CN103059015A - Bifendate derivative, preparation method and application of bifendate derivative for treating autoimmune disease - Google Patents

Bifendate derivative, preparation method and application of bifendate derivative for treating autoimmune disease Download PDF

Info

Publication number
CN103059015A
CN103059015A CN2011103184677A CN201110318467A CN103059015A CN 103059015 A CN103059015 A CN 103059015A CN 2011103184677 A CN2011103184677 A CN 2011103184677A CN 201110318467 A CN201110318467 A CN 201110318467A CN 103059015 A CN103059015 A CN 103059015A
Authority
CN
China
Prior art keywords
alkyl
independently
alkoxyl group
cycloalkyl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN2011103184677A
Other languages
Chinese (zh)
Other versions
CN103059015B (en
Inventor
陈俐娟
魏于全
罗有福
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan University
Original Assignee
Sichuan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan University filed Critical Sichuan University
Priority to CN201110318467.7A priority Critical patent/CN103059015B/en
Publication of CN103059015A publication Critical patent/CN103059015A/en
Application granted granted Critical
Publication of CN103059015B publication Critical patent/CN103059015B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention belongs to the chemical medicine technical field, and especially relates to a bifendate derivative, a preparation method and an application of the bifendate derivative for treating autoimmune disease. A structure of the bifendate derivative is shown as a formula I, and has good effects for inhibiting autoimmune diseases such as acute hepatitis, chronic hepatic fibrosis and pulmonary fibrosis, and the bifendate derivative provides a new choice for medicines exploitation for treating the diseases.

Description

Biphenylylmethylcarbinol derivative, preparation method and the application in the treatment autoimmune disorder thereof
Technical field
The invention belongs to chemical medical technical field, particularly Biphenylylmethylcarbinol derivative, preparation method and the application in the treatment autoimmune disorder thereof.
Background technology
Biphenylylmethylcarbinol (4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group-2,2 '-biphenyl dicarboxylic acid methyl esters) be the analogue of the Wuweizisu C of synthetic, prove through pharmacological evaluation, the high serum glutamic pyruvic transminase effect of mouse that has reduction tetracol phenixin and thioacetamide to cause now is used for the treatment of acute, chronic hepatitis clinically.
Study discovery by the metabolism to Biphenylylmethylcarbinol, Biphenylylmethylcarbinol is in gi tract and be not destroyed, and absorbs seldom, only has about 20%.Experimental results show that rat, mouse, and normal people's oral bifendate starch suspension or tablet after, bioavailability only 25～30%.Clinical study shows that Biphenylylmethylcarbinol has powerful restraining effect to the gpt in the liver; so after the medication in the serum gpt can drop at short notice normally; but the recovery that does not normally represent hepatic disease of gpt or normal in the serum; patient should process for curing by hepatitis; so patient by " knock-on " phenomenon often occurring, can not reach good curative effect in drug withdrawal.5-α-tolylene-2; the 4-thiazolidinediones is that our previous research has a compounds (patent of invention: 5-α-tolylene-2 for the treatment of hepatitis gravis; 4-thiazolidine diketone derivative and its production and use; application number: 201010530519.2); experimentation on animals shows that this compound plays a role by transferring the body specific immune function; suppress the inflammatory cytokine secretion, thereby hepatocellular apoptosis is then played a protective role.
Utilize Biphenylylmethylcarbinol anti-inflammatory ability and 5-α-tolylene-2, the hepatocellular effect of significant protection of 4-thiazolidinedione, we link to each other these two compounds according to twin medicine principle design with ester bond.Can improve pharmacokinetic property on the one hand, improve bioavailability.Medicine can be become this two prototype medicines by enzymic hydrolysis in vivo on the other hand.Utilize efficient effect of reducing enzyme levels and the 5-α-tolylene-2 of Biphenylylmethylcarbinol, the 4-thiazolidine dione compounds suppresses the effect of liver injury, thereby the performance synergy plays better result for the treatment of.
