEA (0.23mL, 1.34mmol) add in the suspension DPPA (0.29mL, 1.34mmol).The mixture that stirring at room temperature generates 15 minutes is heated to then and refluxed 3.5 hours.Make mixture be cooled to room temperature, add chemical compound 8 (278mg, THF solution (6.0mL) 1.34mmol) and THF (0.7mL) flushing liquor by sleeve pipe.At room temperature stir the mixture overnight that generates, after the ethyl acetate dilution, with 2N HCl (twice), saturated NaHCO 3Aqueous solution and salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Residue is through the silica gel chromatography purification, with 7: 3, use 3: 2 then, use 1: 1 hexane at last: eluent ethyl acetate obtains the chemical compound 55 (60mg, 20%) into water white oil.
Step 5: to chemical compound 55 (60mg, add in the THF solution (3mL) 0.12mmol) 0.192N NaOH (0.65mL, 0.12mmol) and methanol (2mL).The mixture that stirring at room temperature generates 24 hours is used H then 2The O dilution.Remove organic solvent under the decompression, with the aqueous mixtures of ether extraction generation.The water lyophilizing is obtained (3S)-3-{[({1-[(2-chlorophenyl into pale solid) methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid sodium salt (56,56mg, 95%).MS:(C 24H 23ClN 3O 4) -Value of calculation: 452.14m/z; Measured value: 451.99m/z.
Embodiment 15
(3S)-and 3-(1,3-benzo dioxole-5-yl)-3-[({[2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propanoic acid (62) synthetic
Step 1: under dry nitrogen atmosphere, by syringe to the 2-thenyl alcohol (1.015g, CH 8.89mmol) that are cooled to 0 ℃ 2Cl 2(17.8ml) add continuously in the solution triethylamine (2.98ml, 21.4mmol) and mesyl chloride (0.69ml, 8.9mmol).Stirred down the mixture that generates 15 minutes at 0 ℃, add then the 2-hydroxy-3-nitropyridine (1.496g, 10.7mmol) and 4-dimethylaminopyridine (catalytic amount).Make mixture be warmed to room temperature gradually, stir then and spend the night.With ethyl acetate diluted mixture thing, use 2N HCl, H then 2O, saturated NaHCO 3Aqueous solution and salt water washing.Organic facies is through MgSO 4Dry after-filtration and concentrating under reduced pressure filtrate obtain being solid 58 (395mg) of yellow wax shape.This material need not purification and can use.
Step 2: under dry nitrogen atmosphere, (330mg adds iron powders (154mg, 2.8mmol ,-325 orders) in glacial acetic acid solution 1.40mmol) (6.6ml) to 58 in room temperature.In oil bath under the vigorous stirring, the solution that generates be heated to 60 ℃ 20 minutes.Mixture is cooled to room temperature,, filters through celite with the ethyl acetate dilution.Use H 2O, saturated NaHCO 3With the saline wash filtrate.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Residue is by filtered through silica gel, and with 1: 1 hexane: ethyl acetate increases to 1: 3 hexane: eluent ethyl acetate obtained 59 (188mg, two go on foot 12%) into green solid.
Step 3: under dry nitrogen atmosphere, by syringe to 59 (111mg, CH 0.54mmol) that are cooled to 0 ℃ 2Cl 2(2.7ml) add continuously N in the solution, the N-diisopropylethylamine (0.23ml, 1.30mmol) photoreactive gas (0.31ml, the toluene solution of 1.9M, 0.59mmol).The mixture that stirring generates under 0 ℃ 15 minutes adds beta-amino ester 60 (167mg, CH 0.70mmol) by sleeve pipe then 2Cl 2Solution (2.7ml) and CH 2Cl 2Flushing liquor (1.0ml).Make the mixture of generation be warmed to room temperature, stirred 2 hours,, use 2N HCl, H then with the ethyl acetate dilution 2O, saturated NaHCO 3With the salt water washing.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Through silica gel chromatography purification residue, with 1: 1 hexane: eluent ethyl acetate obtains being foamy 61 (231mg, 91%) of purple.
Step 4: at room temperature, (add NaOH (2ml, the H of 2N among the 227mg, THF solution (6ml) 0.48mmol) to ester 61 2O solution, 4mmol) and methanol (be enough to obtain settled solution, approximately 2ml).The mixture that stir to generate 15 minutes, dilute with water and use ether extraction then.With HCl (2N) acidify water, use ethyl acetate extraction then.With salt water washing organic facies, through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 62 (191mg, 90%) into white solid. 1H?NMR(400MHz，CD 3SOCD 3)δ2.63(d，J＝7.3Hz，2H)，4.99(dt，J＝8.4，7.3Hz，1H)，5.30(s，2H)，5.98(m，2H)，6.21(dd，J＝7.5，7.0Hz，1H)，6.78(dd，J＝8.1，1.6Hz，1H)，6.85(d，J＝8.1Hz，1H)，6.88(d，J＝1.6Hz，1H)，6.97(dd，J＝5.1，3.5Hz，1H)，7.17(dd，J＝3.5，1.1Hz，1H)，7.35(dd，J＝7.0，1.8Hz，1H)，7.44(dd，J＝5.1，1.1Hz，1H)，7.67(d，J＝8.4Hz，1H)，7.94(dd，J＝7.5，1.8Hz，1H)，8.40(s，1H)。
Embodiment 16
(3S)-and 3-(1,3-benzo dioxole-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienyl methyl) six hydrogen-3-pyridine radicals] amino } carbonyl) amino] propanoic acid (68) synthetic
Step 1: in room temperature under dry nitrogen atmosphere, by syringe to N-α-tert-butoxycarbonyl-N-δ-benzyloxycarbonyl-L-ornithine 63 (1.00g, 2.73mmol) and cesium carbonate (adding iodomethane among the 1.33g, DMF solution (10ml) 4.1mmol) (0.22ml, 3.3mmol).The mixture that stirring at room temperature generates 18 hours with the ethyl acetate dilution, is used H then 2O, 10%Na 2S 2O 5, saturated NaHCO 3With the salt water washing.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the ester 64 (1.21g) into light yellow oil.This material contains DMF but need not purification and can use.
Step 2: 0 ℃ under dry nitrogen atmosphere, in the methanol solution (10ml) of 64 (the crude product material that the above method of 0.86g makes, 1.94mmol theoretical values), add palladium on carbon (300mg, 10%Pd, Degussa E101 NE/W type, wet, 50% (weight) water).With hydrogen place of nitrogen atmosphere (between the hydrogen that vacuum and balloon are supplied with alternately 5 times) and stirred the mixture under 0 ℃ 30 minutes, (177mg is in flask 1.58mmol) to 2 thiophene carboxaldehyde is housed for Direct Filtration then.Enriched mixture (in the water-bath at room temperature) is dissolved in the dichloroethanes (6ml) residue.In this solution, add sodium triacetoxy borohydride (479mg, 2.26mmol) and stirred the mixture 2 hours, with the ethyl acetate dilution saturated NaHCO in back 3(twice) and the salt water washing.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.By the filtered through silica gel residue, with 7: 3 hexanes: eluent ethyl acetate obtains the lactams 65 (75mg, two steps, 12%) into water white oil.
Step 3: in room temperature under dry nitrogen atmosphere, by syringe to Rubber Diaphragm Seal be equipped with 65 (89mg, add in flask 0.29mmol) HCl (7.2ml, the dioxane solution of 4.0M, 28.8mmol).Remove the nitrogen pin and stir mixture overnight in the sealed flask.Use CH 2Cl 2The diluted mixture thing is used saturated NaHCO then 3Washing.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the amine 66 (60mg, 100%) into light yellow oil.This material need not purification and can use.
Step 4: in room temperature under dry nitrogen atmosphere, to beta-amino ester 60 (75mg, CH 0.32mmol) 2Cl 2Adding carbonyl dimidazoles in the solution (0.6ml) (51mg, 0.32mmol).The mixture that stirring at room temperature generates 5 minutes adds amine 66 (60mg, CH 0.29mmol) through sleeve pipe 2Cl 2Solution (0.6ml) and CH 2Cl 2(0.2mL) flushing liquor.The mixture that stirring at room temperature generates 3 days is then with the ethyl acetate dilution, with 2N HCl (twice), H 2O, saturated NaHCO 3With the salt water washing.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Residue is by filtered through silica gel, and with 1: 1 hexane: ethyl acetate increases to 2: 3 hexanes: eluent ethyl acetate obtained urea 67 (110mg, 80%).
Step 5: at room temperature, to urea 67 (108mg, add in the THF solution (3ml) 0.23mmol) NaOH (1ml, the 2N aqueous solution, 2mmol) and methanol (being enough to obtain settled solution, about 2ml).The mixture that stirring generates 15 minutes, dilute with water is used ether extraction then.With HCl (2N) acidify water, use ethyl acetate extraction afterwards.With salt water washing ethyl acetate layer, through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 68 (92mg, 90%) into white foam. 1H NMR (400MHz, CD 3SOCD 3) δ 1.45 (m, 1H), 1.76 (m, 2H), 2.62 (m, 2H), 3.25 (the overlapping H of m 2O, 2H), 4.01 (m, 1H), 4.59 (d, J=15.0Hz, 1H), 4.68 (d, J=15.0Hz, 1H), 4.96 (m, 1H), 5.97 (s, 2H), 6.24 (d, J=6.6Hz, 1H), 6.71 (d, J=8.4Hz, 1H), 6.75 (dd, J=8.1,1.5Hz, 1H), 6.82 (d, J=8.1Hz, 1H), 6.85 (d, J=1.5Hz, 1H), 6.97 (dd, J=5.1,3.3Hz, 1H), 7.03 (dd, J=3.3,1.5Hz, 1H), 7.42 (dd, J=5.1,1.5Hz, 1H), 12.06 (br.s, 1H).
