CN101184739A - Polycyclic oxadiazoles or isoxazoles and their use as S1P receptor ligands - Google Patents
Polycyclic oxadiazoles or isoxazoles and their use as S1P receptor ligands Download PDFInfo
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- CN101184739A CN101184739A CNA2006800186926A CN200680018692A CN101184739A CN 101184739 A CN101184739 A CN 101184739A CN A2006800186926 A CNA2006800186926 A CN A2006800186926A CN 200680018692 A CN200680018692 A CN 200680018692A CN 101184739 A CN101184739 A CN 101184739A
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Abstract
Disclosed are polycyclic compounds of formula I which are useful as sphingosine-1 -phosphate (S 1 P) receptor ligands, particularly as immunosuppressants.
Description
The present invention relates to polynuclear compound, its preparation method, it is as the purposes of medicine and the pharmaceutical composition that contains them.
More particularly, on the one hand, the invention provides hydrolyzable derivative, its salt, hydrate and/or solvate on formula I compound or its physiology:
Wherein:
X is-N=and Y be-O-; Perhaps X be-O-and Y be-N=; Perhaps X is that CH and Y are O;
R
1Be xenyl, 4-phenoxy group-phenyl or 4-(the phenyl C that replaces
1-4Alkoxyl group)-and phenyl, wherein at least one phenyl group is mono-substituted; By the phenyl that one or more substituting groups that are selected from following groups replace, described group is: halogen, itrile group, C
1-8Alkyl, halo C
1-8Alkyl, C
1-8Alkoxyl group, halo C
1-8Alkoxyl group, C
1-8Alkoxy-C
1-8Alkoxyl group, C
1-8Alkyl-C
1-8Alkoxyl group, C
1-8Alkyl-halo C
1-8Alkoxyl group, halo C
1-8Alkyl-C
1-8Alkoxyl group, halo C
1-8Alkyl-halo C
1-8Alkoxyl group, halo C
1-8Alkoxy-C
1-8Alkoxyl group, C
1-8Alkoxyl group-halo C
1-8Alkoxyl group, halo C
1-8Alkoxyl group-halo C
1-8Alkoxyl group, C
1-8Alkoxy-C
1-8Alkyl, halo C
1-8Alkoxy-C
1-8Alkyl, C
1-8Alkoxyl group-halo C
1-8Alkyl, halo C
1-8Alkoxyl group-halo C
1-8Alkyl, C
2-6Thiazolinyl oxygen base, C
2-6Alkynyloxy base, C
3-6Cycloalkyl, C
3-6Cycloalkyl C
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkoxyl group, C
3-6Cycloalkyl-oxygen base, phenyl-C
1-4Alkoxyl group and heterocycle-C
1-4Alkoxyl group; Or 5 or the 6-that replace unit heteroaryl;
R
2For choosing wantonly by halogen, OH, NH
2, C
1-4Alkoxyl group or C
1-4The C that the alkyl-carbonyl oxygen base replaces
1-6Alkyl; Amino; Carboxyl; Sulfamyl; Formamyl; Or HN-CO-C
1-4Alkyl; Perhaps
R
2Be R
3-R
4-COOH or R
3-R
4-CONR
5R
6,
R wherein
3Be SO
2-NH, SO
2-N (C
1-4Alkyl), CO-NH, CO-N (C
1-4Alkyl), CH
2-O, NH-CO or N (C
1-4Alkyl) CO; R
4For choosing wantonly by O, S or C=CH
2C at interval
1-6Alkylidene group perhaps is optional phenylene or the C that replaces
3-6Cycloalkylidene; R
5And R
6Independent separately is hydrogen or C
1-6Alkyl, perhaps R
5And R
6Form heterocyclic radical with their bonded nitrogen-atoms, and
Ring A can choose wantonly and be substituted,
Prerequisite be when Y be O, X for-N=or-CH=and R
2Be SO
2NH-R
4-COOH (R wherein
4C for side chain
1-6Alkylidene group) time, then
I.R
1Be not by halogen, C
1-8Alkyl, C
1-8Alkoxyl group, halo C
1-8Alkyl or halo C
1-8The mono-substituted phenyl of alkoxyl group or be selected from halogen, C by one or two
1-8Alkyl and C
1-8The dibasic phenyl of the substituting group of alkoxyl group; Perhaps
Ii.R
1Be not mono-substituted thienyl or furyl.
Halogen can be fluorine, chlorine or bromine, preferred fluorine or chlorine.As the alkyl of group itself or the alkyl that exists in group or alkoxyl group can be straight or branched.C
1-6Alkylidene group can be a straight or branched.
As halo C group itself or that in group, exist
1-8Alkyl or halo C
1-8Alkoxyl group can be by the C of 1-5 halogen replacement
1-8Alkyl or C
1-8Alkoxyl group, for example CF
3Or CF
3-CH
2-O-.C1-8 alkyl-halo C
1-8Alkoxyl group can be in addition by C
1-8The halo C that alkyl replaces
1-8Alkoxyl group for example is substituted at 1.This equally also goes for other group.
Work as R
1Be xenyl, 4-phenoxy group-phenyl or the 4-(phenyl-C that replaces
1-4Alkoxyl group)-during phenyl, one of them and/or two phenyl groups all can be substituted, and are for example single or two replace by following groups: halogen, C
1-8Alkyl, C
1-8Alkoxyl group, halo C
1-8Alkyl, halo C
1-8Alkoxyl group or itrile group.Preferred xenyl, 4-phenoxy group-phenyl or 4-(phenyl-C
1-4Alkoxyl group)-phenyl at least one phenyl group be mono-substituted, for example, as mentioned above.Perhaps, xenyl, 4-phenoxy group-phenyl or 4-(phenyl-C
1-4Alkoxyl group)-phenyl in each phenyl group be mono-substituted (for example, as mentioned above, for example by halo C
1-8Alkyl replaces), and optional halogen, C
1-8Alkyl or C
1-8Alkoxyl group, halo C
1-8Alkyl or halo C
1-8Alkoxyl group is as the substituting group on second phenyl.
Work as R
1During for the phenyl that replaces, it can be single or dibasic.Work as R
1During for dibasic phenyl, a substituting group can be preferably halo C
1-8Alkyl or halo C
1-8Alkoxyl group, second substituting group as mentioned above.
As R
15 or 6-the unit heteroaryl example comprise for example thienyl, furyl or pyridyl.Be preferably thienyl.Work as R
1During for the heteroaryl that replaces, it can be preferably dibasic for single or dibasic.Substituting group can be for example halogen, halo C
1-8Alkyl (CF for example
3), C
1-8Alkoxyl group, halo C
1-8Alkoxyl group, C
1-8Alkyl, halo C
1-8Alkyl, C
3-6Cycloalkyl-C
1-4Alkoxyl group, C
3-6Cycloalkyl-C
1-4Alkyl and/or optional by halogen, C
1-4Alkyl or C
1-4The phenyl that alkoxyl group replaces.
By NR
5R
6The heterocyclic radical that forms is meant saturated, the undersaturated or aromatic heterocycle of 3-8 (preferred 5-8) unit, and this heterocycle contains 1 or 2 heteroatoms and optional being substituted that is preferably selected from N, O and S.
Work as R
2For choosing wantonly by halogen, OH, NH
2, C
1-4Alkoxyl group or C
1-4The C that the alkyl-carbonyl oxygen base replaces
1-6During alkyl, substituting group is preferably placed on last carbon atom, i.e. ω-position.
Work as R
4Be optional phenylene or the C that replaces
3-6During cycloalkylidene, it can be 1,4-phenylene or C
3-6Cycloalkylidene, for example optional cyclohexylidene that is replaced by halogen.
Ring A can choose wantonly and be substituted, for example by halogen, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group or itrile group replace.
Independently, common or the following meanings in any combination or subgroup are closed are preferred:
I) R
1Be xenyl, 4-phenoxy group-phenyl or 4-(phenyl-C
1-4Alkoxyl group)-and phenyl, wherein at least one phenyl carries halo C
1-4Alkyl or halo C
1-8Alkoxyl group (CF for example
3);
Ii) R
1For by halo C
1-4Alkyl or halo C
1-8Alkoxyl group (CF for example
3) phenyl that replaces, and replaced by another aforesaid substituting group;
Iii) R
1For by halo C
1-4Alkyl or halo C
1-8Alkoxyl group (CF for example
3) dibasic thienyl and phenyl;
Iv) R
2Be SO
2NH
2
V) R
2For in ω-position by NH
2The C that replaces
1-6Alkyl, wherein R
2Be side chain or straight chain C
1-6Alkyl, for example C
1-4Alkyl; Preferred R
2Be CH
2-NH
2
Vi) R
2Be R
3-R
4COOH;
Vii) R
2Be R
3-R
4-CONR
5R
6
Viii) R
3Be SO
2-NH; SO
2-N (C
1-4Alkyl); NH-CO; Or N (C
1-4Alkyl) CO;
Ix) R
4For choosing side chain or linear C at interval wantonly by O
1-6Alkylidene group; Preferred R
4Be linear C
1-6Alkylidene group;
X) R
5And R
6Independent separately is H or C
1-2Alkyl;
Xi) ring A is unsubstituted.
Formula I compound can exist with free form or salt form, and for example, with the additive salt that for example organic or inorganic acid forms, described acid is hydrochloric acid or acetate for example; Perhaps, work as R
2For COOH or when containing COOH, the salt that forms with alkali, alkali salt for example, for example sodium or sylvite, or that replace or unsubstituted ammonium salt.
Should be appreciated that formula I compound can exist with optically active isomer, racemoid or diastereomeric form.For example, work as R
4During for branched alkylidene, R
4Can contain unsymmetrical carbon.Should be appreciated that the present invention comprises all enantiomers and conformer and composition thereof.This is equally applicable to aforesaid starting raw material with unsymmetrical carbon.
Hydrolyzable derivative is meant under physiological conditions and can hydrolysis obtains formula I compound and its compound for acceptable by product on the physiology on the physiology of formula I compound, ester for example, this ester can hydrolysis obtain formula I compound and non-toxicity alcohol in the required dosage level.
The present invention also comprises the method for preparation I compound, and this method comprises:
A) be O and R in order to prepare wherein X for-N=and Y
2Formula I compound as hereinbefore defined,
Make formula II compound
Wherein encircle A and R
2As hereinbefore defined,
With formula III compound or its functional group derivant (for example activatory ester, acyl chlorides or acid anhydrides) reaction,
R wherein
1As hereinbefore defined; Perhaps
B) for preparation I compound, wherein X is O and R for-N=and Y
2Be R
3-R
4-COOH or R
3-R
4-CONR
5R
6(R wherein
3Be NH-CO or N (C
1-4Alkyl) CO, R
4, R
5And R
6As hereinbefore defined),
Make formula IV compound
R wherein
1With the ring A as hereinbefore defined, R '
2Be NH
2Or NH (C
1-4Alkyl),
With the acylating reagent reaction,
Perhaps carry out the Sandmeyer reaction; Or
C) be the formula I compound of O in order to prepare wherein Y for-N=and X,
In the presence of Burgess reagent for example, make formula V compound carry out cyclization:
R wherein
1, R
2With the ring A as hereinbefore defined; Or
D) Y is that O and X are the formula I compound of CH in order to prepare wherein,
Make formula VI compound
R wherein
1As hereinbefore defined,
React with formula VII compound
R wherein
2As hereinbefore defined; Perhaps
E) formula I compound is converted into another kind of formula I compound,
And reclaim the free form obtain or the formula I compound of salt form, and if necessary, will be converted into salt form with the formula I compound that free form obtains, perhaps, will be converted into free form with the formula I compound that salt form obtains.
Step a) is to e) can carry out by method well known in the art or according to disclosed method among the following embodiment.