Summary of the invention
First technical problem to be solved by this invention provides a class Biphenylylmethylcarbinol derivative, and structure is suc as formula shown in the I:
Wherein, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000022
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000023
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Preferably, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000024
And have at least a substituting group to be among R6～R10 Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure BDA0000100150240000031
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000032
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H or C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group; R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000033
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000034
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H or C1～C4 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group; R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000035
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000036
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group, And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000038
Having a substituting group among R6～R10 at least is C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group, And only has one among R6～R10
Figure BDA0000100150240000042
Having a substituting group among R6～R10 at least is that C4～C8 contains the tertiary carbon alkyl.
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group, And only has one among R6～R10
Figure BDA0000100150240000044
Having a substituting group among R6～R10 at least is that C4～C8 contains the tertiary carbon alkyl.
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl,
Figure BDA0000100150240000045
And only has one among R6～R10
Figure BDA0000100150240000046
Having a substituting group among R6～R10 at least is the tertiary butyl.
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently be H, the tertiary butyl,
Figure BDA0000100150240000047
And only has one among R6～R10 Having a substituting group among R6～R10 at least is the tertiary butyl.
Further, Biphenylylmethylcarbinol derivative of the present invention, structure is suc as formula shown in the II:
Figure BDA0000100150240000051
Wherein, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R9 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000052
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000053
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Preferably, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000054
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000055
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure BDA0000100150240000056
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000061
R11 is H or C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000062
And have at least a substituting group to be among R6～R10
R11 is H or C1～C4 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000064
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000065
R11 is H.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group, And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000067
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R9 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure BDA0000100150240000068
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000069
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R9 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group, And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000072
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R9 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl,
Figure BDA0000100150240000073
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000074
Further, Biphenylylmethylcarbinol derivative of the present invention, structure is shown in formula III:
Wherein, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R8, R10 independently are H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group, And have at least a substituting group to be among R6～R10
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Preferably, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000081
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000082
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure BDA0000100150240000083
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000084
R11 is H or C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000085
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000086
R11 is H or C1～C4 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group, And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000088
R11 is H.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000091
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000092
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R8, R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure BDA0000100150240000093
And have at least a substituting group to be among R6～R10
Figure BDA0000100150240000094
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R8, R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure BDA0000100150240000095
And only has one among R6～R10
Figure BDA0000100150240000096
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R8, R10 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl,
Figure BDA0000100150240000097
And only has one among R6～R10
Figure BDA0000100150240000098
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H; R6～R8, R10 independently be H, C1～C2 alkoxyl group,
Figure BDA0000100150240000099
And only has one among R6～R10
Figure BDA00001001502400000910
Further, Biphenylylmethylcarbinol derivative of the present invention, structure is suc as formula shown in the IV:
Figure BDA0000100150240000101
Wherein, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently are H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000102
And has one among R6～R10 at least
Figure BDA0000100150240000103
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Preferably, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group, And has one among R6～R10 at least
Figure BDA0000100150240000105
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure BDA0000100150240000106
And has one among R6～R10 at least
Figure BDA0000100150240000107
R11 is H or C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000111
And has one among R6～R10 at least
Figure BDA0000100150240000112
R11 is H or C1～C4 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000113
And has one among R6～R10 at least
R11 is H.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000115
And has one among R6～R10 at least
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure BDA0000100150240000117
And has one among R6～R10 at least
Figure BDA0000100150240000118
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure BDA0000100150240000119
And only has one among R6～R10
Figure BDA00001001502400001110
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl,