Embodiment 17
(3S)-and 3-(1,3-benzo dioxole-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienyl methyl) tetrahydro-1 H-pyrrolo-3-yl] amino } carbonyl) amino] propanoic acid (74) synthetic
Step 1: under dry nitrogen atmosphere, by syringe to the N-tert-butoxycarbonyl-L-aspartic acid α-benzyl ester (2.10g that is cooled to-15 ℃ (bathe temperature), 6.5mmol) dimethoxy-ethane solution (15ml) in add continuously 4-methyl morpholine (0.71ml, 6.5mmol) and the chloro-carbonic acid isobutyl (0.84ml, 6.5mmol).The mixture that stirring generates 2 minutes filters then, with dimethoxy-ethane (10ml) washing solid filter cake.Filtrate is cooled to once more-15 ℃ (bathing temperature), adds sodium borohydride (370mg, H 9.7mmol) 2O solution (3ml) immediately adds H 2O (100ml).With ethyl acetate extraction mixture (three times), merge organic layer, with cold (0 ℃) HCl (0.2N), H 2O, saturated NaHCO 3With the salt water washing.Through MgSO 4The dry organic layer that generates filters, and concentrating under reduced pressure filtrate obtains 69 (2.50g) into water white oil.This material contains some unreduced mixed acid anhydrides but need not purification can use.
Step 2: under dry nitrogen atmosphere, by syringe to the oxalyl chloride (2.4ml, the CH of 2.0M that are cooled to-65 ℃ 2Cl 2Solution, CH 4.8mmol) 2Cl 2Add methyl sulfoxide (0.55ml, CH 7.8mmol) in the solution (30ml) 2Cl 2Solution (8ml).The mixture that stirring generates under-65 ℃ 15 minutes adds alcohol 69 (1.00g, CH 3.2mmol) through sleeve pipe then 2Cl 2Solution (29ml) and CH 2Cl 2(3ml) flushing liquor.Under-65 ℃, stirred the mixture 3 hours, and made it to be warmed to-20 ℃ (bathing temperature) then.(0.96ml 6.9mmol), adds H subsequently to add triethylamine 2O (20ml).Use CH 2Cl 2Extract water layer, through MgSO 4The dry organic facies that merges is filtered.Concentrating under reduced pressure filtrate obtains the aldehyde 70 into white solid.This material need not purification and can use immediately.
Step 3: in room temperature under dry nitrogen atmosphere, to crude product aldehyde 70 (3.2mmol, theoretical value) and 2-amino methyl thiophene (add among the 402mg, dichloroethane solution 3.35mmol) (13ml) sodium triacetoxy borohydride (959mg, 4.5mmol).At room temperature stir the mixture overnight that generates, with the ethyl acetate dilution, use saturated NaHCO then 3With the salt water washing.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.Residue is through the silica gel chromatography purification, and with 1: 1 hexane: eluent ethyl acetate obtained the lactams 71 (220mg, 3 steps, 23%) into white solid.
Step 4: in room temperature under dry nitrogen atmosphere, by syringe to Rubber Diaphragm Seal 71 (220mg, add in dioxane solution 0.74mmol) (1.5ml) HCl (1.5ml, the dioxane solution of 4.0M, 6.0mmol).Remove the nitrogen pin and stir mixture 5 hours in the sealed flask.Use CH 2Cl 2The diluted mixture thing is used saturated NaHCO then 3Washing.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains the amine 72 (129mg, 89%) into light yellow oil.This material need not purification and can use.
Step 5: in room temperature under dry nitrogen atmosphere, to amine 72 (123mg, CH 0.63mmol) 2Cl 2Adding carbonyl dimidazoles in the solution (1.5ml) (112mg, 0.69mmol).At room temperature stir the mixture 5 minutes of generation and add beta-amino ester 60 (164mg, CH 0.69mmol) through sleeve pipe 2Cl 2Solution (0.8ml) and CH 2Cl 2(0.2ml) flushing liquor.At room temperature stir the mixture overnight that generates, then with the ethyl acetate dilution, with 2N HCl (twice), H 2O, saturated NaHCO 3With the salt water washing.Organic facies is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate.By the filtered through silica gel residue, with 49: 1 chloroforms: methanol-eluted fractions, obtain urea 73 (230mg, 80%) into water white oil, when leaving standstill, urea 73 slowly solidifies.
Step 6: at room temperature, to urea 73 (230mg, add in the THF solution (3ml) 0.50mmol) NaOH (1ml, the aqueous solution of 2N, 2mmol) and methanol (1ml).The mixture that stir to generate 1 hour, dilute with water and use ether extraction then.With HCl (2N) acidify water, use ethyl acetate extraction.With salt water washing ethyl acetate layer, through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 74 (181mg, 84%) into white foam. 1H?NMR(400MHz，CD 3SOCD 3)δ1.64(m，1H)，2.30(m，1H)，2.64(m，2H)，3.20(m，2H)，4.17(dd，J＝8.8，8.4Hz，1H)，4.56(s，2H)，4.96(m，1H)，5.97(s，2H)，6.30(d，J＝7.0Hz，1H)，6.58(d，J＝8.8Hz，1H)，6.77(m，1H)，6.80-6.90(m，2H)，6.96-7.04(m，2H)，7.45(dd，J＝5.1，0.7Hz，1H)，12.10(br.s，1H)。Embodiment 18
(3S)-and 3-[({[5-chloro-2-hydroxyl-3-(phenyl methyl) phenyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid synthetic
Step 1: to 2-phenyl methyl-3-chlorophenol (5.00g, Et 22.9mmol) 2Add KNO in the mixture of O (20mL) and 6N HCl (50mL) continuously 3(2.30g, 22.9mmol) and NaNO 2(20mg, catalysis).The mixture that stirring generates 2 hours, dilute with water is also used ethyl acetate extraction.Water and salt water washing organic layer are through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate obtains 99 (6.0g, 100%).
Step 2: to 99 (add among the 6.0g, methanol solution 22.8mmol) (360mL) zinc powder (6.0g, 92mmol) and saturated NH 4Cl aqueous solution (6mL).The heterogeneous mixture backflow that generates is spent the night.After filtering the mixture and concentrating under reduced pressure filtrate of heat, be dissolved in residue in the ethyl acetate and use saturated NaHCO 3With the salt water washing.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains chemical compound 100 (2.93g, 55%).
Step 3: under 0 ℃, to 25 (0.20g, CH 0.96mmol) 2Cl 2Add continuously in the solution DIPEA (0.40mL, 2.4mmol) photoreactive gas (toluene solution of 1.93M, 0.60mL, 1.2mmol).Make the mixture of generation be warmed to room temperature, stirred 20 minutes, and then be cooled to 0 ℃.In this mixture, drip 100 (0.25g, CH 1.1mmol) 2Cl 2Solution.Make the mixture of generation be warmed to ambient temperature overnight, dilute with water is also used CH 2Cl 2Extract.Water and salt water washing organic layer are through MgSO 4Dry after-filtration.Concentrating under reduced pressure filtrate, through silica gel chromatography purification residue, with 9: 1 and increase to 5: 1 hexanes: eluent ethyl acetate obtains 101 (60mg, 12%).
According to the method for in embodiment 1, describing, from 101 preparation (3S)-3-[({[5-chloro-2-hydroxyl-3-(phenyl methyl) phenyl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid. 1H?NMR(400MHz，CD 3SO 2CD 3)δ2.26(s，3H)，2.58(dd，J＝15.8，6.6Hz，1H)，2.67(dd，J＝15.8，8.4Hz，1H)，3.49(s，2H)，4.88(m，1H)，7.00-7.70(m，13H)，11.95(br.s，1H)。Embodiment 19
(3S)-and 3-(1,3-benzo dioxole-5-yl)-3-[({ butyl [2,5-dioxo-1-(phenyl methyl) tetrahydro-1 H-pyrrolo-3-yl] amino } carbonyl) amino] propanoic acid synthetic
Step 1: at room temperature, with N-benzyl maleimide (2.60g, 13.9mmol) and n-butylamine (1.00g, 13.7mmol) THF solution (15mL) stir and spend the night and concentrating under reduced pressure.Through silica gel chromatography purification residue, increased to 2: 1 hexanes with 4: 1: eluent ethyl acetate obtains 102 (3.25g, 90%).
According to the method for in embodiment 1, describing, with 102 preparation (3S)-3-(1,3-benzo dioxole-5-yl)-3-[({ butyl [2,5-dioxo-1-(phenyl methyl) tetrahydro-1 H-pyrrolo-3-yl] amino } carbonyl) amino] propanoic acid.MP：80-85℃。
Embodiment 20
(3S)-and 3-(1,3-benzo dioxole-5-yl)-3-[({1-(cyclopentyl-methyl)-2-oxo-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propanoic acid synthetic
Step 1: at 0 ℃ under blanket of nitrogen, to 2-hydroxy-3-nitropyridine (200mg, CH 1.4mmol) 2Cl 2Add in the solution (14mL) Pentamethylene. methanol (178mg, 1.78mmol), add subsequently triphenylphosphine (551mg, 2.1mmol).0 ℃ of following agitating solution 15 minutes and by syringe drip azo-2-carboxylic acid's diethyl ester (366mg, 2.1mmol).Reactant was stirred 1 hour, at room temperature stir then and spend the night.With methanol (20mL) chilled mixture, wash (twice) with water.Use the dichloromethane extraction water layer, through the organic layer after-filtration of dried over mgso merging.Concentrated filtrate, through silica gel chromatography purification residue, with 1: 1 hexane: eluent ethyl acetate obtains 103 (299mg, 96% yields) into yellow solid.
According to the method for in embodiment 1, describing, with 103 preparation (3S)-3-(1,3-benzo dioxole-5-yl)-3-[({1-(cyclopentyl-methyl)-2-oxos-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propanoic acid. 1H?NMR(400MHz，CDCl 3)：δ1.2-1.7(m，8H)，2.34(m，1H)，2.81(dd，J＝，1H)，2.95(dd，J＝，1H)，3.92(d，J＝7.7Hz，2H)，5.30(m，1H)，5.92(m，2H)，6.30(t，J＝7.1Hz，1H)，6.68-7.00(m，5H)，8.33(d，J＝7.7Hz，1H)，8.89(s，1H)。Embodiment 21
(3S)-and 3-(1,3-benzo dioxole-5-yl)-3-{[({3-[(2-thiophenyl methyl) amino] phenyl } amino) carbonyl] amino } propanoic acid synthetic
Step 1: to 2 thiophene carboxaldehyde (0.48g, add in dichloromethane solution 4.0mmol) the 3-nitroaniline (0.51g, 3.7mmol).Solution concentration is added 1 to dry doubling, 2-dichloroethanes (16mL).(3 1.1g), add NaBH (OAc) subsequently to add molecular sieve 3(1.01g, 4.8mmol).At room temperature agitating solution spends the night, with chloroform dilution and wash with water.Organic layer is through MgSO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 104 (0.72g, 84%).