Formula I compound is converted into another kind of formula I examples for compounds and for example can comprises:
I) in order to prepare wherein R
1Be xenyl, 4-phenoxy group-phenyl or the 4-(phenyl-C that replaces
1-4Alkoxyl group)-the formula I compound of phenyl (wherein at least one phenyl group is mono-substituted), wherein R
1Not xenyl, 4-phenoxy group-phenyl or the 4-(phenyl-C that replaces
1-4Alkoxyl group)-the formula I compound of phenyl (wherein at least one phenyl group is mono-substituted) is converted into wherein R
1Be xenyl, 4-phenoxy group-phenyl or the 4-(phenyl-C that replaces
1-4Alkoxyl group)-the formula I compound of phenyl (wherein at least one phenyl group is mono-substituted).
Ii) in order to prepare wherein R
2Be R
3-R
4The formula I compound of-COOH, hydrolyzing type I compound, wherein R
2In COOH exist with the form of hydrolyzable ester on the physiology (for example methyl esters).
Iii) in order to prepare wherein R
2Be R
3-R
4-CONR
5R
6Formula I compound, will be wherein R
2Be R
3-R
4The formula I compound of-COOH is converted into the activatory ester, with this activatory ester and the reaction of required amine, introduces required R then
5And R
6Group.
Formula II compound as raw material can followingly obtain: make formula VIII compound
R wherein
2With the ring A as hereinbefore defined,
With azanol reaction.
Formula IV compound can be as making:
Make formula IX compound or its functional group derivant (for example activatory ester, acyl chlorides or acid anhydrides)
R
1-COOH IX
R wherein
1As hereinbefore defined,
React with formula X compound:
R ' wherein
2As hereinbefore defined.
Formula V compound can be by making the reaction of formula III compound and formula XI compound,
R wherein
2With the ring A as hereinbefore defined.
Under the situation that the preparation to starting raw material does not have to specify, this compound may be known, perhaps can according to method well known in the art or hereinafter disclosed method be prepared.
The following example is used to illustrate the present invention.EDC represents 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.
Embodiment 1: 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-benzsulfamide
A) 2-trifluoromethyl-xenyl-4-formic acid
Under inert atmosphere, in the THF solution of 4-chloro-3-trifluoromethylbenzoic acid (1 equivalent), add corresponding boric acid (1.5 equivalent), X-Phos (0.05 equivalent), KF (3 equivalent), add Pd (OAc) at last
2(0.05 equivalent) stirs reaction mixture 15 hours at 90 ℃ then.Reaction mixture is concentrated into dried, adopts purification by flash chromatography to obtain title compound.
B) N-hydroxyl-4-sulfamyl-benzenyl amidine
Under-25 ℃ (ice/methanol bath), in the THF solution of 4-sulfamyl benzonitrile (1 equivalent), add the aqueous solution (20 equivalent) of azanol.Then reaction mixture was at room temperature stirred 16 hours.With the reaction mixture ethyl acetate extraction, and wash with water, organic layer is through Na
2SO
4Drying is filtered and concentrating under reduced pressure.Use ethyl acetate/hexanes mixtures, obtain N-hydroxyl-4-sulfamyl-benzenyl amidine by precipitate and separate.
C) target compound is prepared as follows:
Under inert atmosphere, in the dioxane solution of the compound (1 equivalent) of step a), add EDC (1.3 equivalent) and HOBt (1.3 equivalent), reaction mixture was at room temperature stirred 30 minutes.N-hydroxyl-sulfamyl-benzenyl amidine (1.3 equivalent) with step b) adds in the reaction mixture then, at room temperature stirs 30 minutes, spends the night 95 ℃ of stirrings subsequently.Then reaction mixture is concentrated into driedly, adopts purification by flash chromatography, obtain 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-benzsulfamide (m/z=446 (M+H)
+).
Embodiment 2: N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-phenyl }-succinamic acid
A) 2-trifluoromethyl-xenyl-4-formic acid
Under inert atmosphere, in the THF solution of 4-chloro-3-trifluoromethylbenzoic acid (1 equivalent), add corresponding boric acid (1.5 equivalent), X-Phos (0.05 equivalent), KF (3 equivalent), add Pd (OAc) at last
2(0.05 equivalent) stirs reaction mixture 15 hours at 90 ℃ then.Reaction mixture is concentrated into dried, adopts purification by flash chromatography, obtain title compound.
B) N4-amino-N-hydroxyl-benzenyl amidine
-25 ℃ (ice/methanol bath), in the THF solution of 4-aminobenzonitrile (1 equivalent), add the aqueous solution (20 equivalent) of azanol.Reaction mixture was at room temperature stirred 16 hours.The reaction mixture ethyl acetate extraction, and wash with water, organic layer is through Na
2SO
4Drying is filtered and concentrating under reduced pressure.Use ethyl acetate/hexanes mixtures, obtain 4-amino-N-hydroxyl-benzenyl amidine by precipitate and separate.
C) 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-aniline:
Under inert atmosphere, in the dioxane solution of the compound (1 equivalent) of step a), add EDC (1.3 equivalent) and HOBt (1.3 equivalent), reaction mixture was at room temperature stirred 30 minutes.N-hydroxyl-benzenyl amidine (1.3 equivalent) with step b) adds in the reaction mixture then, at room temperature stirs 30 minutes, stirs down at 95 ℃ then and spends the night.Then reaction mixture is concentrated into driedly, adopts purification by flash chromatography, obtain 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-aniline.
G) under inert atmosphere, to 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-add succinyl oxide (1.1 equivalent) in the acetonitrile solution of aniline (1 equivalent), reaction mixture was stirred 16 hours at 90 ℃.Then reaction mixture is concentrated into driedly, with ethyl acetate/hexanes mixtures post precipitation, filtering separation obtains required product.m/z=480(M-H)
-。
Embodiment 3: 4-[5-(4-phenoxy group-3-trifluoromethyl-phenyl)-[1,2,4] diazole-3-yl]-benzsulfamide
Under 0 ℃ (ice/water-bath) and inert atmosphere, to the 4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-[1 that obtains according to embodiment 1 described method, 2,4] diazole-3-yl]-add phenol (3 equivalent) and NaH (3 equivalent) in the DMF solution of benzene sulfonyl (1 equivalent).Reaction mixture was at room temperature stirred 16 hours.Reaction mixture with the careful cancellation of 2NHCl solution, is used ethyl acetate extraction, wash with water, organic layer is through Na
2SO
4Drying is filtered and concentrating under reduced pressure.Separate with ethyl acetate extraction/hexanes mixtures precipitation or by anti-phase preparation HPLC, obtain required product (m/z=460 (M-H)
-).
Embodiment 4: N-{4-[5-(4-phenoxy group-3-trifluoromethyl-phenyl)-[1,2,4] diazole-3-yl]-phenyl }-succinamic acid
Repeat the method for embodiment 3, but adopt N-{4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-[1,2,4] diazole-3-yl]-phenyl }-succinamic acid is a starting raw material, obtains title compound (m/z=498.4 (M+H)
+).
According to the method described in the embodiment 1-4, adopt suitable starting raw material, make formula X
1Compound
R wherein
1, R
3And R
4Such as in the following table 1 definition.
Table 1
Embodiment | R 1 | R 3 | R 4 | ESI+MS: |
5 | 2-CF 3-4-xenyl | SO 2-NH | CH 2 | m/z= 502(M-H) - |
6 | 2-CF 3-4-xenyl | SO 2-NH | CH 2-CH 2 | m/z= 518(M+H) + |
7 | 2-CF 3-3-phenyl-5-thienyl | SO 2-NH | CH 2-CH 2 | m/z= 522(M-H) - |
8 | 2-CF 3-4-xenyl | NH-CO | CH 2-CH 2 | m/z= 480(M-H) - |
9 | 2-CF 3-4-xenyl | CO-NH | 4-Cl-1, the 3-phenylene | m/z= 564(M+H) + |
10 | 2-CF 3-4-xenyl | CO-NH | CH 2-CH 2 | m/z= 482(M+H) + |
11 | 2-CF 3-3-phenyl-5-thienyl | SO 2-NH | CH 2 | m/z= 508(M-H) - |
12 | 2-CF 3-3-phenyl-5-thienyl | CO-NH | 4-Cl-1, the 3-phenylene | m/z= 570.9(M+H) + |
13 | 2-CF 3-4-xenyl | CO-NH | CH 2 | m/z= 466(M-H) - |
14 | 2-CF 3-3-phenyl-5-thienyl | CH 2-O | 1, the 4-phenylene | m/z= 523.1(M+H) + |
15 | 2-CF 3-3-phenyl-5-thienyl | CH 2-NH | 4-Cl-1, the 3-phenylene | m/z= 556.1(M+H) + |
16 | 2-CF 3-4 '-fluoro-4-xenyl | SO 2-NH | CH 2 | m/z= 520(M-H) - |
17 | 2-CF 3-4-(3 '-fluorophenoxy)-phenyl | SO 2-NH | CH 2 | m/z= 536(M-H) - |
18 | 2-CF 3-4-oxyethyl group-phenyl | SO 2-NH | CH 2 | m/z= 470(M-H) - |
19 | 2-CF 3-2 '-fluoro-4-xenyl | SO 2-NH | CH 2 | m/z= 520(M-H) - |
20 | 2-CF 3-2 '-trifluoromethyl-4-xenyl | SO 2-NH | CH 2 | m/z= 570(M-H) - |