Figure BDA00001001502400001111
And only has one among R6～R10
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H; R6～R7, R9～R10 independently be H, F, Br, C1～C2 alkoxyl group,
Figure BDA0000100150240000122
And only has one among R6～R10
Figure BDA0000100150240000123
Used intermediate when second technical problem to be solved by this invention provides Biphenylylmethylcarbinol derivative shown in the preparation formula I, structure is suc as formula shown in the V:
Figure BDA0000100150240000124
Wherein, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000125
And have at least one to be among R6～R10
Figure BDA0000100150240000126
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Preferably, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000127
And have at least one to be among R6～R10
Figure BDA0000100150240000128
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure BDA0000100150240000131
And have at least one to be among R6～R10
Figure BDA0000100150240000132
R11 is H or C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000133
And have at least one to be among R6～R10
Figure BDA0000100150240000134
R11 is H or C1～C4 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000135
And have at least one to be among R6～R10
Figure BDA0000100150240000136
R11 is H.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure BDA0000100150240000137
And have at least one to be among R6～R10
Figure BDA0000100150240000138
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group, And only have one to be among R6～R10
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group, And only have one to be among R6～R10
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl,
Figure BDA0000100150240000143
And only has one among R6～R10
Figure BDA0000100150240000144
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently be H, the tertiary butyl, And only has one among R6～R10
Figure BDA0000100150240000146
Further, used intermediate during the derivative of Biphenylylmethylcarbinol shown in the preparation formula I, structure is suc as formula shown in the VI:
Figure BDA0000100150240000147
Wherein, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently are H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Preferably, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group;
R11 is H or C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R7, R9～R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group;
R11 is H or C1～C4 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R7, R9～R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group;
R11 is H.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group.
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group for H, F, Br, Cl, C4～C8.
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group for H, F, Br, Cl, C4～C8.
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently are H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl.
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H; R6～R7, R9～R10 independently are H, F, Br, C1～C2 alkoxyl group.
Further, used intermediate during the derivative of Biphenylylmethylcarbinol shown in the preparation formula I, structure is suc as formula shown in the VII:
Wherein, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R8, R10 independently are H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Preferably, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R8, R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R8, R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group;
R11 is H or C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R8, R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group;
R11 is H or C1～C4 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R8, R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group;
R11 is H.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R8, R10 independently are H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group.
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R8, R10 independently contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group for H, F, Br, Cl, C4～C8.
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R8, R10 independently contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group for H, F, Br, Cl, C4～C8.
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R8, R10 independently are H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl.
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H; R6～R8, R10 independently are H, C1～C2 alkoxyl group.
Further, used intermediate during the derivative of Biphenylylmethylcarbinol shown in the preparation formula I, structure is suc as formula shown in the VIII:
Figure BDA0000100150240000171
Wherein, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R9 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Preferably, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R9 independently is H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R9 independently is H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group;
R11 is H or C1～C8 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R9 independently is H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group;
R11 is H or C1～C4 alkyl.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R9 independently is H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group;
R11 is H.
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R9 independently is H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group.
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R9 independently contains tertiary carbon alkyl, C1～C4 straight chain alkoxyl group for H, F, Br, Cl, C4～C8.
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R9 independently contains tertiary carbon alkyl, C1～C4 straight chain alkoxyl group for H, F, Br, Cl, C4～C8
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R9 independently is H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl.
The 3rd technical problem to be solved by this invention provides the preparation method of Biphenylylmethylcarbinol derivative shown in the formula I,
Figure BDA0000100150240000191
Wherein, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure BDA0000100150240000192
And have at least one to be among R6～R10
Figure BDA0000100150240000193
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl;
1) compound a and compound b generation esterification obtain compound V;
2) take Beta-alanine as catalyzer, the aldehyde radical among R6～R10 of compound V becomes 2,4-thiazolidinedione-5-methylene radical with the thiazolidinedione coupling.
Step 1) reaction solvent can be dioxane, methylene dichloride etc.; Used alkali can be triethylamine DIEA, DMAP etc.; Reaction times is 10～20h.
Step 2) used alkali is Beta-alanine, sodium acetate, potassium acetate, KF/Al during coupling 2O 3, piperidines etc.; Reaction solvent is methyl alcohol, ethanol, acetic acid etc.; Temperature of reaction is 100～140 ℃; Reaction times is 2～8h.