Step 2: under 0 ℃, to 104 (0.30g, CH 1.3mmol) 2Cl 2(5.2mL) and triethylamine (0.215mL, 1.5mmol) add in the solution trifluoroacetic anhydride (0.193mL, 1.4mmol).0 ℃ of following agitating solution 15 minutes, removed ice bath and restir mixture 15 minutes.Use CH 2Cl 2The diluted mixture thing is with 2N HCl, water and salt water washing.Organic layer is through Na 2SO 4Dry after-filtration, concentrating under reduced pressure filtrate obtains 105 (0.38g, 100%) into yellow solid.
Step 3: at room temperature, (0.38g, (0.36g 6.5mmol) and at 40 ℃ of following vigorous stirring suspensions shows 105 full consumptions up to TLC to add the Fe powder in ethanol 1.4mmol) (2.6mL) and acetic acid (2.6mL) solution to 105.Through the celite filtering mixt, wash with chloroform.Dilute filtrate with saturated sodium bicarbonate, through Na 2SO 4Dry chloroform layer after-filtration.Concentrating under reduced pressure filtrate, (6: 1 to 4: 1 hexanes of gradient: ethyl acetate) purification residue obtains chemical compound 106 (0.102g, 25%) through silica gel column chromatography.
According to the method for in embodiment 1, describing, with 106 preparation (3S)-3-(1,3-benzo dioxole-5-yl)-3-{[({3-[(2-thiophenyl methyl) amino] phenyl } amino) carbonyl] amino } propanoic acid. 1H NMR (400MHz, CD 3SO 2CD 3) δ 2.50 (m, the overlapping DMSO of 2H), 4.37 (d, J=5.9Hz, 2H), 4.94 (m, 1H), 5.94 (m, 2H), 6.06 (t, J=5.8Hz, 1H), 6.16 (m, 1H), 6.59 (d, J=8.8Hz, 1H), 6.78 (m, 3H), 6.85 (dd, J=8.8,7.7Hz, 1H), 6.90 (s, 1H), 6.94 (dd, J=5.2,3.7Hz, 1H), 7.00 (d, J=3.3Hz, 1H), 7.33 (dd, J=5.1,1.1Hz, 1H), 8.5 (s, 1H).Embodiment 22
3-(1,3-benzo dioxole-5-yl)-2,2-two fluoro-3-[({[2-oxo-1-(2-thiophenyl methyl) 1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propanoic acid synthetic
Step 1: in 15 minutes, to be cooled to-78 ℃ (1S, 2R, 5S)-(+)-methyl (R)-to toluenesulfinic acid ester (3.00g, 10.2mmol) THF solution (25.5mL) in drip two (trimethyl silyl) lithium amides (the THF solution of 1.0M, 15.3mL).The mixture that stirring at room temperature generates 6 hours is cooled to 0 ℃ then.Add rapidly piperonal (3.06g, 20.4mmol) and CsF (3.10g, 20.4mmol), at room temperature stirred suspension is 36 hours.Use saturated NH 4Cl quenching reactant is used ethyl acetate extraction.With salt water washing organic layer, through Na 2SO 4Dry after-filtration, concentrating under reduced pressure filtrate, recrystallization residue from hexane and dichloromethane obtains chemical compound 108 (1.36g, 46%).
Step 2: (0.78mL, (2.00g is in THF 30.5mmol) (20.2mL) suspension and refluxed 15 minutes 6.1mmol) to join the Zn powder with the bromo difluoro acetate ethyl ester.Suspension is cooled to 0 ℃, and adding 108 (0.87g, 3.0mmol).Making suspension be warmed to room temperature and stir spends the night.Saturated NH with minimum 4The Cl chilled mixture is used ethyl acetate extraction.Use saturated NaHCO 3Aqueous solution and salt water washing organic layer are through Na 2SO 4Dry after-filtration.Concentrating under reduced pressure filtrate, (6: 1 to 4: 1 hexanes of gradient: ethyl acetate) purification residue obtains 109 (0.607g is 61% during 80% conversion) through silica gel column chromatography.
Step 3: under 0 ℃, to 109 (add among the 0.700g, methanol solution 1.70mmol) (4.3mL) trifluoroacetic acid (0.26mL, 3.4mmol).0 ℃ of following agitating solution 2 hours, be evaporated to driedly then, external temperature is remained on below 30 ℃.Use the ether dissolution residue, then with 2N HCl washing (twice).With excessive saturated NaHCO 3The water layer that careful alkalization merges is used ether extraction.Through MgSO 4Dry ether layer after-filtration, concentrating under reduced pressure filtrate obtains 110 (0.326g, 80%).
According to the method for in embodiment 1, describing, with 110 preparation 3-(1,3-benzo dioxole-5-yl)-2,2-two fluoro-3-[({[2-oxo-1-(2-thiophenyl methyl)-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propanoic acid.MS: value of calculation (M-H) -=476.07; Measured value (M-H) -=476.00.Embodiment 23
(3S)-3-(1,3-benzo dioxole-5-yl)-3-({ [9-oxo-8-(phenyl methyl)-2,3,4,5,8,9-six hydrogen-1H-pyrido [3,4-b] azepine-1-yl] carbonyl } amino) propanoic acid synthetic
Step 1: under-20 ℃, by syringe to 3 (0.74g, 3.6mmol) at THF (14.4mL) and TMEDA (1.60mL, 10.8mmol) in solution in drip continuously the n-BuLi (hexane solution of 1.6M, 3.4mL, 5.4mmol) and tert-butyl lithium (pentane solution of 1.7M, 2.5mL, 4.3mmol).Temperature is warmed between-10 and 0 ℃ and kept 2 hours.Add 1 rapidly in the mixture that generates, (1.75mL 14.7mmol), makes solution be warmed to room temperature and stirred 4 days the 4-dibromobutane.Use CHCl behind the water quenching reactant 3Extract (three times).With the extracting solution of salt water washing merging, through Na 2SO 4Dry after-filtration.Concentrating under reduced pressure filtrate, through silica gel column chromatography purification residue, with 4: 1 hexanes: eluent ethyl acetate obtains 111 (0.41g, 44%).
According to the method for in embodiment 4, describing, with 111 preparation (3S)-3-(1,3-benzo dioxole-5-yl)-3-({ [9-oxo-8-(phenyl methyl)-2,3,4,5,8,9-six hydrogen-1H-pyrido [3,4-b] azepine-1-yl] carbonyl } amino) propanoic acid.MS: value of calculation (M-H) -=488.18; Measured value (M-H) -=488.21.
Embodiment 24
(3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-hydroxy phenyl) propanoic acid synthetic
Step 1: under 0 ℃ under nitrogen, (make 0.19g, CH 0.39mmol) by syringe to 112 according to the method for in embodiment 15, describing 2Cl 2Add BBr in the solution 3(the CH of 1.0M 2Cl 2Solution, 1.2mL, 1.2mmol).Make mixture be warmed to room temperature gradually, stir then and spend the night.The dilute with water mixture also stirred 30 minutes, used saturated NaHCO 3Aqueous solution further dilutes.Wash organic layer with water, combining water layer with 2N HCl acidify, is used ethyl acetate extraction (three times) then.Through MgSO 4The dry ethyl acetate layer after-filtration that merges, concentrating under reduced pressure filtrate obtains (3S)-3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-hydroxy phenyl) propanoic acid (113,120mg, 70%). 1H?NMR(400MHz，CD 3SO 2CD 3)δ2.95(d，J＝5.2Hz，2H)，5.28(s，2H)，5.35(ddd，J＝9.2，4.8，4.4Hz，1H)，6.33(t，J＝7.1Hz，1H)，6.60(d，J＝8.8Hz，2H)，7.04(m，5H)，7.22(m，3H)，7.37(dd，J＝7.7，1.5Hz，1H)，8.35(dd，J＝7.6，1.5Hz，1H)，8.80(s，1H)。
Can use the synthetic method similar to obtain table 1,2 and 3 chemical compound to above description.
Embodiment 25
Wherein make the 26-amino acid peptide (CDELPQLVTLPHPNLHGPEILDVPST) of the CSl sequence that comprises fibronectin and the effectiveness that the link coupled method of the activatory ovalbumin of maleimide is used to measure institute's synthetic compound with the terminal Cys of N-.Under 4 ℃, with bovine serum albumin (BSA) and in conjunction with the ovalbumin of CS1 with 0.5ug/ml TBS (50mM TRIS, pH7.5; 150mM NaCl) was coated on for 96 hole polystyrene plate last 16 hours.After at room temperature plate being washed three times, with the TBS sealing that comprises 3%BSA 4 hours with TBS.Before the test, with binding buffer liquid (TBS; 1mM MgCl 21mM CaCl 21mM MnCl 2) with closure plate washing three times.To be resuspended in binding buffer liquid (10 with the fluorescently-labeled Ramos cell of calcein AM 7In the cell/ml), with the same buffer that contains or do not contain chemical compound by dilution in 1: 2.Add the 100uM chemical compound.In each hole, add cell (2.5 * 10 rapidly 5Cells/well), under 37 ℃, hatched 30 minutes.After binding buffer liquid washing three times,, use exometer quantitative with the adherent cell cracking.The results are shown in Table 1-3.IC 50Be defined as and reach 50% and suppress needed dosage, table 1 is to 3 be IC with μ M measurement 50IC 50Be worth lowlyer, it is just higher to suppress percentage rate, and chemical compound stops cell adhesion more effectively.