21 | 2-CF 3-4-Phenoxyphenyl | SO 2-NH | CH 2CH 2 | m/z= 532(M-H) - |
22 | 2-CF 3-4-Phenoxyphenyl | SO 2-NH | CH 2 | m/z= 518(M-H) - |
23 | 2-CF 3-4-benzyloxy phenyl | SO 2-NH | CH 2 | m/z= 532(M-H) - |
24 | 2-CF 3-4-trifluoro ethoxy-phenyl | SO 2-NH | CH 2 | m/z= 524(M-H) - |
25 | 2-CF 3-4-isopropyl phenyl | SO 2-NH | CH 2CH 2 | m/z= 498(M-H) - |
26 | 2-CF 3-4-(2 '-fluorophenoxy)-phenyl | SO 2-NH | CH 2 | m/z= 536(M-H) - |
27 | 2-CF 3-2 '-methyl-4-xenyl | SO 2-NH | CH 2 | m/z= 516(M-H) - |
28 | 2-CF 3-4-cyclopentyloxy phenyl | SO 2-NH | CH 2 | m/z= 510(M-H) - |
29 | 2-CF 3-4-(2 '-fluorophenoxy)-phenyl | SO 2-NH | CH 2CH 2 | m/z= 550(M-H) - |
30 | 2-CF 3-2 '-fluoro-4-xenyl | SO 2-NH | CH 2CH 2 | m/z= 536(M+H) + |
31 | 2-CF 3-4-trifluoro ethoxy-phenyl | SO 2-NH | CH 2CH 2 | m/z= 538(M-H) - |
32 | 2-CF 3-4-(1 '-methyl trifluoro second | SO 2-NH | CH 2CH 2 | m/z= |
The oxygen base)-phenyl | 552(M-H) - | |||
33 | 2-CF 3-4-(1 '-cyclopropyl oxyethyl group)-phenyl | SO 2-NH | CH 2 | m/z= 510(M-H) - |
34 | 2-CF 3-4-cyclopentyloxy-phenyl | SO 2-NH | CH 2CH 2 | m/z= 524(M-H) - |
35 | 2-CF 3-4-(1 '-cyclopropyl oxyethyl group)-phenyl | SO 2-NH | CH 2CH 2 | m/z= 524(M-H) - |
36 | 2-CF 3-4-xenyl | NH-CO | CH 2-C(CH 2) | m/z= 494.4(M+H) + |
37 | 2-CF 3-4-xenyl | NH-CO | CH 2-O-CH 2 | m/z= 496(M-H) - |
38 | 2-CF 3-4-xenyl | NH-CO | CH 2-C(CH 3) 2 | m/z= 510(M+H) + |
39 | 2-CF 3-4-xenyl | NH-CO | CH 2 | m/z= 468(M+H) + |
40 | 3-CF 3-4-neopentyl oxygen-phenyl | SO 2-NH | CH(CH 3) | m/z= 526.4(M-H) - |
41 | 3-CF 3-4-propine-2-base oxygen base-phenyl | SO 2-NH | CH(CH 3) | m/z=494.3 (M-H) - |
42 | 3-CF 3-4-isobutoxy-phenyl | SO 2-NH | CH(CH 3) | m/z=512.2 (M-H) - |
43 | 3-CF 3-4-Phenoxyphenyl | SO 2-NH | C(CH 3) 2 | m/z= 548.3(M+H) + |
44 | 3-CF 3-4-(cyclobutyl-methoxyl group)-phenyl | SO 2-NH | CH(CH 3) | m/z=524.2 (M-H) - |
45 | 2-CF 3-2 '-ethyl-4-xenyl | SO 2-NH | CH 2 | m/z= 530(M-H) - |
46 | 2-CF 3-2 '-methyl-4-xenyl | SO 2-NH | CH 2-CH 2 | m/z=546.3 (M-H) - |
47 | 2-CF 3-3 '-methoxyl group-4-xenyl | SO 2-NH | CH 2-CH 2 | m/z= 562(M-H) - |
48 | 2-CF 3-2 '-chloro-4-xenyl | SO 2-NH | CH 2-CH 2 | m/z= 550(M-H) - |
49 | 3-CF 3-4-isopropoxy-phenyl | SO 2-NH | CH(CH 3) | m/z= 498(M-H) - |
50 | 3-CF 3-4-(2 ', 2 ', 2 '-three fluoro-1 ', 1 '-dimethyl-ethyls)-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 498.4(M+H) + |
51 | 2-CF 3-3 '-fluoro-4-xenyl | SO 2-NH | CH 2-CH 2 | m/z= 534(M-H) - |
52 | 3-CF 3-4-(cyclopropyl-methoxy | NH-CO | CH 2-CH 2 | m/z= 476.4(M+H) + |
Base)-phenyl | ||||
53 | 2-CF 3-2 '-methyl 4 xenyls | SO 2-NH | CH 2-CH 2 | m/z= 530(M-H) - |
54 | 3-CF 3-4-(3 '-fluorophenoxy)-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 550(M-H) - |
55 | 2-CF 3-4-xenyl | NH-CO | 1, the 2-phenylene | m/z= 536.4(M+H) + |
56 | 2-CF 3-2’-CF 3-4-xenyl | SO 2-NH | CH 2-CH 2 | m/z= 583.9(M-H) - |
57 | 3-CF 3-4-(2 '-methyl-phenoxy group)-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 534.2(M+H) + |
58 | 3-CF 3-4-(2 '-fluoro-oxyethyl group)-phenyl | SO 2-NH | CH(CH 3) | m/z= 504.3(M+H) + |
59 | 3-CF 3-4-phenoxy group | SO 2-NH | CH(CH 3) | m/z= 533.4(M+H) + |
60 | 3-CF 3-4-(2 ', 2 ', 2 '-three fluoro-oxyethyl groups)-phenyl | SO 2-NH | CH(CH 3) | m/z= 540.2(M+H) + |
61 | 3-CF 3-4-(3 '-fluoro-phenoxy group)-phenyl | SO 2-NH | CH(CH 3) | m/z= 552.1(M+H) + |
62 | 2-CF 3-2’-CF 3-4-xenyl | SO 2-NH | CH 2 | m/z= 588.3(M+H) + |
63 | 3-CF 3-4-(2 '-fluoro-phenoxy group)-phenyl | SO 2-NH | CH(CH 3) | m/z 552.1(M+H) + |
64 | 2-CF 3-4 '-fluoro-4-xenyl | SO 2-NH | CH 2-CH 2 | m/z= 534(M-H) - |
65 | 2-CF 3-4-xenyl | NH-CO | CH 2-CH 2-CH 2 | m/z= 496.4(M+H) + |
66 | 3-CF 3-4-phenoxy group-phenyl | NH-CO | CH 2-CH 2 | m/z= 498.4(M+H) + |
67 | 3-CF 3-4-(2 '-CF3-phenoxy group)-phenyl | NH-CO | CH 2-CH 2 | m/z= 5663(M+H) + |
68 | 3-CF 3-isopropoxy-phenyl | NH-CO | CH 2-CH 2 | m/z= 469.4(M+H) + |
69 | 2-CF 3-2 '-Cl-4-xenyl | SO 2-NH | CH 2 | m/z= 536(M-H) - |
70 | 3-CF 3-4-(2 ', 2 ', 2 '-three fluoro-oxyethyl groups)-phenyl | NH-CO | SO 2-NH | m/z= 5043(M+H) + |
71 | 3-CF 3-4-(2 '-methyl-phenoxy group)-phenyl | NH-CO | CH 2-CH 2 | m/z= 512.4(M+H) + |
72 | 2-CF 3-3 '-fluoro-4-xenyl | SO 2-NH | CH 2 | m/z= |
520(M-H) - | ||||
73 | 3-CF 3-4-(2 ', 2 ', 2 ' ,-three fluoro-1 '-methyl-oxyethyl group)-phenyl | SO 2-NH | CH 2 | m/z= 538(M-H) - |
74 | 3-CF 3-4-(3 '-fluoro-phenoxy group)-phenyl | NH-CO | CH 2-CH 2 | m/z= 516.4(M+H) + |
75 | 2-CF 3-4-xenyl | NH-CO | 2,2-dimethyl-propyl group | m/z= 524.5(M+H) + |
76 | 3-CF 3-4-(2 '-fluoro-phenoxy group)-phenyl | NH-CO | CH 2-CH 2 | m/z= 516.4(M+H) + |
77 | 3-CF 3-4-fluoro-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 458(M-H) - |
78 | 3-CF 3-4-(benzyloxy)-phenyl | SO 2-NH | CH 2 | m/z= 532(M-H) - |
79 | 3-CF 3-4-Cl-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 474(M-H) - |
80 | 2-CF 3-2’-CF 3The O-4-xenyl | SO 2-NH | CH 2-CH 2 | m/z= 586(M-H) - |
81 | 3-bromo-4-(phenoxy group)-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 545.9(M+H) + |
82 | 3-bromo-4-(isopropoxy)-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 513.1(M+H) + |
83 | 3-bromo-4-(2 '-F-phenoxy group)-phenyl | SO 2-NH | CH 2 | m/z= 548.4(M+H) + |
84 | 3-bromo-4-(cyclopentyloxy)-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 536.1(M+H) + |
85 | 3-bromo-4-(2 '-F-phenoxy group)-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 562.4(M+H) + |
86 | 3-bromo-4-(three fluoro-oxyethyl groups)-phenyl | SO 2-NH | CH 2 | m/z= 536.3(M+H) + |
87 | 3-bromo-4-(three fluoro-oxyethyl groups)-phenyl | SO 2-NH | CH 2-CH 2 | m/z= 550.3(M+H) + |
88 | 3-CN-4-(three fluoro-oxyethyl groups)-phenyl | SO 2-NH | CH 2 | m/z= 481.1(M-H) - |
89 | 3-CN-4-(phenoxy group)-phenyl | SO 2-NH | CH 2 | m/z= 475.0(M-H) - |
According to the method described in the embodiment 1-4, adopt suitable starting raw material, make formula X
2Compound:
R wherein
1And R
2Such as following table 2 definition.
Table 2
Embodiment | R 1 | R 2 | ESI+MS: |
90 | 2-CF 3-2 '-fluoro-4-xenyl | SO 2-NH 2 | m/z=462(M-H) - |
91 | 2-CF 3-4-xenyl | SO 2-NH 2 | m/z=446(M+H) + |
92 | 2-CF 3-3-phenyl-5-thienyl | SO 2-NH 2 | m/z=452.1 |
93 | 2-CF 3-2 '-methyl-4-xenyl | SO 2-NH 2 | m/z=460(M+H) + |
94 | 2-CF 3-3-phenyl-5-thienyl | CH 2-NH 2 | m/z=402.1 |
95 | 2-CF 3-3-phenyl-5-thienyl | CH 2-OH | m/z=403.1 |
96 | 2-CF 3-3-phenyl-5-thienyl | CO-NH 2 | m/z=4163 |
97 | 2-CF 3-4 '-methyl-4-xenyl | SO 2-NH 2 | m/z=460(M+H) + |
98 | 2-CF 3-3-phenyl-5-thienyl | C(CH 3) 2-OH | m/z=430.2 |
99 | 2-CF 3-4-xenyl | NH-CO-CH 3 | m/z=422(M-H) - |
100 | 2-CF 3-4 '-fluoro-4-xenyl | SO 2-NHN 2 | m/z=464(M+H) + |
101 | 2-CF 3-3-phenyl-5-thienyl | CH 2-O-CO-CH 3 | m/z=445.2 |
102 | 2-CF 3-4-xenyl | NH 2 | m/z=382(M+H) + |
103 | 4-cyclohexyl-phenyl | SO 2-NH 2 | m/z=384.5(M+H) + |
104 | 2-CF 3-3 '-methoxyl group-4-xenyl | SO 2-NH 2 | m/z=474(M-H) - |
105 | 2-CF 3-3-phenyl-5-thienyl | CH 2-F | m/z=405.2 |
106 | 2-CF 3-4-xenyl | CF 3 | m/z=435(M+H) + |
107 | 2-methoxyl group-4-xenyl | SO 2-NH 2 | m/z=408(M+H) + |
108 | 2-CF 3-4 '-methoxyl group-4-xenyl | SO 2-NH 2 | m/z=4743(M-H) - |
109 | 2-CF 3-3-phenyl-5-thienyl | CH 2-O-CH 3 | m/z=417.2 |
110 | 2-CF 3-3-phenyl-5-thienyl | CH 2-CH 3 | m/z=401.2 |
111 | 2-CF 3-3-phenyl-5-thienyl | COOH | m/z=417.1 |
112 | 2-CF 3-4-Phenoxyphenyl | SO 2-NH 2 | m/z=460(M-H) - |
113 | 3-phenyl-5-thienyl | SO 2-N 2 | m/z=383(M+H) + |
114 | 2-CF 3-4-(2 '-fluorine oxyethyl group) phenyl | SO 2-NH 2 | m/z=430(M-H) - |
115 | 2-CF 3-4-isopropyl phenyl | SO 2-NH 2 | m/z=426(M-H) - |
116 | 2-CF 3-4-trifluoro ethoxy phenyl | SO 2-NH 2 | m/z=466(M-H) - |
117 | 2-CF 3-4-2 '-fluorophenoxy phenyl | SO 2-NH 2 | m/z=478(M-H) - |
118 | 2-CF 3-4-benzyloxy phenyl | SO 2-NH 2 | m/z=474(M-H) - |
119 | 2-fluoro-4-xenyl | SO 2-NH 2 | m/z=396.4(M+H) + |
120 | 2-CF 3-4-(1 '-methyl trifluoro oxyethyl group)-phenyl | SO 2-NH 2 | m/z=480(M-H) - |
121 | 2-CF 3-4-(1 '-methyl propoxy-)-phenyl | SO 2-NH 2 | m/z=440(M-H) - |
122 | 2-CF 3-4-cyclopentyloxy-phenyl | SO 2-NH 2 | m/z=454(M+H) + |
123 | 2-CF 3-4-(1 '-cyclopropyl-oxyethyl group)-phenyl | SO 2-NH 2 | m/z=454(M+H) + |
124 | 3-CF 3-4-(3 '-fluoro-phenoxy group)-phenyl | SO 2-NH 2 | m/z=478.1(M-H) - |
125 | 2-CF 3-2’-CF 3-4-xenyl | SO 2-NH 2 | m/z=528.1(M-H) - |
126 | 3-CF 3-4-(4 '-chloro-phenoxy group)-phenyl | SO 2-NH 2 | m/z=494.1(M-H) - |