The preparation method of compound a is as follows:
Figure BDA0000100150240000201
Wherein, R1～R3, R12, R13 are C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group.
Step (1) compound d places inorganic base aqueous solution to be hydrolyzed, and transfers pH=1～4 to obtain Verbindung;
Step (2) Verbindung places diacetyl oxide to reflux, and obtains compound f;
Step (3) compound f places R1-OH to reflux, and obtains compound g;
Step (4) compound g and sulfur oxychloride reaction obtain compound a.
Step (1) mineral alkali is KOH or NaOH, 80～120 ℃ of hydrolysis heating.Transferring pH reagent is concentrated hydrochloric acid, dilute hydrochloric acid, the vitriol oil, dilute sulphuric acid.
Step (4) solvent is dioxane, toluene, methylene dichloride, tetrahydrofuran (THF), chloroform, and temperature of reaction is reflux temperature.
The 4th technical problem to be solved by this invention provides the purposes of Biphenylylmethylcarbinol derivative shown in formula I～IV, having proved by experiment that NO that the Biphenylylmethylcarbinol derivative shown in the formula I induces LPS is synthetic has obvious restraining effect, can be used in the medicine of preparation treatment autoimmune disorder.
Described autoimmune disorder can be acute hepatitis, hepatic fibrosis or pulmonary fibrosis.
Pharmaceutical composition is take Biphenylylmethylcarbinol derivative shown in formula I～IV as activeconstituents, and adding pharmaceutically, auxiliary material commonly used is prepared from.
The invention has the beneficial effects as follows: proved that by experiment the Biphenylylmethylcarbinol derivative shown in the formula I has the effect of the more excellent autoimmune disorders such as inhibition acute hepatitis, hepatic fibrosis or pulmonary fibrosis, for the drug development for the treatment of such disease provides a kind of new selection.
Description of drawings
Fig. 1 is that compound 6m inhibition LPS induces scavenger cell RAW 264.7 NO to generate as a result figure, and DBD represents Biphenylylmethylcarbinol, and LPS represents lipopolysaccharides.
Fig. 2 is the biochemical evaluation comparison diagram of compound (6m) serum transaminase ALT.
Fig. 3 is hepatic tissue H﹠amp; Pathology section examination figure (200X) is carried out in E dyeing: (A), and normal group; (B), model group: D-Galn/LPS induces; (C) control group: D-Galn/LPS+4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group-2,2 '-biphenyl dicarboxylic acid methyl esters (25mg/kg); (E) treatment group: D-Galn/LPS+ compound (6m) (25mg/kg).
Fig. 4 is hepatic tissue H﹠amp; Pathology section examination figure (400X) is carried out in E dyeing: model group: (A), and normal group; (B), model group: D-Galn/LPS induces; (C) control group: D-Galn/LPS+4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group-2,2 '-biphenyl dicarboxylic acid methyl esters (25mg/kg); (E) treatment group: D-Galn/LPS+ compound (6m) (25mg/kg).
The immunohistochemical staining of hepatic tissue under Figure 52 00X visual field: CD 11b:(A), normal group; (B), model group: D-Galn/LPS induces; (D) treatment group: D-Galn/LPS+ compound (6m) (25mg/kg)
The immunohistochemical staining of hepatic tissue under Figure 62 00X visual field: CD 68:(A), normal group; (B), model group: D-Galn/LPS induces; (D) treatment group: D-Galn/LPS+ compound (6m) (25mg/kg)
Embodiment
Figure BDA0000100150240000211
Embodiment 1:4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group-2, the preparation of 2 '-biphenyl dicarboxylic acid (compound 2)
4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group-2,2 '-biphenyl dicarboxylic acid methyl esters (compound 1) 10g, add 15g KOH and 300ml water, reflux 6 hours, the TLC detection reaction is complete, cool to room temperature removes by filter not tolerant, and regulating pH with concentrated hydrochloric acid is 2, and have a large amount of white solid powder to separate out this moment, filtered water is washed till neutrality, vacuum-drying gets white solid powder 8.34g, yield 89.5%. 1H-NMR(d 6-DMSO，400MHz)δ：3.88(s，6H)，5.96(s，2H)，5.99(s，2H)，7.26(s，2H)，12.36(s，2H).MS(ESI，m/z)：389.19[M-H] -.