Table 1
Title IC 50Mass spectrometric data (m/z) (3S)-3-(1,3-benzo dioxole-5-yl)-3-0.2 value of calculation (M-H) -=444.12; [([(3S)-2-oxo-1-(2-thienyl methyl) six hydrogen-3-pyridine measured value (M-H) -=444.08 bases] amino } carbonyl) amino] propanoic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3-15 value of calculation (M-H) -=430.11; [([(3S)-2-oxo-1-(2-thienyl methyl) tetrahydrochysene-1H-pyrrole measured value (M-H) -=430.06 cough up-the 3-yl] amino } carbonyl) amino] propanoic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3-2 value of calculation (M-H) -=444.12; [([(3R)-2-oxo-1-(2-thienyl methyl) six hydrogen-3-pyridine measured value (M-H) -=444.05 bases] amino } carbonyl) amino] propanoic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3-0.9 value of calculation (M-H) -=440.09; [({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-pyridine measured value (M-H) -=439.98 bases] amino } carbonyl) amino] propanoic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3-0.0003 value of calculation (M-H) -=586.23; ({ [((3S)-2-oxo-1-{4-[(2-toluidino carbonyl) amino] measured value (M-H) -=586.17 benzyls } six hydrogen-3-pyridine radicals) amino] carbonyl } amino) propanoic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3-0.001 value of calculation (M-H) -=582.20; [([2-oxo-1-{4-[(2-toluidino carbonyl) amino] benzyl measured value (M-H) -=582.20 bases }-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propanoic acid (3S)-3-(1,3-benzo dioxole-5-yl)-and 3-nd nd ({ [((3S)-1-{4-[(2-methyl-benzyl) amino] benzyl }-2-oxo six hydrogen-pyridine radicals) amino] carbonyl } amino) propanoic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3-20 value of calculation (M-H) -=496.15; [({ butyl [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-measured value (M-H) -=496.10 pyridine radicals] amino } carbonyl) amino] propanoic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3-0.015 value of calculation (M-H) -=458.13; [([(3S)-and 2-oxo-1-(2-thienyl methyl) azepanyl] ammonia measured value (M-H) -=458.09 bases } carbonyl) amino] propanoic acid
Table 2
Compound I C50(nM) mass spectrometric data (3S)-3-[({[2-methyl-4-(2-methyl-propyl)-6-10 calculated values (M-H)-=475.23m/z; Oxo-1-(phenyl methyl)-1,6-dihydro-5-pyrimidine measured value (M-H)-=475.02m/z yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-(1,3-benzo dioxole-5-, 10 calculated values (M-H)-=476.18m/z; Base)-3-[({[2-oxo-1-(phenyl methyl)-4-propyl group measured value (M-H)-=475.99m/z-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propionic acid (3S)-3-(1,3-benzo dioxole-5-, 4000 calculated values (M-R)-=488.18m/z; Base)-3-({ [9-oxo-8-(phenyl methyl)-measured value (M-H)-=488.19m/z 2,3,4,5,8,9-six hydrogen-1H-pyrido [3,4-b] azepine-1-yl] carbonyl } amino) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-second 10 calculated values (M-H)-=466.15m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=465.95m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxygen 4 calculated values (M-H)-=480.17m/z; Generation-4-propyl group-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=480.00m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-first 5 calculated values (M+H)-=454.15m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M+H)-=454.09m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({6-methyl-2-oxo-1-(phenyl first 5 calculated values (M-H)-=524.22m/z; Base)-4-[(phenyl methyl) oxygen base]-1,2-dihydro-3-pyrrole measured value (M-H)-=524.02m/z pyridine base } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2,4-10 calculated values (M-H)-=467.15m/z; Dimethyl-6-oxo-1,6-dihydro-5-pyrimidine radicals } ammonia measured value (M-H)-=467.00m/z yl) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2, the 4-dichlorophenyl) methyl]-4-30 calculated values (M-H)-=486.10m/z; Methyl-2-oxo-1,2-dihydro-3-pyridine radicals } ammonia measured value (M-H)-=485.95m/z yl) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({4-amino-1-[(2-chloro phenyl) first 10 calculated values (M-H)-=467.15m/z; Base]-6-methyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H)-=467.14m/z yl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-[({[1-[(2-chloro phenyl) methyl]-4-(first 20 calculated values (M-H)-=468.13m/z; The oxygen base)-2-oxo-1,2-dihydro-3-pyridine radicals] ammonia measured value (M-H)-=467.97m/z yl } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({4-chloro-1-[(2-chloro phenyl) first 20 calculated values (M-H)-=472.08m/z; Base]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=471.91m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-first 15 calculated values (M-H)-=482.15m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=481.93m/z carbonyl] amino }-3-[3-methyl-4-(methoxyl group) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-first 3 calculated values (M-H)-=470.15m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=470.01m/z carbonyl] amino }-3-[4-(methoxyl group) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-first 10 calculated values (M-H)-=468.17m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=468.05m/z carbonyl] amino }-3-(3,4-3,5-dimethylphenyl) propionic acid (3S)-3-{[({4-amino-1-[(2-chloro phenyl) first 10 calculated values (M-H)-=453.13m/z; Base]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=453.01m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-fluorine 15 calculated values (M-H)-=456.12m/z;-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl measured value (M-H)-=455.94m/z yl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-[({[1-[(2-chloro phenyl) methyl]-2-oxygen 20 calculated values (M-H)-=529.16m/z; Generation-4-(phenyl amino)-1,2-dihydro-3-pyridine radicals] measured value (M-H)-=529.02m/z is amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-[({[1-[(2-chloro phenyl) methyl]-2-oxygen 15 calculated values (M-H)-=530.16m/z; Generation-4-(the 2-pyridine radicals is amino)-1,2-dihydro-3-pyridine measured value (M-H)-=529.99m/z yl] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 10 calculated values (M-H)-=454.11m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=454.05m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxygen 15 calculated values (M-H)-=544.17m/z; Generation-4-[(2-pyridine radicals methyl) amino]-1,2-dihydro-measured value (M-H)-=544.03m/z 3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxygen 20 calculated values (M-H)-=544.17m/z; Generation-4-[(3-pyridine radicals methyl) amino]-1,2-dihydro-measured value (M-H)-=544.02m/z 3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-[({[1-[(2-chloro phenyl) methyl]-4-1 calculated value (M-H)-=523.17m/z; (Isosorbide-5-Nitrae-oxazinan-4-yl)-2-oxo-1,2-dihydro-measured value (M-H)-=523.02m/z 3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-[({[1-[(2-chloro phenyl) methyl]-2-oxygen 10 calculated values (M-H)-=495.18m/z; Generation-4-(propyl group is amino)-1,2-dihydro-3-pyridine radicals] measured value (M-H)-=495.04m/z is amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-difluorophenyl) methyl]-4-first 20 calculated values (M-H)-=436.17m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=435.99m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2, the 6-dichlorophenyl) methyl]-4-20 calculated values (M-H)-=486.10m/z; Methyl-2-oxo-1,2-dihydro-3-pyridine radicals } ammonia measured value (M-H)-=485.95m/z yl) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3R)-3-{[({1-[(2-chloro phenyl) methyl]-4-first 30 calculated values (M-H)-=376.11m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=376.00m/z carbonyl] amino } butyric acid (3S)-3-{[({1-[(2-bromo phenyl) methyl]-4-first 10 calculated values (M-H)-=496.09m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=495.87m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-[({[4-methyl-2-oxo-1-(phenyl first 30 calculated values (M-H)-=418.17m/z; Base)-1,2-dihydro-3-pyridine radicals] amino } carbonyl) ammonia measured value (M-H)-=417.96m/z yl]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 8 calculated values (M-H)-=484.12m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=484.03m/z carbonyl] amino }-3-[3-methyl-4-(methoxyl group) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxygen 10 calculated values (M-H)-=514.15m/z; Generation-4-phenyl-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=514.00m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({4-bromo-1-[(2-chloro phenyl) first 20 calculated values (M-H)-=516.03m/z; Base]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=515.90m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-(1,3-benzo dioxole-5-, 20 calculated values (M-H)-=484.09m/z; Base)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl measured value (M-H)-=484.03m/z base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-2 calculated values (M-H)-=556.18m/z; [(2-{[2-(methoxyl group) ethyl] the oxygen base } ethyl) oxygen measured value (M-H)-=556.03m/z yl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 15 calculated values (M-H)-=468.13m/z; Base-6-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } measured value (M-H)-=468.05m/z is amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-3 calculated values (M-H)-=509.20m/z; [(1,1-dimethyl ethyl) amino]-2-oxo-1,2-two measured values (M-H)-=509.06m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 10 calculated values (M-H)-=440.10m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=440.04m/z carbonyl] amino }-3-phenylpropionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-[4-3 calculated values (M-H)-=536.20m/z; Methyl tetrahydrochysene-1 (2H)-pyrazinyl]-2-oxo-1,2-measured value (M-H)-=636.12m/z dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 5 calculated values (M-H)-=470.11m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=470.05m/z carbonyl] amino }-3-[4-(methoxyl group) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 20 calculated values (M-H)-=530.13m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=530.05m/z carbonyl] amino }-3-[3,4,5-trimethoxy phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 15 calculated values (M-H)-=468.13m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=468.08m/z carbonyl] amino }-3-(3,5-3,5-dimethylphenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-15 calculated values (M-H)-=534.15m/z; [(3-methyl-5-isoxazolyl) amino]-2-oxo-measured value (M-H)-=534.01m/z 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 20 calculated values (M-H)-=454.17m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=454.04m/z carbonyl] amino }-3-(3-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 5 