127 | 3-CF 3-4-(cyclobutyl-methoxyl group)-phenyl | SO 2-NH 2 | m/z=452.1(M-H) - |
128 | 3-CF 3-4-isobutoxy-phenyl | SO 2-NH 2 | m/z=440.1(M-H) - |
129 | 3-CF 3-4-(2 '-methoxyl group-phenoxy group)-phenyl | SO 2-NH 2 | m/z=490.1(M-H) - |
130 | 3-CF 3-4-(3 '-methoxyl group-phenoxy group)-phenyl | SO 2-NH 2 | m/z=490.2(M-H) - |
131 | 3-CF 3-4-(2 '-cyclopropyl-oxyethyl group)-phenyl | SO 2-NH 2 | m/z=452.2(M-H) - |
132 | 3-CF 3-4-(propine-2-base oxygen base)-phenyl | SO 2-NH 2 | m/z=422.1(M-H) - |
133 | 3-CF 3-4-(2 '-five fluoro-1 '-methoxyl group-oxyethyl group)-phenyl | SO 2-NH 2 | m/z=530.1(M-H) - |
134 | 3-CF 3-4-(cyclopropyl-methoxyl group)-phenyl | SO 2-NH 2 | m/z=438.1(M-H) - |
135 | 3-CF 3-4-cyclobutoxy group-phenyl | SO 2-NH 2 | m/z=438.2(M-H) - |
136 | 3-CF 3-4-cyclohexyl-oxygen base-phenyl | SO 2-NH 2 | m/z=466.2(M-H) - |
137 | 3-CF 3-4-(2 '-chloro-phenoxy group)-phenyl | SO 2-NH 2 | m/z=494.1(M-H) - |
138 | 3-CF 3-4-(2 '-methyl-phenoxy group)-phenyl | SO 2-NH 2 | m/z=474.1(M-H) - |
139 | 3-CF 3-4-(2 '-oxyethyl group-oxyethyl group)-phenyl | SO 2-NH 2 | m/z=456.4(M-H) - |
140 | 3-CF 3-4-(2 '-methoxyl group-1 '-methyl)-phenyl | SO 2-NH 2 | m/z=456.1(M-H) - |
141 | 3-CF 3-4-(4 '-fluoro-phenoxy group)-phenyl | SO 2-NH 2 | m/z=478.1(M-H) - |
142 | 3-CF 3-4-(5 '-pyrrolidone-base-methoxyl group)- | SO 2-NH 2 | m/z=528.1(M-H) - |
Phenyl | |||
143 | 3-CF 3-4-neopentyl oxygen-phenyl | SO 2-NH 2 | m/z=454.1(M-H) - |
144 | 3-CF 3-4-(2 '-2 ', 2 '-three fluoro-1 ', 1 '-dimethyl-oxyethyl groups)-phenyl | SO 2-NH 2 | m/z=496.2(M+H) + |
145 | 3-CF 3-4-cyclopentyloxy-phenyl | SO 2-NH 2 | m/z=454(M+H) + |
146 | 3-CF 3-4-oxyethyl group-phenyl | SO 2-NH 2 | m/z=412(M-H) - |
147 | 3-CF 3-4-(1 '-methyl-allyl group)-phenyl | SO 2-NH 2 | m/z=438(M-H) - |
148 | 3-CF 3-4-(3 '-methyl-butene-2-yl)-phenyl | SO 2-NH 2 | m/z=452(M-H) - |
149 | 3-Cl-4-(isopropoxy)-phenyl | SO 2-NH 2 | m/z=393.9(M+H) + |
150 | 3-Cl-4-(trifluoro ethoxy)-phenyl | SO 2-NH 2 | |
151 | 3-bromine 4-(cyclopropane-methoxyl group)-phenyl | SO 2-NH 2 | m/z=450.0(M+H) + |
152 | 3-bromo-4-(trifluoro ethoxy)-phenyl | SO 2-NH 2 | m/z=478.5(M-H) - |
153 | 3-bromo-4-(3 '-trifluoro isopropoxy)-phenyl | SO 2-NH 2 | |
154 | 3-bromo-4-(1-methyl-cyclopropane methoxyl group)-phenyl | SO 2-NH 2 | m/z=464.2(M+H) + |
155 | 3-bromine 4-(phenoxy group)-phenyl | SO 2-NH 2 | m/z=472.1(M+H) + |
156 | 3-bromo-4-(cyclobutoxy group)-phenyl | SO 2-NH 2 | |
157 | (R) 3-bromo-4-(fourth-2-oxygen base)-phenyl | SO 2-NH 2 | m/z=452.4(M+H) + |
158 | (S) 3-bromo-4-(fourth-2-oxygen base)-phenyl | SO 2-NH 2 | m/z=452.4(M+H) + |
159 | 3-bromine 4-(2 '-methyl-third-1-oxygen base)-phenyl | SO 2-NH 2 | |
160 | 3-bromo-4-(isopropoxy)-phenyl | SO 2-NH 2 | m/z=438.0(M+H) + |
161 | 3-bromo-4-(3 '-F-phenoxy group)-phenyl | SO 2-NH 2 | m/z=490.4(M+H) + |
162 | 3-bromo-4-(2 '-Cl-phenoxy group)-phenyl | SO 2-NH 2 | m/z=507.8(M+H) + |
163 | 3-bromo-4-(2 '-F-phenoxy group)-phenyl | SO 2-NH 2 | m/z=491.1(M+H) + |
164 | 3-bromo-4-(isopropoxy)-phenyl | SO 2-NH 2 | m/z=493.3(M+H) + |
165 | 3-bromo-4-(2 '-methyl-phenoxy group)-phenyl | SO 2-NH 2 | m/z=486.3(M+H) + |
166 | 3-CN-4-(trifluoro ethoxy)-phenyl | SO 2-NH 2 | m/z=423.1(M-H) - |
167 | 3-CN-4-(encircling third methoxyl group)-phenyl | SO 2-NH 2 | m/z=395.2(M-H) - |
168 | 3-CN-4-(isopropoxy)-phenyl | SO 2-NH 2 | m/z=383.2(M-H) - |
169 | 3-CN-4-(phenoxy group)-phenyl | SO 2-NH 2 | m/z=417.2(M-H) - |
170 | 3-CN-4-(3 '-trifluoro isopropoxy)-phenyl | SO 2-NH 2 | |
171 | 3-CN-4-(2 '-F-phenoxy group)-phenyl | SO 2-NH 2 | m/z=435.2(M-H) - |
172 | 5-chloro-4-isopropoxy-3-pyridyl | SO 2-NH 2 | |
173 | 5-chloro-4-cyclobutoxy group-3-pyridyl | SO 2-NH 2 | m/z=406.8(M +H) + |
174 | 5-chloro-4-trifluoro ethoxy-3-pyridyl | SO 2-NH 2 | m/z=434.6(M-H) - |
175 | 2-CF 3-4-xenyl | CH 2-NH 2 | m/z=396.4(M +H) + |
176 | 2-CF 3-4-xenyl | C(CH 3) 2-NH 2 | m/z=324.4(M+H) + |
177 | 3-CF 34-trifluoro ethoxy-phenyl | CH 2-NH 2 | m/z=418.3(M +H) + |
178 | 3-CF 3-4-isopropoxy-phenyl | CH 2-NH 2 | m/z=378.4(M +H) + |
Embodiment 175: embodiment 175 compounds are to be prepared by the method that repeats embodiment 1, but it adopts [4-(N-hydroxy formamidine base)-benzyl]-t-butyl carbamate (can followingly to make: will use BOC in dioxane/water/NaOH available from the 4-amino methyl-benzonitrile hydrochloride of commerce
2After O carries out N-protected, subsequently with THF as solvent, with 50% aqueous hydroxylamine reaction, form the N-hydroxyamidines) be starting raw material, usefulness TFA/ water (95/5; 5 minutes, room temperature) remove the Boc-blocking group after, obtain target compound.
Embodiment 176: according to embodiment 175 disclosed methods, (1-amino-1-methyl-ethyl)-benzonitrile is a starting raw material, prepares this compound but adopt 4-.
Embodiment 177: under 0 ℃ (ice/water-bath) and inert atmosphere, to { 4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-[1 according to embodiment 1 and embodiment 175 described methods acquisitions, 2,4] diazole-3-yl]-benzyl }-add NaH (3 equivalent) in the DMF solution of t-butyl carbamate (1 equivalent), add trifluoroethanol (5 equivalent) after 30 minutes.Reaction mixture was at room temperature stirred 16 hours.The cancellation reaction mixture is also concentrated carefully with acetate (95%).Then, residue is dissolved in methylene dichloride, washes with water, organic layer is through Na
2SO
4Drying is filtered and is concentrated.Through silica gel purification (cyclohexane/ethyl acetate 4/1 is a moving phase), go protection (according to embodiment 175) subsequently, obtain required product.
Embodiment 179: diazole-2-yl 4-[5-2-trifluoromethyl-biphenyl-4-yl)-[1,3,4]]-benzsulfamide
4-diazanyl carbonyl-benzsulfamide.
Under inert atmosphere, in the THF solution of 4-sulfonamido benzoic acid (1 equivalent), add Et
3N (1.3 equivalent) and SULPHURYL CHLORIDE (1.1 equivalent).Reaction mixture was stirred under room temperature 30 minutes.Temperature is reduced to 0 ℃ (ice/water-bath), in reaction mixture, slowly adds the methanol solution (30 equivalent) of hydrazine, with the mixture that obtains from 0 ℃ to stirring at room 2 hours.Water cancellation reaction mixture is used ethyl acetate extraction.Organic layer is through Na
2SO
4Drying is filtered and concentrating under reduced pressure.Precipitate with the ethyl acetate/hexane mixture, separate obtaining required product.
Under inert atmosphere, in the THF solution of 4-phenyl-3-trifluoromethylbenzoic acid (as described previously) (1 equivalent), add Et
3N (1.3 equivalent) and SULPHURYL CHLORIDE (1.1 equivalent).Reaction mixture was at room temperature stirred 5 hours.Water cancellation reaction mixture is used ethyl acetate extraction.Organic layer is through Na
2SO
4Drying is filtered and concentrating under reduced pressure.Obtain 4-[N '-(2-trifluoromethyl-xenyl-4-carbonyl)-diazanyl carbonyl with the flash chromatography separation]-benzsulfamide.
Under inert atmosphere, to 4-[N '-(2-trifluoromethyl-xenyl-4-carbonyl)-diazanyl carbonyl]-add Et in the acetonitrile solution of benzsulfamide (1 equivalent)
3N (1.3 equivalent) and Burgess reagent (1.5 equivalent).Then reaction mixture was stirred 10 hours under refluxing.Reaction mixture is concentrated into dried, adopts purification by flash chromatography (ethyl acetate/hexane), obtain required 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-benzsulfamide (m/z=444 (M-H)
-).
According to embodiment 179 described methods, adopt suitable raw material, obtain formula X
3Compound
R wherein
1And R
2Such as following table 3 definition.
Table 3
Embodiment | R 1 | R 2 | ESI+MS: |
180 | 2-CF 3-3-phenyl-5-thienyl | SO 2-NH 2 | m/z=450(M-H) - |
181 | 2-CF 3-3-phenyl-5-thienyl | CH 2-OH | m/z=401(M-H) - |
182 | 2-CF 3-4-xenyl | SO 2-NH 2 | m/z=444(M-H) - |
Embodiment 183: 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-aniline
2-trifluoromethyl-xenyl-4-formic acid
With 4-chloro-3-(trifluoromethyl)-phenylformic acid (1 equivalent), phenyl-boron dihydroxide (1.8 equivalent), Pd (OAc)
2With dicyclohexyl phosphino--2,4, the 6-tri isopropyl biphenyl is dissolved among the THF and refluxed 90 minutes.After the cooling, reaction mixture is passed through Hyflo Super Cel
Filter and concentrate.Employing ether/hexanaphthene is a moving phase, with the crude product residue through silica gel purification.