Embodiment 2:4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group-2, the preparation of 2 '-biphenyl dicarboxylic acid acid anhydride (compound 3)
8.3g compound 2 adds diacetyl oxide 50ml, reflux 12h reacts complete rear cool to room temperature, revolve desolventizing and get the faint yellow solid powder, the gained pressed powder is added dry toluene 50ml, suction filtration behind the mixing, and with dry toluene washing 3 times, get white solid powder 6.1g, yield 73.6%.Products obtained therefrom is not further purified, and is directly used in next step reaction.
Embodiment 3:2-(2,4-di-t-butyl-6-formyl radical phenyl)-2 '-methyl-4,4 '-dimethoxy-5,6, the preparation of 5 ', 6 '-secondary methylenedioxy group biphenyl dicarboxylic acid ester (5m)
Take by weighing 1.212g compound (4), add the anhydrous dioxane of 10ml, the 1.5ml sulfur oxychloride, 1 DMF, reflux 2 hours, the evaporated under reduced pressure solvent adds dry toluene 20ml behind the evaporate to dryness, continue the pressurization evaporate to dryness behind the mixing, gets the yellow solid powder.Gained yellow solid powder is dissolved in the 20ml anhydrous methylene chloride, adds triethylamine 1.5ml, 3,5-di-tert-butyl salicylaldehyde 1.1248g, stirred overnight at room temperature, stopped reaction is washed three times with 20ml * 3, the saturated common salt washing once, add anhydrous sodium sulfate drying, filter purification by silica gel column chromatography, get white foam shape solid (5m) 1.4593g, yield 78.5%.1H-NMR(CDCl 3，400MHz)δ：1.32(s，9H)，1.35(s，9H)，3.69(s，3H)，3.90(s，3H)，4.02(s，3H)，6.01-6.05(m，4H)，7.35(s，1H)，7.66(d，1H，J＝2.4Hz)，7.74(d，1H，J＝2.4Hz)，7.77(s，1H)，9.94(s，1H).MS(ESI，m/z)：643.48[M+Na] +.
Figure BDA0000100150240000221
Embodiment 4:(Z)-and 2-[2,4-di-t-butyl-6-(2,4-thiazolidinedione-5-methylene radical) phenyl]-2 '-methyl-4,4 '-dimethoxy-5,6, the preparation of 5 ', 6 '-secondary methylenedioxy group biphenyl dicarboxylic acid ester (6m)
Take by weighing 0.6206g compound (5m), add 0.35g thiazolidinedione, 0.105g Beta-alanine and 10ml glacial acetic acid.Backflow 5h is cooled to room temperature, adds entry 50ml, with 30ml * 3 dichloromethane extractions three times, combining extraction liquid with the saturated common salt washing once, adds anhydrous sodium sulfate drying, filters, be spin-dried for, silica gel column chromatography gets pale pressed powder (6m) 0.44g, yield 61.1%.1H-NMR(d 6-DMSO，400MHz)δ：1.20(s，5H)，1.26(s，4H)，1.30(m，9H)，3.53-3.57(m，3H)，3.84(s，3H)，3.96(s，3H)，5.85-6.10(m，4H)，7.21-7.23(m，1H)，7.37-7.37(m，1H)，7.48(s，1H)，7.59(s，1H)，7.68(s，1H)，12.62(s，1H).MS(ESI，m/z)：718.53[M-H] -.