calculated values (M-H)-=470.11m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=470.03m/z carbonyl] amino }-3-[3-(methoxyl group) phenyl] propionic acid (3S)-3-[3, two (methoxyl group) phenyl of 5-]-3-{[({1-3 calculated values (M-H)-=500.12m/z; [(2-chloro phenyl) methyl]-4-hydroxyl-2-oxo-measured value (M-H)-=500.07m/z 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 8 calculated values (M-H)-=504.13m/z; Base-2-oxo-1,2-dihydro-3-quinolyl } amino) measured value (M-H)-=504.06m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 20 calculated values (M-H)-=508.04m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=508.09m/z carbonyl] amino }-3-[3-(trifluoromethyl) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-2 calculated values (M-H)-=595.21m/z; [({ ethyl [(ethyl is amino) carbonyl] amino } carbonyl) measured value (M-H)-=594.97m/z is amino]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({4-(1-azetanyl)-1-[(2-chloro benzene 5 calculated values (M-H)-=493.16m/z; Base) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } measured value (M-H)-=493.05m/z is amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 30 calculated values (M-H)-=458.09m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=458.03m/z carbonyl] amino }-3-(4-fluorophenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 40 calculated values (M-H)-=458.09m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=458.06m/z carbonyl] amino }-3-(3-fluorophenyl) propionic acid (3S)-3-[({[1-[(2-chloro phenyl) methyl]-4-2 calculated values (M-H)-=600.21m/z; (2-[(2-{[2-(methoxyl group) ethyl] and the oxygen base } ethyl) measured value (M-H)-=600.10m/z oxygen base] ethyl } the oxygen base)-2-oxo-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 25 calculated values (M-H)-=508.09m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=508.02m/z carbonyl] amino }-3-[4-(trifluoromethyl) phenyl] propionic acid (3S)-3-{[({1-[(2-difluorophenyl) methyl]-4-hydroxyl 30 calculated values (M-H)-=438.15m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=438.07m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro-6-fluorophenyl) methyl]-4-10 calculated values (M-H)-=472.11m/z; Hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } ammonia measured value (M-H)-=472.06m/z yl) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl 400 calculated values (M-H)-=496.16m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino) measured value (M-H)-=496.11m/z carbonyl] amino }-3-[4-(1,1-dimethyl ethyl) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-5-first 70 calculated values (M-H)-=452.14m/z; Base-2-oxo-1,2-dihydro-3-pyridine radicals } amino } measured value (M-H)-=451.99m/z carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid 3-(4-chloro phenyl)-3-{[({1-[(2-chloro phenyl) 30 calculated values (M-H)-=474.06m/z; Methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H)-=474.07m/z yl } amino) carbonyl] amino } propionic acid (3S)-3-[({[2-methyl-6-oxo-1-(phenyl first 25 calculated values (M+H)-=498.22m/z; Base)-4-(2-pyridine radicals)-1,6-dihydro-5-pyrimidine radicals] measured value (M+H)-=498.10m/z is amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid 3-(3-chloro phenyl)-3-{[({1-[(2-chloro phenyl) 30 calculated values (M-H)-=474.06m/z; Methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine measured value (M-H)-=474.03m/z yl } amino) carbonyl] amino } propionic acid 3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl-2-40 calculated values (M-R)-=508.02m/z; Oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] measured value (M-H)-=507.97m/z is amino }-3-(3,4-dichlorophenyl) propionic acid
Table 3
Title IC50Mass spectrometric data (3S)-3-(1,3-benzo dioxole-5-yl)-3 0.015 calculated values (M-H)-=452.18m/z;-[({ [2-oxo-1-(phenyl methyl)-3-azepanyl] amino } measured value (M-H)-=452.10m/z carbonyl) amino] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 0.04 calculated values (M-H)-=477.18m/z;-[(1-[(3-cyano group phenyl) methyl]-2-oxo-3-measured value (M-H)-=477.14m/z azepanyl} is amino) carbonyl] amino } propionic acid (3S)-3-(4-aminomethyl phenyl)-3 0.6 calculated values (M-H)-=410.11m/z;-[({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-measured value (M-H)-=410.00m/z pyridine radicals] amino } carbonyl) amino] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 0.5 calculated values (M-H)-=434.13m/z;-[({ [2-oxo-1-(phenyl methyl)-1,2-dihydro-3-pyridine measured value (M-H)-=434.05m/z yl] amino } carbonyl) amino] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 1 calculated values (M-H)-=448.14m/z;-[(the 1-[(4-aminomethyl phenyl) methyl]-2-oxo-1,2-two measured values (M-H)-=448.02m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 3 calculated values (M-H)-=464.14m/z;-([(1-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1,2-measured value (M-H)-=464.03m/z dihydro-3-pyridine radicals) amino] carbonyl } amino) propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 1.5 calculated values (M-H)-=448.15m/z;-[(the 1-[(3-aminomethyl phenyl) methyl }-2-oxo-1,2-two measured values (M-H)-=448.04m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-[3, two (methoxyl group) phenyl of 5-]-3-[({[2-oxo-0.7 calculated value (M-H)-=456.12m/z; 1-(2-thienyl methyl)-1,2-dihydro-3-pyridine radicals] ammonia measured value (M-H)-=456.00m/z yl } carbonyl) amino] propionic acid (3S)-3-[4-(methoxyl group) phenyl]-3-[({[2-oxo-1-(2-0.8 calculated value (M-H)-=426.11m/z; Thienyl methyl)-1,2-dihydro-3-pyridine radicals] amino } carbonyl measured value (M-H)-=426.00m/z yl) amino] propionic acid (3S)-3-[({[2-oxo-1-(2-thienyl methyl)-1,2-2 2.5 calculated values (M-H)-=464.09m/z; Hydrogen-3-pyridine radicals] amino } carbonyl) amino]-3-[3-(trifluoro measured value (M-H)-=463.99m/z methyl) phenyl] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 50 calculated values (M-H)-=419.12m/z;-[({ [3-(phenoxy group) phenyl] amino } carbonyl) amino] propionic acid measured value (M-H)-=418.97m/z (3S)-3-(1,3-benzo dioxole-5-yl)-3 5 calculated values (M-H)-=438.11m/z;-[(the 3-[(2-thienyl methyl) and amino] phenyl } amino) carbonyl measured value (M-H)-=438.00m/z yl] amino } propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 0.8 calculated values (M-H)-=468.09m/z;-[(1-[(3-chloro phenyl) methyl]-2-oxo-1,2-two measured values (M-H)-=468.01m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 0.8 calculated values (M-H)-=502.12m/z;-([(2-oxo-1-{[3-(trifluoromethyl) phenyl] methyl }-measured value (M-H)-=502.03m/z 1,2-dihydro-3-pyridine radicals) amino] carbonyl } amino) propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 1.6 calculated values (M-H)-=502.12m/z;-([(2-oxo-1-{[4-(trifluoromethyl) phenyl] methyl }-measured value (M-H)-=502.01m/z 1,2-dihydro-3-pyridine radicals) amino] carbonyl } amino) propionic acid (3S)-3-(4-fluorophenyl)-3 1.6 calculated values (M-H)-=414.09m/z;-[({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-measured value (M-H)-=414.01m/z pyridine radicals] amino } carbonyl) amino] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 3 calculated values (M-H)-=468.09m/z;-[(1-[(4-chloro phenyl) methyl]-2-oxo-1,2-two measured values (M-H)-=467.99m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 0.5 calculated values (M-H)-=464.14m/z;-([(1-{[2-(methoxyl group) phenyl] methyl }-2-oxo-1,2-measured value (M-H)-=464.04m/z dihydro-3-pyridine radicals) amino] carbonyl } amino) propionic acid (3S)-3-[3-(methoxyl group) phenyl]-3 1.4 calculated values (M-H)-=426.11m/z;-[({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-measured value (M-H)-=426.02m/z pyridine radicals] amino } carbonyl) amino] propionic acid (3S)-3-1 calculated value (M-H)-=396.10m/z;-[({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-measured value (M-H)-=396.01m/z pyridine radicals] amino } carbonyl) amino]-3-phenylpropionic acid (3S)-3-0.3 calculated value (M-H)-=486.13m/z;-[({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-measured value (M-H)-=485.98m/z pyridine radicals] amino } carbonyl) amino]-3-[3,4,5-trimethoxy phenyl] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 0.3 calculated values (M-H)-=468.08m/z;-[(1-[(2-chloro phenyl) methyl]-2-oxo-1,2-two measured values (M-H)-=468.03m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 2 calculated values (M-H)-=452.12m/z;-[(the 1-[(4-difluorophenyl) methyl]-2-oxo-1,2-two measured values (M-H)-=452.00m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid 3-(1,3-benzo dioxole-5-yl)-2,2-two＞100 calculated values (M-H)-=476.07m/z; Fluoro-3 measured values (M-H)-=476.00m/z-[({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 14 calculated values (M-H)-=478.16m/z;-[(2-oxo-1-[3-(phenoxy group) propyl group] and-1,2-dihydro-measured value (M-H)-=478.09m/z 3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 4 calculated values (M-H)-=502.05m/z;-[(1-[(3,4-dichlorophenyl) methyl]-2-oxo-1,2-two measured values (M-H)-=501.98m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 5 calculated values (M-H)-=502.05m/z;-[(1-[(3,5-dichlorophenyl) methyl]-2-oxo-1,2-two measured values (M-H)-=501.94m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 6 calculated values (M-H)-=426.16m/z;-[({ [1-(cyclopentyl-methyl)-2-oxo-1,2-dihydro-3-pyrrole measured value (M-H)-=426.09m/z pyridine base] amino } carbonyl) amino] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 15 calculated values (M-H)-=454.09m/z;-[(2-oxo-1-[2-(2-thienyl) ethyl] and-1,2-dihydro measured value (M-H)-=453.99m/z-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.1 calculated value (M+H)-=440.14m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M+H)-=440.09m/z aminomethyl phenyl) propionic acid (3S)-3-(2,3-dihydro-1-benzofuran-5-yl)-3 0.14 calculated values (M-H)-=438.11m/z;-[({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-measured value (M-H)-=437.99m/z pyridine radicals] amino } carbonyl) amino] propionic acid (3S)-3-(3-fluorophenyl)-3 3 calculated values (M-H)-=414.09m/z;-[({ [2-oxo-1-(2-thienyl methyl)-1,2-dihydro-3-measured value (M-H)-=413.99m/z pyridine radicals] amino } carbonyl) amino] propionic acid (3S)-3-[({[2-oxo-1-(2-thienyl methyl)-1,2-2 1.5 calculated values (M-H)-=464.09m/z; Hydrogen-3-pyridine radicals] amino } carbonyl) amino]-3-[4-(trifluoro measured value (M-H)-=463.99m/z methyl) phenyl] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 0.5 calculated values (M-H)-=434.13m/z;-[({ 6-oxo-1-(phenyl methyl)-1,6-dihydro-3-pyridine measured value (M-H)-=434.02m/z yl] amino } carbonyl) amino] propionic acid (3S)-3-[4-fluoro-3-(trifluoromethyl) phenyl]-3-[({[2-oxygen 0.35 calculated value (M-H)-=482.08m/z; Generation-1-(2-thienyl