5-(4-nitro-phenyl)-3-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole
2-trifluoromethyl-xenyl-4-formic acid (1 equivalent) is dissolved in POCl
3In, add 4-oil of mirbane hydrazides (1 equivalent).Reflux after 3 hours, add the 4-oil of mirbane hydrazides of another part equivalent, refluxed again 3 hours.POCl is removed in decompression
3After, residue is dissolved in ethyl acetate, with saturated NaHCO
3Solution extraction.Organic layer is through Na
2SO
4Drying, target product need not to be further purified and can be directly used in next step.
4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-aniline
5-(4-nitro-phenyl)-3-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole is dissolved in the methanol/ethyl acetate (1/1), under normal pressure and room temperature, adopts Pd/C
10%As catalyzer hydrogenation 16 hours.By HyfloSuper Cel
After the filtration, concentrated reaction mixture is through silica gel purification (methylene dichloride → methylene chloride 95/5 is a moving phase).
ESI-MS(ESI
-):380(M-1H)
-
Embodiment 184: N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-phenyl }-succinamic acid
With 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-aniline (1 equivalent) is dissolved in the methylene dichloride, adds 4-methylmorpholine (2 equivalent) and succinyl oxide (2 equivalent).After at room temperature reacting 16 hours,, obtain pure target product through silica gel column chromatography (methylene dichloride → methylene chloride 90/10 is a moving phase) purifying.
ESI-MS(ESI-):(M-1H)
-:480(M-1H)
-
Embodiment 185: 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-phenyl }-methyl alcohol
4-ethynyl-2-trifluoromethyl-biphenyl
Under inert atmosphere and 50 ℃ of conditions, in the benzole soln of 4-bromo-2-trifluoromethyl aniline (1 equivalent), add n-amyl nitrite (1 equivalent).Reflux after 1 hour, add the n-amyl nitrite of another equivalent.After refluxing again 2 hours, reaction mixture is cooled to room temperature and concentrating under reduced pressure.Adopting hexanaphthene → cyclohexane/ethyl acetate 9/1 is moving phase, and the residue of dark color through silica gel purification, is obtained 4-bromo-2-trifluoromethyl-biphenyl (light orange oily matter).
Under argon gas atmosphere, 4-bromo-2-trifluoromethyl-biphenyl (1 equivalent) is dissolved in toluene/triethylamine (4/1), add CuI (0.33 equivalent) and Pd (Ph
3P)
2Cl
2(0.42 equivalent) placed 20 minutes down at 60 ℃.Then, in reaction mixture, drip trimethyl silane ethyl-acetylene (11.6 equivalent).Reaction mixture is cooled to room temperature, by Hyflo Super Cel in reaction under 60 ℃ after 18 hours
Filter, with saturated NH
4Cl aqueous solution extraction 3 times.Organic layer is through Na
2SO
4Drying concentrates, and adopt cyclohexane give be eluent through silica gel purification, obtain light brown liquid, trimethylammonium-(2-trifluoromethyl-biphenyl-4-ethyl-acetylene base)-silane.
Trimethylammonium-(2-trifluoromethyl-biphenyl-4-ethyl-acetylene base)-silane is dissolved among methyl alcohol/1N NaOH (4/1), at room temperature kept 1 hour.After methyl alcohol is removed in decompression, residue is dissolved in methylene dichloride, with rare HCl aqueous solution extraction.Organic phase is through Na
2SO
4Drying is filtered and is concentrated, and obtains the 4-ethynyl-2-trifluoromethyl-biphenyl into light brown liquid.
4-bromo-benzaldoxime
At room temperature, in the ethanolic soln of 4-bromobenzaldehyde (1 equivalent), add K
2CO
3(1.1 equivalent) and hydroxylamine hydrochloride (1 equivalent).After at room temperature reacting 18 hours, reaction mixture is filtered and concentrating under reduced pressure.Crystalline residue is dissolved in methylene dichloride, with rare HCl aqueous solution dilution.Aqueous solution ethyl acetate extraction merges organic phase, through Na
2SO
4Drying is filtered and is concentrated.Crystalline light brown residue (4-bromo-benzaldoxime) need not to be further purified and is used to form different azoles.
3-(4-bromo-phenyl)-5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles
Under 0 ℃, in the dichloromethane solution of 4-ethynyl-2-trifluoromethyl-biphenyl (1 equivalent), add 10% the NaOCl aqueous solution.Then, add 4-bromo-benzaldoxime (1.1 equivalent) (b), at room temperature stirred subsequently 1 hour.Use the methylene dichloride diluted reaction mixture, water extraction 3 times.Organic layer is through Na
2SO
4Drying is filtered and is concentrated.In methyl alcohol, obtain pure 3-(4-bromo-phenyl)-5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles (light brown crystal) behind the recrystallization.
4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-phenyl }-methyl alcohol
According to the method for preparing 3-(4-bromo-phenyl)-5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles, replace 4-bromo-benzaldoxime with 4-hydroxymethyl-benzaldoxime, the preparation target compound.
ESI-MS(ESI
+):396(M+1H)
+
Embodiment 186: 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzylamine
Methylene dichloride/CCl to the end product of embodiment 185 { 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-phenyl }-methyl alcohol (1 equivalent)
4Add sodiumazide (1.2 equivalent) and triphenyl phosphine (2.1 equivalent) in 1/4 solution.Reflux after 6 hours, reaction mixture is cooled to room temperature, dichloromethane extraction 3 times are used in the water cancellation.With methylene dichloride is moving phase, with crude product (trinitride) through silica gel purification.The intermediate (trinitride) of purifying is dissolved in methyl alcohol, under normal pressure, uses Pd/C
10%Hydrogenation all disappears up to starting raw material as catalyzer.Then, reaction mixture is passed through Hyflo Super Cel
Filter, concentrate, and adopt methylene chloride/acetate
50%9/1/0.125 be eluent,, obtain target compound (acetate) into light yellow lyophilized powder (lyophilisate) through silica gel purification.
ESI-MS(ESI
+):395(M+1H)
+
Embodiment 187: 4-[5-2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzenesulfonyl-amino }-propionic acid
4-ethynyl-2-trifluoromethyl-biphenyl
Under inert atmosphere, reach under 50 ℃ of conditions, in the benzole soln of 4-bromo-2-trifluoromethyl aniline (1 equivalent), add n-amyl nitrite (1 equivalent).Reflux after 1 hour, add the n-amyl nitrite of another equivalent.After refluxing again 2 hours, reaction mixture is cooled to room temperature and concentrating under reduced pressure.Dark residue obtains 4-bromo-2-trifluoromethyl-biphenyl (light orange oily matter) through silica gel purification (adopting hexanaphthene → cyclohexane/ethyl acetate 9/1 is moving phase).
Under argon gas atmosphere, 4-bromo-2-trifluoromethyl-biphenyl (1 equivalent) is dissolved in toluene/triethylamine (4/1), add CuI (0.33 equivalent) and Pd (Ph
3P)
2Cl
2(0.42 equivalent) kept 20 minutes at 60 ℃.Then, in reaction mixture, drip trimethyl silane ethyl-acetylene (11.6 equivalent).After 18 hours, reaction mixture is cooled to room temperature, 60 ℃ of reactions by Hyflo Super Cel
Filter, with saturated NH
4Cl aqueous solution extraction 3 times.Organic layer is through dried over sodium sulfate, concentrate, and to adopt hexanaphthene is the eluent silica gel purification, obtains light brown liquid (trimethylammonium-(2-trifluoromethyl-biphenyl-4-ethyl-acetylene base)-silane).
Trimethylammonium-(2-trifluoromethyl-biphenyl-4-ethyl-acetylene base)-silane is dissolved in methyl alcohol/1N NaOH (4/1), at room temperature kept 1 hour.After methyl alcohol is removed in decompression, residue is dissolved in methylene dichloride, with rare HCl aqueous solution extraction.Organic phase is filtered and is concentrated through dried over sodium sulfate.Obtain light brown liquid.
3-[4-(oxyimino-methyl)-benzenesulfonyl amino]-methyl propionate
At room temperature, in the anhydrous pyridine solution of 4-cyano group-benzene sulfonyl chloride (1 equivalent), add H-β-Ala-OMe (1 equivalent).After at room temperature reacting 1 hour,, residue is dissolved in ethyl acetate, tucks in extraction with rare HCl is water-soluble with the reaction mixture concentrating under reduced pressure.Organic phase is filtered and is concentrated through dried over sodium sulfate.Honey sample light brown residue (3-(4-cyano group-benzenesulfonyl amino)-methyl propionate) need not any being further purified and can be used for step b).
3-(4-cyano group-benzenesulfonyl amino)-methyl propionate (1 equivalent) is dissolved in formic acid (75%), and (FLUKA 83440 to add Ra-Ni; 4 equivalents).After 3 hours, reaction mixture is passed through HyfloSuper Cel 100 ℃ of reactions
Filter, with catalyzer/Hyflo Super Cel
With washing with alcohol 2 times (careful → inflammable).With the solution concentration that obtains, need not any being further purified and to be used for step 3).
Hydroxylamine hydrochloride (1.25 equivalent) is water-soluble, add NaHCO
3(1.9 equivalent).After at room temperature reacting 30 minutes, add the step 2 be dissolved in methyl alcohol) end product.After at room temperature reacting 2 hours, reaction mixture is concentrated residue ethyl acetate extraction 3 times.The organic phase that merges is filtered and is concentrated through dried over sodium sulfate.Purifying (flash chromatography; Silica gel; Methylene chloride 95/5 is a moving phase) after, separate obtaining target compound.
3-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzene sulfo group amino }-propionic acid
At 0 ℃, in the dichloromethane solution of 4-ethynyl-2-trifluoromethyl-biphenyl (1 equivalent), add 10% the NaOCl aqueous solution.Add 3-[4-(oxyimino-methyl)-benzenesulfonyl amino then]-methyl propionate (1.1 equivalent), at room temperature stirred 1 hour.Use the methylene dichloride diluted reaction mixture, and water extracts 3 times.Merge organic layer,, filter and concentrate through dried over sodium sulfate.
Carry out saponification with the ester that obtains is following:
LiOH (1.6 equivalent) is dissolved in methanol (1/1), adds ester (1 equivalent).After 4 hours, methyl alcohol is removed in decompression 50 ℃ of reactions, with 1N HCl with pH regulator to~3, with reaction mixture with ethyl acetate extraction 3 times.The organic layer that merges filters through dried over sodium sulfate, concentrates and through silica gel purification (methylene chloride 95/5 is a moving phase).
ESI-MS(ESI
-):515(M-1H)
-
Embodiment 188: 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-aniline
3-(4-nitro-phenyl)-5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles
According to the method for preparing 3-(4-bromo-phenyl)-5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles, replace 4-bromo-benzaldoxime with 4-nitro-benzaldoxime, the preparation target compound.
ESI-MS(ESI
+):411(M+1H)
+
4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-aniline
3-(4-nitro-phenyl)-5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles is dissolved in methanol/ethyl acetate 1/1, uses Pd/C under the room temperature normal pressure
10%As catalyzer hydrogenation 16 hours.By Hyflo Super Cel
After the filtration, reaction mixture is concentrated, through silica gel purification (methylene dichloride → methylene chloride 95/5 is a moving phase).Separate 4-[5-(2-trifluoromethyl-biphenyl-4-the yl)-different azoles-3-yl that obtains to brown oil]-aniline.