The pharmacodynamics test part
Nitrogen protoxide (NO) the assay experiment of embodiment 1 compound 6m
Cell: RAW 264.7 mouse macrophages
Substratum: RPMI 1640 substratum
Culture condition: 37 ℃, 5%CO2
Experimental technique: with RAW 264.7 cells with 10 5Individual/hole is inoculated in 96 orifice plates, adds first 1640 culture medium culturing 12 hours of 100 μ l serum-frees.Then substratum is washed off, add contain LPS (1 μ g/ml) blood serum medium 200 μ l are arranged as model group.What other sieve medicine groups added respectively compound 6a～6m (10 μ M) and LPS (1 μ g/ml) has blood serum medium 200 μ l, cultivates 24 hours.Then every hole absorption 50 μ L supernatant are measured NO content with the Griess method, the results are shown in Figure 1, Fig. 1 and show, most Biphenylylmethylcarbinol derivatives have preferably antiphlogistic effects, and wherein compound 6k and 6m effect are optimum.
The acute hepatitis that embodiment 2 compound 6m treatment D-Galn/LPS induces
1, experiment material and modeling method:
Modeling method: first abdominal injection D-Galn 700mg/kg, again abdominal injection LPS 4 μ g/kg
Laboratory animal: BALB/c is available from Sichuan University's West China animal center
The animal grouping: 7 every group, totally 4 groups
Model group: D-Galn/LPS induces
Treatment group: compound (6m) 25.0mg/kg treatment; The D-Galn/LPS abdominal injection is induced for the first time perfusion of rear 0.5h, for the second time perfusion behind the 2.5h.
Control group: positive drug 4,4 '-dimethoxy-5,6,5 ', 6 '-secondary methylenedioxy group-2,2 '-biphenyl dicarboxylic acid methyl esters 25.0mg/kg treatment; The D-Galn/LPS abdominal injection is induced for the first time perfusion of rear 0.5h, for the second time perfusion behind the 2.5h.
Wait for the morbidity of 7～8h model, more than each treated animal get blood and liver.
2, contrast conclusion:
Fig. 2 Serum ALT detection display: compound 6m 25.0mg/kg can significantly reduce the rising of the serum transaminase that D-Galn/LPS induces.
Fig. 4 shows: the liver sinusoid expansion of Fig. 4 B (model group), hyperemia, with the profit of invading of inflammatory cell, the liver cell big area is downright bad.The liver cell of Fig. 4 C (control group) only has local necrosis, still has the profit of invading of inflammatory cell.The liver sinusoid of Fig. 4 E (6m treatment group) does not have inflammatory cell to invade profit substantially, illustrates that compound (6m) has significantly result for the treatment of.
Fig. 5 shows: the hepatic tissue of Fig. 5 B (model group) has a large amount of CD11b positive cells, illustrates that scavenger cell seriously invaded the profit hepatic tissue.The positive cell of Fig. 5 D (6m treatment group) is less, illustrates that scavenger cell invades the comparatively small amt of profit.
Fig. 6 shows: the hepatic tissue of Fig. 6 B (model group) has a large amount of CD68 positive cells, illustrates that scavenger cell seriously invaded the profit hepatic tissue.The positive cell of Fig. 6 D (6m treatment group) is less, illustrates that scavenger cell invades the comparatively small amt of profit.
The safe Pharmacological Evaluation of embodiment 5 compound 6m
Compound (6m) is 25mg/kg to the effective dose of mouse, and being converted to the dog dose,equivalent is 5.75mg/kg.This experimental design dog medication group dosage is respectively 20,100,300mg/kg.Other establishes one group of solvent control group, gives equal-volume 2.5% tween 80.
Table 1
Figure BDA0000100150240000241
According to the dosage medication of table 1, the result shows: compound 6m security is good, and high dosage (be equivalent to dog effective dose 57 times) is without obvious abnormal electrocardiographic pattern.