methyl)-1,2-dihydro-3-pyridine radicals] measured value (M-H)-=481.97m/z is amino } carbonyl) amino] propionic acid (3S)-3-[4-(1,1-dimethyl ethyl) phenyl]-3-[({[2-2 calculated values (M-H)-=452.16m/z; Oxo-1-(2-thienyl methyl)-1,2-dihydro-3-pyridine measured value (M-H)-=452.02m/z yl] amino } carbonyl) amino] propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 70 calculated values (M-H)-=494.19m/z;-[({ butyl [2,5-dioxo-1-(phenyl methyl) tetrahydrochysene-measured value (M-H)-=494.12m/z 1H-pyrroles-3-yl] amino } carbonyl) amino] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.04 calculated value (M+H)-=516.16m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M+H)-=516.02m/z [3,4,5-trimethoxy phenyl] propionic acid (3S)-3-{[({1-[(2, the 6-dichlorophenyl) methyl]-2-oxo-0.2 calculated value (M+H)-=474.10m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M+H)-=474.04m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.2 calculated value (M+H)-=512.10m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[4-measured value (M+H)-=512.04m/z fluoro-3-(trifluoromethyl) phenyl] propionic acid (3S)-3-{[({1-[(2-difluorophenyl) methyl]-2-oxo-0.1 calculated value (M-H)-=422.15m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=422.01m/z aminomethyl phenyl) propionic acid (3S)-3-(4-aminomethyl phenyl)-3-{[({1-[(2-aminomethyl phenyl) 0.1 calculated value (M-H)-=418.18m/z; Methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl measured value (M-H)-=418.02m/z yl] amino } propionic acid (3S)-3-{[({1-[(2-bromo phenyl) methyl]-2-oxo-0.05 calculated value (M+H)-=484.09m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M+H)-=484.03m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2, the 4-dichlorophenyl) methyl]-2-oxo-0.4 calculated value (M+H)-=474.10m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M+H)-=474.05m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.04 calculated value (M-H)-=466.11m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=466.00m/z (2,3-dihydro-1-benzofuran-5-yl) propionic acid (3S)-3-(1,3-benzo dioxole-5-yl)-3 2 calculated values (M-H)-=468.09m/z;-[(1-[(2-chloro phenyl) methyl]-2-oxo-1,2-two measured values (M-H)-=467.97m/z hydrogen-3-pyridine radicals } amino) carbonyl] amino } propionic acid (3S)-3-(4-aminomethyl phenyl)-3-({ [(2-oxo-1-{[2-1 calculated value (M+H)-=474.10m/z; (trifluoromethyl) phenyl] methyl }-1,2-dihydro-3-pyridine radicals) measured value (M+H)-=474.09m/z is amino] carbonyl } amino) propionic acid (3S)-3-{[({1-[(2, the 5-dichlorophenyl) methyl]-2-oxo-0.15 calculated value (M+H)-=474.10m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M+H)-=474.04m/z aminomethyl phenyl) propionic acid (2R)-2-{[({1-[(2-chloro phenyl) methyl]-2-oxo-50 calculated value (M-H)-=424.10m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-benzene measured value (M-H)-=423.99m/z base propionic acid (2R)-2-{[({1-[(2-chloro phenyl) methyl]-2-oxo-80 calculated value (M-H)-=410.08m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-2-benzene measured value (M-H)-=409.95m/z guanidine-acetic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.1 calculated value (M-H)-=452.14m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=451.96m/z (3,5-3,5-dimethylphenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.1 calculated value (M-H)-=424.10m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-benzene measured value (M-H)-=424.07m/z base propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.1 calculated value (M-H)-=454.11m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[4-measured value (M-H)-=454.01m/z (methoxyl group) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.1 calculated value (M-H)-=440.10m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=440.00m/z hydroxy phenyl) propionic acid (3S)-3-({ [(1-{[3-(methoxyl group) phenyl] methyl }-2-oxygen 0.2 calculated value (M-H)-=434.17m/z; Generation-1,2-dihydro-3-pyridine radicals) amino] carbonyl } amino)-3-measured value (M-H)-=434.01m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-bromo phenyl) methyl]-2-oxo-0.08 calculated value (M-H)-=558.09m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=557.87m/z [3,4,5-trimethoxy phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.09 calculated value (M+H)-=454.15m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M+H)-=454.07m/z (3,4-3,5-dimethylphenyl) propionic acid (3S)-3-[({[5-chlorine-2-hydroxyl-3-(phenyl methyl) phenyl] 0.8 calculated value (M-H)-=437.12m/z; Amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid measured value (M-H)-=437.06m/z (3S)-3-(4-aminomethyl phenyl)-3-[({[3-(phenyl methyl) benzene 10 calculated values (M-H)-=387.17m/z; Base] amino } carbonyl) amino] propionic acid measured value (M-H)-=387.00m/z (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.04 calculated value (M-H)-=468.13m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[3-measured value (M-H)-=468.01m/z methyl-4-(methoxyl group) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.07 calculated value (M-H)-=454.11m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=454.00m/z hydroxyl-3-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2, the 3-dichlorophenyl) methyl]-2-oxo-0.35 calculated value (M-H)-=472.08m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=471.94m/z aminomethyl phenyl) propionic acid (3S)-3-[({[1-([1,1 '-xenyl]-2-ylmethyl)-2-oxygen 2.5 calculated values (M-H)-=480.19m/z; Generation-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-measured value (M-H)-=480.05m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.2 calculated value (M-H)-=438.12m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(3-measured value (M-H)-=438.00m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-3 calculated value (M-H)-=438.12m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(2-measured value (M-H)-=437.99m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.3 calculated value (M-H)-=464.13m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=464.03m/z (2,3-dihydro-1H-indenes-5-yl) propionic acid (3S)-3-{[({1-[(2-cyano group phenyl) methyl]-2-oxo-0.1 calculated value (M+H)-=431.18m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(2-measured value (M+H)-=431.09m/z aminomethyl phenyl) propionic acid (3S)-3-[2, two (methoxyl group) phenyl of 6-]-3-{[({1-[(2-6 calculated values (M-H)-=484.14m/z; The chloro phenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine measured value (M-H)-=483.96m/z yl } amino) carbonyl] amino } propionic acid (3S)-3-{[({1-[(3-hydroxy phenyl) methyl]-2-oxo-0.2 calculated value (M+H)-=420.18m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M+H)-=422.05m/z aminomethyl phenyl) propionic acid (3S)-3-[({[2-methyl-6-oxo-1-(phenyl methyl)-0.1 calculated value (M-H)-=419.17m/z; 1,6-dihydro-5-pyrimidine radicals } amino } carbonyl) amino]-3-(4-measured value (M-H)-=419.03m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-0.1 calculated value (M-H)-=438.12m/z; Isosorbide-5-Nitrae-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=438.10m/z aminomethyl phenyl) propionic acid (3S)-3-(4-aminomethyl phenyl)-3-{[({1-[(2-nitrobenzophenone) 1 calculated value (M+H)-=451.17m/z; Methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl measured value (M+H)-=451.07m/z yl] amino } propionic acid (3S)-3-(4-aminomethyl phenyl)-3-{[({1-[(4-nitrobenzophenone) 1 calculated value (M+H)-=451.17m/z; Methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl measured value (M+H)-=451.09m/z yl] amino } propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-3 calculated value (M-H)-=456.10m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=456.04m/z (2,6-dihydroxy phenyl) propionic acid (3S)-3-{[({1-[(2, the 6-difluorophenyl) methyl]-2-oxo-0.3 calculated value (M-H)-=440.14m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=440.00m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2, the 4-difluorophenyl) methyl]-2-oxo-1.3 calculated value (M-H)-=440.14m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=439.96m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2, the 5-difluorophenyl) methyl]-2-oxo-0.8 calculated value (M-H)-=440.14m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=439.96m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-methyl-6-0.09 calculated value (M-H)-=453.13m/z; Oxo-1,6-dihydro-5-pyrimidine radicals } amino) carbonyl] ammonia measured value (M-H)-=453.00m/z yl }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro-6-fluorophenyl) methyl]-2-oxo 0.1 calculated value (M-H)-=456.11m/z;-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=455.94m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-bromo-5-fluorophenyl) methyl]-2-oxo 0.5 calculated value (M-H)-=500.06m/z;-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=499.91m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro-6-fluorophenyl) methyl]-2-oxo 0.35 calculated value (M-H)-=456.11m/z;-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=455.93m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-bromo phenyl) methyl]-2-oxo-0.2 calculated value (M-H)-=512.08m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[3-measured value (M-H)-=511.96m/z methyl-4-(methoxyl group) phenyl] propionic acid (3S)-3-{[({1-[(3,5-dimethyl-4-isoxazolyl) first 3 calculated values (M-H)-=423.17m/z; Base]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] measured value (M-H)-=423.02m/z is amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-(4-aminomethyl phenyl)-3-{[({2-oxo-1-2.5 calculated values (M-H)-=446.21m/z; [(2,4,6-trimethylphenyl) methyl]-1,2-dihydro-3-pyridine measured value (M-H)-=446.08m/z yl } amino) carbonyl] amino } propionic acid (3S)-3-(4-aminomethyl phenyl)-3-{[({1-[(2-methyl isophthalic acid, 3-1 calculated value (M-H)-=425.13m/z; Thiazole-4-yl) methyl]-2-oxo-1,2-dihydro-3-pyridine measured value (M-H)-=424.99m/z yl } amino) carbonyl] amino } propionic acid (3S)-3-([(1-{[4-(1,1-dimethyl ethyl) phenyl] first 6 calculated values (M-H)-=460.22m/z; Base }-2-oxo-1,2-dihydro-3-pyridine radicals) amino] carbonyl } measured value (M-H)-=460.07m/z is amino)-3-(4-aminomethyl phenyl) propionic acid (3S)-3-[({[1-(1,3-benzoxazole-2-ylmethyl)-2-oxygen＞10 calculated values (M-H)-=445.15m/z; Generation-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-measured value (M-H)-=445.01m/z (4-aminomethyl phenyl) propionic acid (3S)-3-({ [(1-{2-[(2-hydroxy phenyl) amino]-2-oxo＞10 calculated values (M-H)-=463.16m/z; Ethyl }-2-oxo-1,2-dihydro-3-pyridine radicals) amino] carbonyl measured value (M-R)-=463.06m/z yl } amino)-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro-6-nitrobenzophenone) methyl]-2-oxygen 