ESI-MS(ESI
+):381(M+1H)
+
Embodiment 189: N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-phenyl }-succinamic acid
With 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-aniline is dissolved in the methylene dichloride, adds 4-methylmorpholine (2 equivalent) and succinyl oxide (2 equivalent).After at room temperature reacting 16 hours, separate (methylene dichloride → methylene chloride 90/10 is a moving phase), obtain pure target product through silica gel column chromatography.
ESI-MS(ESI):(M-1H)
-:479(M-1H)
-
Embodiment 190: (R)-2-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzenesulfonyl amino }-propionic acid
4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzene sulfonyl chloride
[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-aniline (1 equivalent) is dissolved in the acetonitrile, adds HCl (concentration 37%) and NaNO
2Behind the aqueous solution (1.5 equivalent), reaction mixture was kept 30 minutes down for 8 ℃.In this reactant, add saturated SO
2Glacial acetic acid solution (1ml), add CuCl subsequently
2The aqueous solution (0.5 equivalent).After at room temperature reacting 3 hours, leach throw out, be dissolved in the methylene dichloride and through dried over sodium sulfate.Except that after desolvating, obtain target compound into the grey lenticular.
ESI-MS(ESI
+):364(M+1H)
+
With 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzene sulfonyl chloride (1 equivalent) is dissolved among the THF, adds H-DAla-OH (3 equivalent), triethylamine (1 equivalent) and 1N NaOH (2 equivalent).After at room temperature reacting 18 hours, with the reactant dilute with water, with 1NHCl with pH regulator to~3.Behind dichloromethane extraction 3 times, organic layer filters and concentrates through dried over sodium sulfate.Residue is through silica gel purification (methylene chloride/acetate 50%9/1/0.125 is moving phase).
ESI-MS(ESI
+):517(M+1H)
+
Embodiment 191: (S)-2-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzenesulfonyl amino }-propionic acid
With 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzene sulfonyl chloride (1 equivalent) is dissolved among the THF, adds H-Ala-OH (3 equivalent), triethylamine (1 equivalent) and 1N NaOH (2 equivalent).After at room temperature reacting 18 hours, with the reactant dilute with water, with 1N HCl with pH regulator to~3.Behind dichloromethane extraction 3 times, organic layer filters and concentrates through dried over sodium sulfate.Residue is through silica gel purification (methylene chloride/acetate
50%9/1/0.125 be moving phase).
ESI-MS(ESI
+):517(M+1H)
+
Embodiment 192: 4-{5-[4-(2,2,2-three fluoro-oxyethyl groups)-3-trifluoromethyl-phenyl]-different azoles-3-yl }-benzsulfamide
(4-fluoro-3-trifluoromethyl-phenylacetylene base)-trimethylammonium-silane
Synthesize this compound according to method described in the document: organic chemistry magazine (J.Org.Chem.) 46 (11); 1981, the 2283 pages.
4-ethynyl-1-fluoro-2-trifluoromethyl-benzene
The end product of step 1) is according to organic chemistry magazine 46 (11); 1981, the 2283 pages method is reacted.
4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-different azoles-3-yl]-benzsulfamide
Target compound is according to embodiment 183c) method synthetic.
4-{5-[4-(2,2,2-three fluoro-oxyethyl groups)-3-trifluoromethyl-phenyl]-different azoles-3-yl }-benzsulfamide
With 4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-different azoles-3-yl]-benzsulfamide (1 equivalent) is dissolved among the DMF, adds NaH (2 equivalents; FLUKA62863) after, at room temperature reacted 30 minutes, add 2,2,2-three fluoro-ethanol.After at room temperature reacting 3 hours, reaction mixture is concentrated, handle the back with ether and separate the target compound that obtains to light yellow solid.
ESI-MS(ESI
-):465(M-1H)
-
Embodiment 193: 2-ethyl-4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole 3-yl]-benzsulfamide
4-bromo-2-ethyl-benzsulfamide
In dioxane (60ml) solution of 4-bromo-2-ethyl-benzene sulfonyl chloride (4.4g, 0.015 mole), add dense NH
4OH (6ml) solution.Reaction mixture was at room temperature stirred 2 hours.Removal of solvent under reduced pressure is dissolved in ethyl acetate with the oily matter that obtains.Wash organic layer with water, extraction is through dried over sodium sulfate and concentrated.With the crystalline mixture of ethyl acetate and hexane, separate obtaining required product (4g).
4-cyano group-2-ethyl-benzsulfamide.
In NMP (30ml) solution of 4-bromo-2-ethyl-benzsulfamide (1.0g, 0.004 mole), add CuCN (3.6g, 0.04 mole), reaction mixture was stirred 3 days down at 140 ℃.After making the reaction mixture cooling, add ethyl acetate and water, organic layer washes with water, and extraction is through dried over sodium sulfate and concentrated.Obtain required product (160mg) with flash column chromatography purifying post crystallization.
3-ethyl-N-hydroxyl-4-sulfamyl-benzenyl amidine
In THF (6ml) solution of 4-cyano group-2-ethyl-benzsulfamide (160mg, 0.0007 mole), add azanol (50% the aqueous solution) solution (6ml).Reaction mixture was at room temperature stirred 16 hours.Use the ethyl acetate extraction reaction mixture, wash with water, extraction is through dried over sodium sulfate and concentrated.With ethyl acetate and hexanes mixtures crystallization, separate obtaining required product (140mg).
2-trifluoromethyl-xenyl-4-formic acid
Under inert atmosphere, in THF (200ml) solution of 4-chloro-3-trifluoromethylbenzoic acid (5g, 0.02 mole), add phenyl-boron dihydroxide (5.3g, 0.04 mole), X-Phos (1g, 0.002mol), KF (4g, 0.06 mole) and Pd (OAc)
2Stir reaction mixture 15 hours down at 90 ℃ then (240mg, 0.001).Reaction mixture is concentrated into dried, obtains target compound (5g) with purification by flash chromatography.
2-ethyl-4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-benzsulfamide
Under inert atmosphere; to 2-trifluoromethyl-xenyl-4-formic acid (50mg; 0.0002 add EDC (40mg in DMF (2ml) solution mole); 0.0002 HOBt (30mg mole); 0.0002mol); reaction mixture was at room temperature stirred 15 minutes, add DMF (1ml) solution of 3-ethyl-N-hydroxyl-4-sulfamyl-benzenyl amidine (50mg, 0.0002 mole) then.Reaction mixture was stirred 15 hours down at 90 ℃.Reaction mixture is concentrated into dried, obtains target compound (60mg) with purification by flash chromatography.ESI-MS(ESI
+):474(M+1H)
+
Embodiment 194: 2-ethyl-4-[5-(2 '-fluoro-2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-benzsulfamide
The method used according to embodiment 193, adopt 2 '-fluoro-2-trifluoromethyl-xenyl-4-formic acid replaces 2-trifluoromethyl-xenyl-4-formic acid, makes this compound.
ESI-MS(ESI
-):478(M-1H)
-
Embodiment 195: 2-ethyl-4-[5-(4-phenyl-5-trifluoromethyl-thiophene-2-yl)-[1,2,4] diazole-3-yl]-benzsulfamide
The method used according to embodiment 193 adopts 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid to replace 2-trifluoromethyl-xenyl-4-formic acid, makes this compound.
ESI-MS(ESI
-):478(M-1H)
-
Embodiment 196: 4-[5-(4-cyclohexyl-3-trifluoromethyl-phenyl)-[1,2,4) diazole-3-yl]-2-ethyl-benzsulfamide
The method used according to embodiment 193 adopts 4-cyclohexyl-3-trifluoromethyl-phenylformic acid to replace 2-trifluoromethyl-xenyl-4-formic acid, makes this compound.
ESI-MS(ESI
+):480(M+1H)
+
Embodiment 197: 3-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzenesulfonyl-amino }-propionic acid amide
1) according to embodiment 187 described methods, be raw material with 4-ethynyl-2-trifluoromethyl-biphenyl, preparation 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzenesulfonyl-amino }-propionic acid.
2) with 3-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-different azoles-3-yl]-benzenesulfonyl amino }-propionic acid (1 equivalent) is dissolved among the DMF, adds N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (EDC.HCl subsequently; 1.5 hydroxybenzotriazole (HOBt equivalent); 1.3 NH equivalent),
4OH
25%The aqueous solution (1.2 equivalent) and diisopropylethylamine (1.5 equivalent).After at room temperature reacting 16 hours, reaction mixture concentrated and through silica gel purification (methylene chloride 95/5 → methylene chloride/acetate
50%90/10/0.125 be moving phase), obtain pure target compound.
ESI-MS(ESI
-):514(M-1H)
-
ESI-MS(ESI
+):516(M+1H)
+
Embodiment 198: N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-phenyl }-succinic diamide
1) 5-(4-nitro-phenyl)-3-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole
According to embodiment 183 described methods, be raw material with 2-trifluoromethyl-xenyl-4-formic acid, prepare this compound.
2) 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-aniline
According to embodiment 184 described methods, adopting the compound of step 1) is raw material, prepares this compound.
3) N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-phenyl }-succinamic acid
With step 2) end product (1 equivalent) be dissolved in the methylene dichloride, add 4-methylmorpholine (2 equivalent) and succinyl oxide (2 equivalent).After at room temperature reacting 16 hours,, obtain pure target product through silica gel column chromatography chromatography purification (methylene dichloride → methylene chloride 90/10 is a moving phase).
ESI-MS(ESI
-):(M-1H)
-:480(M-1H)
-
4) N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-phenyl }-succinic diamide
Adopt final step (2) among the embodiment 197) identical method, make target compound.
ESI-MS(ESI
-):479(M-1H)
-
ESI-MS(ESI
+):481(M+1H)
+
Embodiment 199: N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-phenyl }-succinic diamide
A) described method preparation 2-trifluoromethyl-xenyl-4-formic acid: according to embodiment 1a).
B) described method preparation N-4-amino-N-hydroxyl-benzenyl amidine: according to embodiment 1b).
C) 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-aniline: according to embodiment 2f) described method preparation.
D) N-{4-[5-(2-trifluoromethyl-biphenyl 4-yl)-[1,2,4] diazole-3-yl]-phenyl }-succinamic acid: according to embodiment 2g) described method preparation.
E) N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-phenyl }-succinic diamide
Under inert atmosphere, to N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-phenyl }-add EDC (1.3 equivalent) and HOBt (1.3 equivalent) in the THF solution of succinamic acid (1 equivalent), reaction mixture was at room temperature stirred 30 minutes.Then solution of ammonium hydroxide (10 equivalent) is added in the reaction mixture, at room temperature stirred 4 hours.Then reaction mixture is concentrated into driedly, obtains N-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl with purification by flash chromatography]-phenyl }-succinic diamide.m/z=479(M-H)
-。
Embodiment 200: N-methyl-N '-4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-phenyl }-succinic diamide
According to embodiment 199e) in disclosed similarity method, the methanol solution shape that in the end adopts methylamine in the step is for ammonium hydroxide, synthetic this target compound.m/z=493(M-H)
-。
Embodiment 201: N, N-dimethyl-N '-4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,2,4] diazole-3-yl]-phenyl }-succinic diamide
According to top embodiment 199e) in disclosed similarity method, in the end adopt the methanol solution of dimethylamine to replace ammonium hydroxide in the step, synthetic this target compound.m/z=507(M-H)
-。
Embodiment 202: 3-{4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-benzenesulfonyl amino }-propionic acid amide
With 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-aniline (1 equivalent) is dissolved in the acetonitrile, adds HCl (0.55ml then; Concentration 37%) and NaNO
2The aqueous solution (1.5 equivalent) keeps reaction mixture 30 minutes at 8 ℃.In this reactant, add SO
2Glacial acetic acid (1ml) saturated solution, add CuCl subsequently
2The aqueous solution (0.5 equivalent).After at room temperature reacting 3 hours, leach precipitation, be dissolved in methylene dichloride, through dried over sodium sulfate.Except that after desolvating, target compound need not any being further purified can be directly used in next step.