Claims (12)

1. Biphenylylmethylcarbinol derivative, structure is suc as formula shown in the I:
Figure FDA0000100150230000011
Wherein, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure FDA0000100150230000012
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000013
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
2. Biphenylylmethylcarbinol derivative according to claim 1, it is characterized in that: R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group, And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000015
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl;
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure FDA0000100150230000021
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000022
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H or C1～C8 alkyl;
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group, And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000024
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H or C1～C4 alkyl;
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group; R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000025
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000026
Having a substituting group among R6～R10 at least is C1～C8 alkyl;
R11 is H;
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000027
And have at least a substituting group to be among R6～R10 Having a substituting group among R6～R10 at least is C1～C8 alkyl;
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure FDA0000100150230000031
And only has one among R6～R10
Figure FDA0000100150230000032
Having a substituting group among R6～R10 at least is that C4～C8 contains the tertiary carbon alkyl;
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure FDA0000100150230000033
And only has one among R6～R10
Figure FDA0000100150230000034
Having a substituting group among R6～R10 at least is that C4～C8 contains the tertiary carbon alkyl;
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl, And only has one among R6～R10
Figure FDA0000100150230000036
Having a substituting group among R6～R10 at least is the tertiary butyl;
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R10 independently be H, the tertiary butyl, And only has one among R6～R10
Figure FDA0000100150230000038
Having a substituting group among R6～R10 at least is the tertiary butyl.
3. Biphenylylmethylcarbinol derivative according to claim 1, it is characterized in that: structure is suc as formula shown in the II:
Figure FDA0000100150230000041
Wherein, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R9 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure FDA0000100150230000042
And have at least a substituting group to be among R6～R10
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
4. Biphenylylmethylcarbinol derivative according to claim 3, it is characterized in that: R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group, And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000045
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl;
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure FDA0000100150230000051
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000052
R11 is H or C1～C8 alkyl;
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group, And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000054
R11 is H or C1～C4 alkyl;
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000055
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000056
R11 is H;
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R9 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group, And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000058
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R9 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure FDA0000100150230000061
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000062
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R9 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group, And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000064
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R9 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl,
Figure FDA0000100150230000065
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000066
5. Biphenylylmethylcarbinol derivative according to claim 1, it is characterized in that: structure is shown in formula III:
Wherein, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R8, R10 independently are H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure FDA0000100150230000068
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000071
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
6. Biphenylylmethylcarbinol derivative according to claim 5, it is characterized in that: R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure FDA0000100150230000072
And have at least a substituting group to be among R6～R10
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl;
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure FDA0000100150230000074
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000075
R11 is H or C1～C8 alkyl;
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000076
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000077
R11 is H or C1～C4 alkyl;
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000081
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000082
R11 is H;
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R8, R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000083
And have at least a substituting group to be among R6～R10
Figure FDA0000100150230000084
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R8, R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure FDA0000100150230000085