4 calculated values (M-H)-=483.11m/z; Generation-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=483.01m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(5-chloro-2-fluorophenyl) methyl]-2-oxo 2.5 calculated values (M-H)-=456.11m/z;-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=456.00m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-amino-6-chlorphenyl) methyl]-2-oxygen 2 calculated values (M-H)-=453.13m/z; Generation-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=453.02m/z (4-aminomethyl phenyl) propionic acid (3S)-3-([(1-{[2-fluoro-4-(trifluoromethyl) phenyl] first 3 calculated values (M-H)-=490.14m/z; Base }-2-oxo-1,2-dihydro-3-pyridine radicals) amino] carbonyl } measured value (M-H)-=489.99m/z is amino)-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(5-chloro-2-thienyl) methyl]-2-oxo 1.3 calculated values (M-H)-=444.08m/z;-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=443.97m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-bromo-5-nitrobenzophenone) methyl]-2-oxygen 2 calculated values (M-H)-=527.06m/z; Generation-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=526.95m/z (4-aminomethyl phenyl) propionic acid 3-(4-chlorphenyl)-3-{[({1-[(2-chloro phenyl) methyl]-0.03 calculated value (M-H)-=474.06m/z; 4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl measured value (M-H)-=474.07m/z yl] amino } propionic acid (3S)-3-[({[2-methyl-6-oxo-1-(phenyl methyl)-4-0.025 calculated value (M+H)-=498.22m/z; (2-pyridine radicals)-1,6-dihydro-5-pyrimidine radicals] amino } carbonyl) measured value (M+H)-=498.10m/z is amino]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(5-amino-2-bromophenyl) methyl]-2-oxygen 0.08 calculated value (M-H)-=497.08m/z; Generation-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=497.02m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2, the 5-3,5-dimethylphenyl) methyl]-2-oxygen 0.15 calculated value (M-H)-=432.19m/z; Generation-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=432.04m/z (4-aminomethyl phenyl) propionic acid 3-(3-chloro phenyl)-3-{[({1-[(2-chloro phenyl) first 0.03 calculated value (M-H)-=474.06m/z; Base]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } ammonia measured value (M-H)-=474.03m/z yl) carbonyl] amino } propionic acid 3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl-2-oxo 0.04 calculated value (M-H)-=508.02m/z;-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=507.97m/z (3,4-dichlorophenyl) propionic acid (3S)-3-({ [(1-{[5-(acetyl-amino)-2-bromo benzene 0.2 calculated value (M-H)-=539.09m/z; Base] methyl }-2-oxo-1,2-dihydro-3-pyridine radicals) amino] measured value (M-H)-=539.02m/z carbonyl } amino)-3-(4-aminomethyl phenyl) propionic acid (3S)-3-[({[1-(2-bromo-5-[(methyl sulphonyl) and amino] 0.25 calculated value (M-H)-=575.06m/z; Phenyl } methyl)-2-oxo-1,2-dihydro-3-pyridine radicals] ammonia measured value (M-H)-=575.01m/z yl } carbonyl) amino]-3-(4-aminomethyl phenyl) propionic acid 3-(4-chloro phenyl)-3-{[({1-[(2-chloro phenyl) first 0.4 calculated value (M-H)-=458.07m/z; Base]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] measured value (M-H)-=457.96m/z is amino } propionic acid 3-(3-chloro phenyl)-3-{[({1-[(2-chloro phenyl) first 1 calculated value (M-H)-=458.07m/z; Base]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] measured value (M-H)-=457.93m/z is amino } propionic acid 3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-1,2-21 calculated values (M-H)-=492.03m/z; Hydrogen-3-pyridine radicals } amino) carbonyl] amino }-3-(3,4-dichloro measured value (M-H)-=491.85m/z phenyl) propionic acid (3S)-3-{[({1-[(2-bromo-4-chlorphenyl) methyl]-2-oxo 1 calculated value (M-H)-=516.03m/z;-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-measured value (M-H)-=515.91m/z (4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(4-chloro phenyl) methyl]-2-oxo-2 calculated value (M-H)-=438.12m/z; 1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-measured value (M-H)-=437.88m/z aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl-2-0.035 calculated value (M-H)-=498.14m/z; Oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] ammonia measured value (M-H)-=498.05m/z yl }-3-[2,3-dimethyl-4-(methoxyl group) phenyl] propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl-2-0.015 calculated value (M-H)-=524.08m/z; Oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] ammonia measured value (M-H)-=524.03m/z yl }-the 3-{4-[(trifluoromethyl) the oxygen base] phenyl } propionic acid (3R)-3-[({[1-[(2-chloro phenyl) methyl]-4-(Isosorbide-5-Nitrae-0.1 calculated value (M-H)-=489.19m/z; The oxazinan-4-yl)-2-oxo-1,2-dihydro-3-pyridine radicals] measured value (M-H)-=489.13m/z is amino } carbonyl) amino]-5-methylhexanoic acid (3S)-3-[({[4-hydroxyl-6-methyl-2-oxo-1-(phenyl 0.1 calculated value (M-H)-=434.17m/z; Methyl)-1,2-dihydro-3-pyridine radicals] amino } carbonyl) ammonia measured value (M-H)-=434.08m/z yl]-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-2-oxo-4-0.030 calculated value (M-H)-=559.14m/z; [(sulfonyl propyl base) amino]-1,2-dihydro-3-pyridine radicals } ammonia measured value (M-H)-=559.04m/z yl) carbonyl] amino }-3-(4-aminomethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl-2-0.025 calculated value (M-H)-=468.13m/z; Oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] ammonia measured value (M-H)-=468.06m/z yl }-3-(4-ethyl phenyl) propionic acid (3S)-3-{[({1-[(2-chloro phenyl) methyl]-4-hydroxyl-2-0.02 calculated value (M-H)-=484.13m/z; Oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] ammonia measured value (M-H)-=484.06m/z yl }-3-[4-(ethyoxyl) phenyl] propionic acid (3S)-3-[({[4-hydroxyl-2-oxo-1-(phenyl methyl)-0.030 calculated value (M-H)-=420.16m/z; 1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-measured value (M-H)-=420.08m/z aminomethyl phenyl) propionic acid
The list of references of all references is attached to herein by reference.
Illustrate the present invention by above explanation and embodiment.Its many change schemes more than are illustrated as non-limiting illustrating, because it will be apparent to those skilled in the art that.Therefore, the present invention includes all interior such change schemes of scope and spirit of appended claim book.
Under the design of the present invention and range of condition that do not depart from the definition of following claims, can to this paper introduction composition, operation and the arrangement of the inventive method change.
The nucleotide of description and aminoacid sequence table sequence table (1) physical data:
(i) applicant: Biediger, Ronald J.; Chen, Qi; Holland, George W.; Kassir, Jamal M; Li,
Wen; Market, Robert V.; Scott, Ian L. and Wu, Chengde
(ii) denomination of invention: the propanoic derivatives of inhibition of integrins and its receptors bind
(iii) sequence number: 1
(iv) mailing address:
(A) address: Rockey, Milnamow ﹠amp; Katz, Ltd.
(B) street: 180 N.Stetson Aveneue, 2 Prudential Plaza, Suite 47
(C) city: Chicago
(D) state: Illinois State
(E) country: the U.S.
(F) postcode: 60601
(v) computer-reader form:
(A) media types: floppy disk
(B) computer: IBC PC compatible
(C) operating system: PC-DOS/MS-DOS
(D) software: PatentIn Release # 1.0, Version # 1.30
(vi) current request for data
(A) application number:
(B) applying date:
(C) classification:
(viii) entrust/act on behalf of data:
(A) name: Katz, Martin L.
(B) number of registration: 25,011
(C) reference number/file number: TEX4542P0400US
(ix) communications data:
(A) phone: 312-616-5400
(B) fax: the information of 312-616-5460 (2) SEQ ID NO:1
(i) sequence signature:
(A) length: 26 aminoacid
(B) type: aminoacid
(C) chain: strand
(D) topological structure: linearity
(ii) molecule type: albumen
(xi) sequence description: SEQ ID NO:1:
Cys?Asp?Glu?Leu?Pro?Gln?Leu?Val?Thr?Leu?Pro?His?Pro?Asn?Leu?His
1???????????????5???????????????????10??????????????????15
Gly?Pro?Glu?Ile?Leu?Asp?Val?Pro?Ser?Thr
20??????????????????25

Claims (15)

1. the chemical compound of structural formula below a kind or its pharmaceutically acceptable salt,
Figure A0080993500021
Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S; Q is the integer of 3-10; A is selected from O, S, C (R 16) (R 17) and NR 6E is selected from CH 2, O, S and NR 7J is selected from O, S and NR 8T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3; M is selected from C (R 9) (R 10) and (CH 2) u, wherein u is the integer of 0-3; L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1; X is selected from CO 2B, PO 3H 2, SO 3H, SO 2NH 2, SO 2NHCOR 12, OPO 3H 2,
C (O) NHC (O) R 13, C (O) NHSO 2R 14, hydroxyl, tetrazole radical and hydrogen; W is selected from C, CR 15And N; And B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13,
R 14, R 15, R 16And R 17When occurring, independently be selected from every turn hydrogen, halogen, hydroxyl,
Alkyl, alkenyl, alkynyl group, alkoxyl, alkenyloxy, chain oxy-acetylene, alkane
Sulfenyl, hydroxyalkyl, aliphatic acyl ,-CF 3, nitro, amino, cyano group, carboxyl,
-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkane
Base) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl), alkyl ammonia
Base, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-
C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH,
-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl alkoxyl, carboxaldehyde radicals, formyl
Amido, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkyl-alkyl, aryl, fragrant acyl
Base, aryloxy group, arylamino, biaryl, thioaryl, ammonia diaryl base,
Heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocycle
Base alkyl, sulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), Asia
Sulfonamido, carbamyl ester group, aryloxy alkyl, carboxylic acid group and-C (O) NH (benzyl
Base) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11,
R 12, R 13, R 14, R 15, R 16And R 17For unsubstituted group or by extremely
A few group of replacing for electronics or electron withdraw group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together;
And wherein when A be NR 6With at least one Y be CR 1The time, R 1And R 6
Can form a ring together;
Prerequisite be when A be C (R 16) (R 17) time, E is not NR 7
2. the chemical compound of claim 1, wherein
A is NR 6
E is NR 7
J is O;
M is C (R 9) (R 10);
Q is 4 or 5;
T is (CH 2) b, wherein b is 0;
L is (CH 2) n, wherein n is 0;
X is CO 2B;
W is C or CR 15
R 4Be selected from aryl, alkylaryl, aralkyl, heterocyclic radical, alkyl heterocyclic and heterocyclic radical
Alkyl; And
R 6, R 7, R 9, R 10And R 15Independently be selected from hydrogen and low alkyl group.