ESI-MS(ESI
+):465(M+1H)
+
With 4-[5-(2-trifluoromethyl-biphenyl-4-yl)-[1,3,4] diazole-2-yl]-benzene sulfonyl chloride (1 equivalent) is dissolved among the THF, adds H-β Ala-NH
2(3 equivalent), triethylamine (1 equivalent) and 1N NaOH (2 equivalent).After at room temperature reacting 18 hours, with the reactant dilute with water, with 1N HCl with pH regulator to~3.Behind dichloromethane extraction (3 times), organic layer filters and concentrates through dried over sodium sulfate.Residue is through silica gel purification (methylene chloride 8/2 is a moving phase).
ESI-MS(ESI
+):517(M+1H)
+
The formula I compound of free form or pharmacy acceptable salt form has valuable pharmacological character, for example is the S1P1 receptor stimulant, and is for example indicated in the experiment in vitro and in vivo, therefore can be used for the treatment of.
A. experiment in vitro
The following formula I compound that experimental results show that has binding affinity to independent human S1P acceptor:
A. experiment in vitro: measure with preparation from the membrane-bound GTP[γ that expresses the Chinese hamster ovary celI of human EDG acceptor-
35S] the GPCR activation experiment
S1P
1(EDG-1) GTP[γ-
35S] in conjunction with testing: self stabilization is expressed the film of the Chinese hamster ovary celI clone preparation homogenizing of human EDG-1N-end c-myc mark.Cell is at two 850cm
2Growth is 3 or 4 days in the suspension in the rolling bottle, collects then.With cell centrifugation, with cold PBS washing 1 time, resuspending is in the buffer A of≤20ml (0mM EDTA does not contain the adequate proteins enzyme inhibitors mixture (cocktail) [1 tablet/25ml] of EDTA for 20mM HEPES, pH7.4).Cell suspending liquid in homogenizing on ice, is adopted the Polytron refiner, rotating speed 30000rpm, homogenize three times, each 15 seconds.At first in the desktop low speed centrifuge with homogenate centrifugal 10 minutes with 2000rpm.Behind the cell nutsche filter, with supernatant liquor under 4 ℃ centrifugal again 25 minutes with 50000 * g.To precipitate (pellet) resuspending in buffer B (pH7.4,0.1mM EDTA does not contain the adequate proteins enzyme inhibitors mixture [1 tablet/10ml] of EDTA for 15% glycerine, 20mM HEPES).Adopting BCA analysis of protein test kit (Pierce) is the protein concn of standard test prepared product with BSA.With the film five equilibrium and place-80 ℃ freezing.
The preparation concentration range is the experimental compound solution of 10mM-0.01nM in DMSO.S1P is diluted as positive control in 4%BSA solution.The membrane product of requirement is adopted ice-cold experiment damping fluid (20mM HEPES, pH7.4,100mM NaCl, 10mM MgCl
2, 0.1% BSA of fatty acids not, 5 μ M GDP) and dilution and abundant vortex.2 μ l or compound still less are distributed in each hole of round bottom 96-hole polystyrene analysis plates, add the membrane product (3-10 μ g/ hole) of 100 μ l dilution subsequently, be placed on ice up to adding hot GTP γ S.With cold experiment damping fluid will [
35S]-GTP γ S dilutes 1: 1000 (v/v), 100 μ l added in each hole.Reaction was at room temperature carried out 90 minutes, with Packard FiltermateHarvester film was collected in Perkin-Elmer Unifilter then
On the GF/B-96 filter membrane.With lavation buffer solution (20mM HEPES, pH7.4,100mM NaCl, 10mM MgCl
2) after the washing for several times, use 95% alcohol flushing, with filter membrane drying 30 minutes in 37 ℃ of following baking ovens.Add MicroScint-20, film phonograph seal is used for scintillation counting on TopCount.By with the dose response curve match instrument match GTP[γ of GraphPad Prism-
35S] binding curve (raw data) can obtain EC
50Value.Produce concentration-response curve (each concentration adopts three data points) with 6 or 12 different concentration.
According to S1P1 GTP[γ-
35S] in conjunction with the experiment similar methods carry out S1P3 ,-5 ,-6 and-8GTP[γ-
35S] in conjunction with experiment, use film in the experiment by the Chinese hamster ovary celI preparation of stably express c-end c-myc mark or unlabelled acceptor.For each membrane product, at first adopt the S1P contrast to carry out titration experiments, to determine to be added to the optimum quantity that each analyzes the film in the hole.
According to above-mentioned experiment formula I compound is measured, shown that it has binding affinity, its EC to S1P acceptor (for example S1P1 acceptor)
50<1 μ M.Particularly, formula I compound has selectivity to the S1P1 acceptor.For example, in above-mentioned S1P1 receptors bind experiment, the EC of embodiment 45,54,145,194 and 196 compounds
50<1nM, and be 20 times of S1P3 acceptor at least to the selectivity of S1P1 acceptor is 20 times of S1P8 acceptor at least to the selectivity of S1P1 acceptor.
B. experiment in vitro: FLIPR calcium flux experiment
With the agonist activity of FLIPR calcium flux experiment test formula I compound to S1P1, S1P3, S1P5 and S1P6.In brief, the Chinese hamster ovary celI of expressing the S1P acceptor is placed the F-12K substratum (ATCC) that contains 5%FBS and 500 μ g/mlG418.Before experiment is carried out, with cell with the concentration distribution of 10000 cells/well/25 μ l substratum in the plate at the bottom of 384 black transparents, described substratum is the F-12K substratum that contains 1%FBS.Second day, cell is washed 3 times (25 μ l/ are each) with lavation buffer solution.Add about 25 μ l staining agents in every hole, at 37 ℃, 5%CO
2Cultivated 1 hour under the condition.Then cell is washed 4 times (25 μ l/ are each) with lavation buffer solution.After in the cell in every hole, adding the SEW2871 solution (Rosen etc. are disclosed, with comparing) of 25 μ l, analyze the calcium flux.The cell of expressing various different S1P acceptors is respectively carried out same analysis.Titration in the FLIPR calcium flux experiment of the 3 minutes records in every interval, quantitative with the maximum peak height percentage responses of comparing with the S1P-1 activation.In this experiment, formula I compound is 10
-12To 3.10
-5Has activity in the concentration range of nM.
C. experiment in the body: measure the screening experiment that blood lymphocytes is subdued
The mensuration of circulation medium size lymphocyte: will treat that experimental compound is dissolved among the DMSO/PEG200, dilutes with deionized water again.With treat experimental compound with the dosed administration of 1mg/kg to rat (Lewis strain, female, 6-12 age in week), the dosage of molten coal is 4ml/kg (the highest 2% DMSO, the highest 2% PEG200/ water), and oral administration.DMSO/PEG200/ water and FTY720 (0.3mg/kg) are respectively as negative control and positive control.
After the administration 2,6,24 and 48 hours, under fugitive different fluorine is washed anesthesia, get blood from sublingual vein.All blood samples is carried out analysis of Hematology Changes.Measure the periphery lymphocyte number with automatic analyser.With fluorescence dye-conjugated specific antibody dyeing lymphocyte subpopulation, analyze with the cell sorter (Facscalibur) of fluorescence-activation.Measure the lymphocyte of each compound of screening with two rats and subdue activity.The result is with ED
50Expression, it is defined as blood lymphocyte and subdues 50% needed effective dose.According to above-mentioned experiment formula I compound is tested, the result shows its ED
50Less than 10mg/kg.
Therefore, formula I compound can be used for treating and/or preventing disease or the illness by the lymphocytes interactions mediation, for example in transplanting, of the same race-or xenograft rejection reaction or graft function delayed recovery, the graft versus host disease (GVH disease) of for example acute or chronic cell, tissue or organ; Autoimmune disorder, for example rheumatoid arthritis, systemic lupus erythematous, struma lymphomatosa, multiple sclerosis, myasthenia gravis, I or type ii diabetes and diseases related thereof, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriatic, Graves illness in eye, alopecia areata etc.; Anaphylactic disease, for example allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis; The optional inflammatory diseases relevant with potential abnormal response, inflammatory bowel for example, Crohn's disease or ulcerative colitis, intrinsic asthma, the inflammatory injury of lung, the inflammatory liver injury, the inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis also comprises eczematoid dermatitis in addition, seborrheic dermatitis, the skin presentation of immune induction disease, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis (for example acute or chronic hepatitis), local asphyxia/reperfusion injury (myocardial infarction for example, apoplexy, the stomach and intestine ischemic, renal failure, hemorrhagic shock or traumatic shock); Cancer, for example mammary cancer, t cell lymphoma or T chronic myeloid leukemia, nephrotic syndrome; Infectious diseases, for example toxic shock (for example superantigen causes), septic shock, adult respiratory distress syndrome or virus infection, AIDS for example, viral hepatitis (for example hepatitis B or C), chronic bacterial infection; Or neurodegenerative disease, for example Alzheimer, amyotrophic lateral sclerosis or senile dementia.The example of cell, tissue or solid organ transplantation thing comprises for example pancreas islet, stem cell, marrow, cornea tissue, neuronal tissue, heart, lung, the heart and lung, kidney, liver, intestines, pancreas, tracheae or oesophagus.For such use, required dosage changes according to administering mode, particular disorder and institute's phase curative effect to be treated certainly.
Can obtain systemic gratifying result when usually, per daily dose is about the 0.03-5.0mg/kg body weight.For large mammal (for example human), the per daily dose of recommendation is about 0.5mg to about 500mg, and the administration easily of this dosage is for example with the every day at the most of 4 times divided dose or with the slowly-releasing form administration.The suitable unit dosage that is used for oral administration comprises about 0.1-50mg activeconstituents.
Formula I compound can be by administration in any the conventional route administration, particularly intestines, and oral administration for example is for example with tablet or capsule form; Or administered parenterally, for example with the form administration of Injectable solution or suspension; Topical is for example with the form of lotion, gel, paste or ointment; Perhaps with in the nose or the form administration of suppository.Can be with ordinary method by producing pharmaceutical composition with pharmaceutically acceptable carrier or mixing diluents, this pharmaceutical composition comprises formula I compound and at least a pharmaceutically acceptable carrier or the thinner of free form or pharmacy acceptable salt form.
Formula I compound can be with aforesaid free form or pharmacy acceptable salt form administration.This type of salt can prepare with ordinary method, and has the activity with the free cpds same levels.
According to noted earlier, the present invention also provides:
1.1 prevention or treatment need the disease of the cell mediated among the patient of this treatment or the method for illness (for example above-mentioned), this method comprises the formula I compound of significant quantity or its pharmacy acceptable salt is administered to described patient;
1.2 prevention or treatment need the cell-mediated inflammatory of acute or chronic allograft rejection among the patient of this treatment or T-or the method for autoimmune disorder (for example above-mentioned), this method comprises the formula I compound of significant quantity or its pharmacy acceptable salt is administered to described patient;
2. the formula I compound that exists with free form or pharmacy acceptable salt form, its for example in the above 1.1 or 1.2 be used as medicine in described any methods down.
3. pharmaceutical composition, 1.1 or 1.2 pharmaceutical compositions that use in described any method down in the above for example, this pharmaceutical composition comprises the formula I compound and the pharmaceutically acceptable diluent or carrier of free form or pharmacy acceptable salt form.
4. be used for preparing formula I compound or its pharmacy acceptable salt of the medicinal compositions that uses in top 1.1 or 1.2 any methods.