3. the chemical compound of claim 1, it is selected from the derivant of ester, carbamate, aminal, amide and prodrug for it.
4. the chemical compound of structural formula below a kind or its pharmaceutically acceptable salt, Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S; Q is the integer of 3-7; T is selected from C (O) and (CH 2) b, wherein b is the integer of O-3; L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1; W is selected from C, CR 15And N; And B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 15Independently be selected from
Hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl group, alkoxyl, alkene oxygen
Base, chain oxy-acetylene, alkylthio group, hydroxyalkyl, aliphatic acyl ,-CF 3, nitro,
Amino, cyano group, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-
NHC (O) N (C 1-C 3Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-
C 6Alkyl), alkyl amino, alkenyl amino, two (C 1-C 3) amino ,-
C (O) O-(C 1-C 3) alkyl ,-C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkane
Base) 2,-CH=NOH ,-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl alcoxyl
Base, carboxaldehyde radicals, formamido, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkyl
Alkyl, aryl, aroyl, aryloxy group, arylamino, biaryl, sulfo-virtue
Base, ammonia diaryl base, heterocyclic radical, alkylaryl, aralkenyl, aralkyl,
Alkyl heterocyclic, heterocyclic radical alkyl, sulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-
SO 3-(C 1-C 3Alkyl), sulfonamido, carbamyl ester group, aryloxy alkyl,
The carboxylic acid group and-C (O) NH (benzyl) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10, R 11And R 15
Replace for electronics or electron withdraw group for unsubstituted group or by at least one
Group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together;
And when A be NR 6With at least one Y be CR 1The time, R 1And R 6Together
Can form a ring.
5. the chemical compound of claim 4, wherein
Q is 4 or 5;
W is C or CR 15
T is (CH 2) b, wherein b is 0;
L is (CH 2) n, wherein n is 0;
R 4Be selected from aryl, alkylaryl, aralkyl, heterocyclic radical, alkyl heterocyclic and heterocyclic radical
Alkyl; And
R 6, R 7, R 9, R 10And R 15Independently be selected from hydrogen and low alkyl group.
6. the chemical compound of claim 4, it is selected from the derivant of ester, carbamate, aminal, amide and prodrug for it.
7. the chemical compound of structural formula below a kind or its pharmaceutically acceptable salt,
Figure A0080993500051
Wherein Y independently is selected from C (O), N, CR at every turn when occurring 1, C (R 2) (R 3), NR 5, CH, O and S; Q is the integer of 2-5; T is selected from C (O) and (CH 2) b, wherein b is the integer of 0-3; L is selected from O, NR 11, S and (CH 2) n, wherein n is 0 or 1; And B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10And R 11Independently be selected from hydrogen,
Halogen, hydroxyl, alkyl, alkenyl, alkynyl group, alkoxyl, alkenyloxy,
Chain oxy-acetylene, alkylthio group, hydroxyalkyl, aliphatic acyl ,-CF 3, nitro, amino,
Cyano group, carboxyl ,-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3
Alkyl) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl), alkyl ammonia
Base, alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-
C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH,
-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl alkoxyl, carboxaldehyde radicals, formyl
Amido, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkyl-alkyl, aryl, fragrant acyl
Base, aryloxy group, arylamino, biaryl, thioaryl, ammonia diaryl base,
Heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocycle
Base alkyl, sulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), Asia
Sulfonamido, carbamyl ester group, aryloxy alkyl, carboxylic acid group and-C (O) NH (benzyl
Base) group;
Wherein B, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 9, R 10And R 11For not
The group that replaces or by at least one base of replacing for electronics or electron withdraw group
Group;
Wherein working as L is NR 11The time, R 4And R 11Can form a ring together;
And R wherein 9And R 10Can form a ring together;
And wherein when A be NR 6With at least one Y be CR 1The time, R 1And R 6Together
Can form a ring.
8. the chemical compound of claim 7, wherein R 5Be selected from hydrogen, alkyl, aryl, cycloalkyl, alkyl heterocyclic, heterocyclic radical alkyl and heterocyclic radical;
T is (CH 2) b, wherein b is 0;
L is (CH 2) n, wherein n is 0;
Y is selected from CR 1And C (R 2) (R 3); And
Q is 2 or 3.
9. the chemical compound of claim 7, it is selected from the derivant of ester, carbamate, aminal, amide, optical isomer and prodrug for it.
10. the chemical compound of claim 7, wherein
Figure A0080993500071
Be selected from
Figure A0080993500072
R wherein 18, R 19, R 20And R 21When occurring, independently be selected from every turn hydrogen, halogen, hydroxyl,
Alkyl, alkenyl, alkynyl group, alkoxyl, alkenyloxy, chain oxy-acetylene, alkane
Sulfenyl, hydroxyalkyl, aliphatic acyl ,-CF 3, nitro, amino, cyano group, carboxyl,
-N (C 1-C 3Alkyl)-C (O) (C 1-C 3Alkyl) ,-NHC (O) N (C 1-C 3Alkane
Base) C (O) NH (C 1-C 3Alkyl) ,-NHC (O) NH (C 1-C 6Alkyl), alkyl amino,
Alkenyl amino, two (C 1-C 3) amino ,-C (O) O-(C 1-C 3) alkyl ,-
C (O) NH-(C 1-C 3) alkyl ,-C (O) N (C 1-C 3Alkyl) 2,-CH=NOH,
-PO 3H 2,-OPO 3H 2, haloalkyl, alkoxyl alkoxyl, carboxaldehyde radicals, formyl
Amido, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, cycloalkyl-alkyl, aryl, fragrant acyl
Base, aryloxy group, arylamino, biaryl, thioaryl, ammonia diaryl base,
Heterocyclic radical, alkylaryl, aralkenyl, aralkyl, alkyl heterocyclic, heterocycle
Base alkyl, sulfonyl ,-SO 2-(C 1-C 3Alkyl) ,-SO 3-(C 1-C 3Alkyl), Asia
Sulfonamido, carbamyl ester group, aryloxy alkyl, carboxylic acid group and-C (O) NH (benzyl
Base) group; C is the integer of 0-2; D is the integer of 0-3;
E is the integer of 0-4; And
F is 0 or 1.
11. the chemical compound of claim 7, wherein R 5Be alkylaryl;
R 4Be aryl;
T is (CH 2) b, wherein b is 0;
L is (CH 2) n, wherein n is 0; And
B, R 6, R 7, R 9And R 10Independent separately is hydrogen.
12. chemical compound, it is selected from: (3S)-and 3-[({[2-methyl-4-(2-methyl-propyl)-6-oxo-1-(phenyl methyl)-1,6-dihydro-5-pyrimidine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-(1,3-benzo dioxole-5-yl)-3-[({[2-oxo-1-(phenyl methyl)-4-propyl group-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-propyl group-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-{[({6-methyl-2-oxo-1-(phenyl methyl)-4-[(phenyl methyl) the oxygen base]-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-{[({4-amino-1-[(2-chlorophenyl) methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[4-(methoxyl group) phenyl] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(3, the 4-3,5-dimethylphenyl) propanoic acid, (3S)-3-{[({4-amino-1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-[({[1-[(2-chlorophenyl) methyl]-4-(1, the 4-oxazinan-4-yl)-2-oxo-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-2-oxo-4-(propyl group amino)-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-{[({1-[(2-bromo phenyl) methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[3-methyl-4-(methoxyl group) phenyl] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[(2-{[2-(methoxyl group) ethyl] the oxygen base } ethyl) the oxygen base]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-6-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[(1, the 1-dimethyl ethyl) amino]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-the 3-phenylpropionic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-[4-methyl tetrahydrochysene-1 (2H)-pyrazinyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[4-(methoxyl group) phenyl] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(3, the 5-3,5-dimethylphenyl) propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(3-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[3-(methoxyl group) phenyl] propanoic acid, (3S)-and 3-[3,5-two (methoxyl group) phenyl]-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino } propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-quinolyl } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-[3-(trifluoromethyl) phenyl] propanoic acid, (3S)-and the 3-{[({1-[(2-chlorophenyl) methyl]-4-[({ ethyl [(ethylamino) carbonyl] amino } carbonyl) amino]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-{[({4-(1-azetanyl)-1-[(2-chlorophenyl) methyl]-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and the 3-[({[1-[(2-chlorophenyl) methyl]-4-(2-[(2-{[2-(methoxyl group) ethyl] and the oxygen base } ethyl) the oxygen base] ethyl } the oxygen base)-2-oxo-1,2-dihydro-3-pyridine radicals] amino } carbonyl) amino]-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-{[({1-[(2-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-and 3-{[({1-[(2-chloro-6-fluoro phenyl) methyl]-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-the 3-{[({1-[(2-chlorophenyl) methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridine radicals } amino) carbonyl] amino }-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-(1,3-benzo dioxole-5-yl)-3-((((2-oxo-1-((4-(trifluoromethyl) phenyl) methyl)-1,2-dihydro-3-pyridine radicals) amino) carbonyl) amino) propanoic acid, (3S)-3-((((1-((2-chlorophenyl) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino carbonyl amino)))-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2-fluoro phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2-bromo phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino carbonyl amino)))-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2, the 4-Dichlorobenzene base) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino) carbonyl) amino)-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2-chloro-6-fluoro phenyl) methyl)-2-oxo-1,2-dihydro-3-pyridine radicals) amino carbonyl amino)))-3-(4-aminomethyl phenyl) propanoic acid, (3S)-3-((((1-((2-chlorophenyl) methyl)-4-hydroxyl-2-oxo-1,2-dihydro-3-pyridine radicals) amino) carbonyl) amino)-3-(4-trifluoromethyl) oxygen base) phenyl) propanoic acid and their pharmaceutically acceptable salt.
13. the chemical compound of claim 11, it is selected from the derivant of ester, carbamate, aminal, amide, optical isomer and prodrug for it.
14. a Pharmaceutical composition, said composition comprises:
The chemical compound of claim 1 and pharmaceutically acceptable carrier.
15. a selectivity suppresses mammal α 4β 1The bonded method of integrin, this method comprise claim 1 chemical compound that gives described mammal therapeutic dose.
CNB008099359A 1999-05-07 2000-05-05 Carboxylic acid derivs. that inhibit binding of integrins to their receptors Expired - Fee Related CN1292744C (en)

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