Formula I compound can be separately as delivery of active ingredients or for example as adjuvant and other medicines Combined Preparation, described other medicines are: for example immunosuppressor or other immunomodulator or other anti-inflammatory drug, they are used for for example treating or prevent of the same race-or heteroplastic acute or chronic rejection or inflammatory or autoimmune disorder, perhaps be chemotherapeutics, for example malignant cell anti-proliferative drugs.For example, formula I compound can use with following drug regimen: calcinerin inhibitor, for example cyclosporin A or FK506; MTOR inhibitor, for example rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, biolimus-7 or biolimus-9; Ascosin with immunosuppression performance, for example ABT-281, ASM981 etc.; Reflunomide; Endoxan; Azathioprine; Methotrexate; Leflunomide; Mizoribine; Mycophenolic acid or salt; Mycophenolate mofetile; The smart guanimycin (15-deoxyspergualine) of 15-deoxidation or its immunosuppression homologue, analogue or derivative; Pkc inhibitor, for example disclosed among WO02/38561 or the WO03/82859, for example embodiment 56 or 70 compounds; The JAK3 kinase inhibitor, N-benzyl-3 for example, 4-dihydroxyl-benzylidene-malonamide nitrile alpha-cyano-(3, the 4-dihydroxyl)-] N-benzyl cinnamide (Tyrphostin AG 490), prodigiosin 25-C (PNU156804), [4-(4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] (WHI-P131), [4-(3 '-bromo-4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] (WHI-P154), [4-(3 ', 5 '-two bromo-4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] WHI-P97, KRX-211,3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-amino]-piperidines-1-yl }-3-oxo-propionitrile (form of free form or pharmacy acceptable salt, list-Citrate trianion (being also referred to as CP-690,550) for example) disclosed compound or among WO04/052359 or the WO05/066156; The immunosuppression monoclonal antibody, for example, the monoclonal antibody of leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their part; Other immunomodulatory compounds, the reorganization binding molecule or its mutant that for example have the part of CTLA4 extracellular domain at least, for example with the extracellular domain at least of non--CTLA4 protein sequence bonded CTLA4 part or its mutant, for example CTLA4Ig (for example ATCC 68629) or its mutant, for example LEA29Y; Adhesion molecule inhibitor, for example LFA-1 antagonist, ICAM-1 or-3 antagonists, VCAM-4 antagonist or VLA-4 antagonist; Or chemotherapeutics, for example taxol, gemcitabine, cis-platinum, Dx or 5 FU 5 fluorouracil; Or anti-infectives.
When formula I compound and other immunosuppressor/immunomodulator, anti-inflammatory drug, chemotherapeutics or anti-infective therapy's Combined Preparation, the dosage of the immunosuppressor of co-administered, immunomodulator, anti-inflammatory, chemotherapy or anti-infective compounds can change according to the type (for example being steroid or calcinerin inhibitor) of the medicine of co-administered, the concrete medicine of administration, illness to be treated etc. certainly.According to aforementioned, on the other hand, the invention provides:
5. method as hereinbefore defined, this method comprises that described another kind of medicine for example is immunosuppressor recited above, immunomodulator, anti-inflammatory drug or chemotherapeutics with the treatment formula I compound of effective nontoxic amount and another kind of at least medicine co-administered (for example while or successively).
6. pharmaceutical combination product, medicine box (kit) for example, this pharmaceutical combination product comprises a) first kind of medicine, it is the formula I compound of free form disclosed herein or pharmacy acceptable salt form, and b) medicine of at least a co-administered, for example immunosuppressor, immunomodulator, anti-inflammatory drug, chemotherapeutics or anti-infectives.Described medicine box can comprise its administration specification sheets.
The term that this paper adopted " co-administered " or " carefully closing administration " or similar terms are meant that the medicine that comprises selected is administered to single patient, and comprise treatment plan, and its Chinese traditional medicine is not must be by identical route of administration or administration at the same time.
Term used herein " pharmaceutical combination product " is meant by the product that mixes or combination various active composition obtains, and it comprises the fixing of activeconstituents and on-fixed combination.Term " fixed combination " is meant activeconstituents (for example medicine of formula I compound and co-administered) is delivered medicine to the patient simultaneously with single entity or formulation.Term " on-fixed combination " is meant that wherein this type of administration provides two kinds of compounds of treatment level of significance in patient's body with activeconstituents (for example medicine of formula I compound and co-administered) with independent entity simultaneously and deposit ground or (do not have specific time limitation ground) successively and be administered to the patient.The latter also is used for cocktail (cocktail) therapy, for example gives 3 kinds or more kinds of activeconstituents.
Claims (9)
1. hydrolyzable derivative, salt, hydrate and/or solvate on formula I compound or its physiology:
Wherein:
X is-N=and Y be-O-; Or X be-O-and Y be-N=; Or X is that CH and Y are O;
R
1Be xenyl, 4-phenoxy group-phenyl or the 4-(phenyl-C that replaces
1-4Alkoxyl group)-and phenyl, wherein at least one phenyl group is mono-substituted; By the phenyl that one or more substituting groups that are selected from following groups replace, described group is: halogen, itrile group, C
1-8Alkyl, halo C
1-8Alkyl, C
1-8Alkoxyl group, halo C
1-8Alkoxyl group, C
1-8Alkoxy-C
1-8Alkoxyl group, C
1-8Alkyl-C
1-8Alkoxyl group, C
1-8Alkyl-halo C
1-8Alkoxyl group, halo C
1-8Alkyl-C
1-8Alkoxyl group, halo C
1-8Alkyl-halo C
1-8Alkoxyl group, halo C
1-8Alkoxy-C
1-8Alkoxyl group, C
1-8Alkoxyl group-halo C
1-8Alkoxyl group, halo C
1-8Alkoxyl group-halo C
1-8Alkoxyl group, C
1-8Alkoxy-C
1-8Alkyl, halo C
1-8Alkoxy-C
1-8Alkyl, C
1-8Alkoxyl group-halo C
1-8Alkyl, halo C
1-8Alkoxyl group-halo C
1-8Alkyl, C
2-6Thiazolinyl oxygen base, C
2-6Alkynyloxy base, C
3-6Cycloalkyl, C
3-6Cycloalkyl-C
1-4Alkyl, C
3-6Cycloalkyl-C
1-4Alkoxyl group, C
3-6Cycloalkyl-oxygen base, phenyl-C
1-4Alkoxyl group and heterocycle-C
1-4Alkoxyl group; Or 5 or the 6-that replace unit heteroaryl;
R
2For choosing wantonly by halogen, OH, NH
2, C
1-4Alkoxyl group or C
1-4The C that the alkyl-carbonyl oxygen base replaces
1-6Alkyl; Amino; Carboxyl; Sulfamyl; Formamyl; Or HN-CO-C
1-4Alkyl; Perhaps
R
2Be R
3-R
4-COOH or R
3-R
4-CONR
5R
6,
R wherein
3Be SO
2-NH, SO
2-N (C
1-4Alkyl), CO-NH, CO-N (C
1-4Alkyl), CH
2-O, NH-CO or N (C
1-4Alkyl) CO; And R
4For choosing wantonly by O, S or C=CH
2C at interval
1-6Alkylidene group perhaps is optional phenylene or the C that replaces
3-6Cycloalkylidene; R
5And R
6Be hydrogen or C independently of one another
1-6Alkyl, perhaps R
5And R
6Form heterocyclic radical with their bonded nitrogen-atoms, and
Ring A can choose wantonly and be substituted,
Prerequisite be when Y be O, X for-N=or-CH=and R
2Be R wherein
4Be side chain C
1-6The SO of alkylidene group
2NH-R
4During-COO, then
I.R
1Be not by halogen, C
1-8Alkyl, C
1-8Alkoxyl group, halo C
1-8Alkyl or halo C
1-8The mono-substituted phenyl of alkoxyl group or be selected from halogen, C by one or two
1-8Alkyl and C
1-8The dibasic phenyl of the substituting group of alkoxyl group; Perhaps
Ii.R
1Be not mono-substituted thienyl or furyl.
2. according to the compound of claim 1, R wherein
1Be xenyl, 4-phenoxy group-phenyl or the 4-(phenyl-C that replaces
1-4Alkoxyl group)-and phenyl, wherein at least one phenyl group is mono-substituted.
3. according to the compound of claim 1 or 2, R wherein
2For choosing wantonly by halogen, OH, NH
2, C
1-4Alkoxyl group or C
1-4The C that the alkyl-carbonyl oxygen base replaces
1-6Alkyl; Amino; Carboxyl; Sulfamyl; Formamyl or HN-CO-C
1-4Alkyl.
4. preparation is according to the method for the formula I compound of claim 1, and this method comprises:
A) X is in order to prepare wherein-N=, Y are O and R
2Formula I compound as defined above,
Make formula II compound
Wherein encircle A and R
2As defined in claim 1,
With formula III compound or its functional group derivant reaction
R wherein
1As defined above; Or
B) X is in order to prepare wherein-N=, Y are O and R
2Be R
3-R
4-COOH or R
3-R
4-CONR
5R
6, R wherein
3Be NH-CO or N (C
1-4Alkyl) CO and R
4, R
5And R
6Formula I compound as defined in claim 1,
Make formula IV compound
R wherein
1With the ring A as defined in claim 1, R '
2Be NH
2Or NH (C
1-4Alkyl), with the acylating reagent reaction, perhaps carry out the Sandmeyer reaction; Or
C) be the formula I compound of O in order to prepare wherein Y for-N=and X,
In the presence of Burgess reagent, make the cyclisation of formula V compound,
R wherein
1, R
2With the ring A as defined in claim 1; Or
D) Y is that O and X are the formula I compound of CH in order to prepare wherein,
Make formula VI compound
R wherein
1As defined in claim 1,
With the reaction of formula VII compound,
R wherein
2Such as power require in 1 definition; Perhaps
E) a kind of formula I compound is converted into another kind of formula I compound,
And reclaim the free form obtain or the formula I compound of salt form, and if necessary, the formula I compound of the free form that obtains is converted into required salt form, perhaps, the formula I compound of the salt form that obtains is converted into required free form.
5. according to any one formula I compound or its pharmacy acceptable salt among the claim 1-3, it is as medicine.
6. pharmaceutical composition, this pharmaceutical composition comprise according among the claim 1-3 any one formula I compound or its pharmacy acceptable salt with and pharmaceutically acceptable diluent or carrier.
7. according to any one formula I compound or its pharmacy acceptable salt among the claim 1-3, be used to prepare prevention or treatment pharmaceutical composition by the disease or the illness of cell mediated.
8. the combined prod of medicine, this pharmaceutical combination product comprises a) first kind of medicine, it is according to the free form of any one or the formula I compound of the form of pharmacy acceptable salt among the claim 1-3, and b) medicine of at least a Combined Preparation, it is immunosuppressor, immunomodulator, anti-inflammatory drug, chemotherapeutics or anti-infectives.
Prevention or treatment need among the patient of this type of treatment by the disease of cell mediated or the method for illness, this method comprises significant quantity is administered to described patient according to formula I compound or its pharmacy acceptable salt of any one among the claim 1-3.
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GB0511684A GB0511684D0 (en) | 2005-06-08 | 2005-06-08 | Organic compounds |
GB0525064.2 | 2005-12-08 | ||
GB0600405.5 | 2006-01-10 |
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CN101747287B (en) * | 2008-12-08 | 2012-02-08 | 中国人民解放军军事医学科学院毒物药物研究所 | 2-oxo-1,3-O-aza-cyclopentane-4-carboxamide derivative and application thereof in preparation of immunosuppressant |
CN102361867A (en) * | 2009-01-23 | 2012-02-22 | 百时美施贵宝公司 | Substituted oxadiazole derivatives as s1p agonists in the treatment of autoimmune and inflammatory diseases |
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2005
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2006
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CN102361867A (en) * | 2009-01-23 | 2012-02-22 | 百时美施贵宝公司 | Substituted oxadiazole derivatives as s1p agonists in the treatment of autoimmune and inflammatory diseases |
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CN103097365B (en) * | 2010-07-08 | 2016-02-24 | 默克塞罗诺股份有限公司 | As 5-(biphenyl-4-base)-3-phenyl-1,2, the 4-oxadiazolyl derivative of the part on sphingosine-1-phosphate (S1P) acceptor |
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