And have at least a substituting group to be among R6～R10
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R8, R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure FDA0000100150230000087
And only has one among R6～R10
Figure FDA0000100150230000088
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R8, R10 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl,
Figure FDA0000100150230000089
And only has one among R6～R10
Figure FDA00001001502300000810
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H; R6～R8, R10 independently be H, C1～C2 alkoxyl group,
Figure FDA0000100150230000091
And only has one among R6～R10
Figure FDA0000100150230000092
7. Biphenylylmethylcarbinol derivative according to claim 1, it is characterized in that: structure is suc as formula shown in the IV:
Figure FDA0000100150230000093
Wherein, R1～R3 is H, C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently are H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure FDA0000100150230000094
And has one among R6～R10 at least
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
8. Biphenylylmethylcarbinol derivative according to claim 7, it is characterized in that: R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure FDA0000100150230000096
And has one among R6～R10 at least
Figure FDA0000100150230000097
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl;
Further preferred, R1～R3 is C1～C8 alkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 alkoxyl group;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C8 alkoxyl group,
Figure FDA0000100150230000101
And has one among R6～R10 at least
Figure FDA0000100150230000102
R11 is H or C1～C8 alkyl;
Further preferred, R1～R3 is C1～C4 alkyl;
R4～R5 independently is H, C1～C4 alkyl, C1～C4 alkoxyl group;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000103
And has one among R6～R10 at least
Figure FDA0000100150230000104
R11 is H or C1～C4 alkyl;
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 independently is H, C1～C4 alkoxyl group;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000105
And has one among R6～R10 at least
Figure FDA0000100150230000106
R11 is H;
Further preferred, R1～R3 is C1～C4 alkyl; R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C8 alkyl, C1～C4 alkoxyl group,
Figure FDA0000100150230000107
And has one among R6～R10 at least
Figure FDA0000100150230000108
Further preferred, R1～R3 is C1～C4 straight chained alkyl; R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure FDA0000100150230000111
And has one among R6～R10 at least
Figure FDA0000100150230000112
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently for H, F, Br, Cl, C4～C8 contain tertiary carbon alkyl, C1～C4 straight chain alkoxyl group,
Figure FDA0000100150230000113
And only has one among R6～R10
Figure FDA0000100150230000114
Further preferred, R1～R3 is CH 3R4～R5 is H; R11 is H;
R6～R7, R9～R10 independently be H, F, Br, Cl, C1～C2 alkoxyl group, the tertiary butyl,
Figure FDA0000100150230000115
And only has one among R6～R10
Figure FDA0000100150230000116
Most preferred, R1～R3 is CH 3R4～R5 is H; R11 is H; R6～R7, R9～R10 independently be H, F, Br, C1～C2 alkoxyl group,
Figure FDA0000100150230000117
And only has one among R6～R10
Figure FDA0000100150230000118
9. the preparation method of each described Biphenylylmethylcarbinol derivative of claim 1～8 is characterized in that:
Figure FDA0000100150230000119
Wherein, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure FDA0000100150230000121
And have at least one to be among R6～R10
Figure FDA0000100150230000122
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl;
1) compound a and compound b generation esterification obtain compound V;
2) take Beta-alanine as catalyzer, the aldehyde radical among R6～R10 of compound V becomes 2,4-thiazolidinedione-5-methylene radical with the thiazolidinedione coupling.
10. used intermediate during preparation claim 1～8 each described Biphenylylmethylcarbinol derivative, structure is suc as formula shown in the V:
Figure FDA0000100150230000123
Wherein, R1～R3 is C1～C8 alkyl, C1～C8 cycloalkyl;
R4～R5 independently is H, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group;
R6～R10 independently is H, F, Br, Cl, NH 2, CN, NO 2, C1～C8 alkylamino, C1～C8 amido, C1～C8 alkyl, C1～C8 cycloalkyl, C1～C8 cycloalkyloxy, C1～C8 alkoxyl group,
Figure FDA0000100150230000124
And have at least one to be among R6～R10
Figure FDA0000100150230000125
R11 is H, C1～C8 alkyl or C1～C8 cycloalkyl.
11. the purposes of each described Biphenylylmethylcarbinol derivative of claim 1～8 in the medicine of preparation treatment autoimmune disorder.
12. pharmaceutical composition, adding pharmaceutically by each described Biphenylylmethylcarbinol derivative of claim 1～8, the complementary composition of acceptable is prepared from.
CN201110318467.7A 2011-10-19 2011-10-19 Biphenylylmethylcarbinol derivative, preparation method and the application in treatment autoimmune disorder thereof Expired - Fee Related CN103059015B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201110318467.7A CN103059015B (en) 2011-10-19 2011-10-19 Biphenylylmethylcarbinol derivative, preparation method and the application in treatment autoimmune disorder thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201110318467.7A CN103059015B (en) 2011-10-19 2011-10-19 Biphenylylmethylcarbinol derivative, preparation method and the application in treatment autoimmune disorder thereof

Publications (2)

Publication Number Publication Date
CN103059015A true CN103059015A (en) 2013-04-24
CN103059015B CN103059015B (en) 2016-01-13

Family

ID=48101944

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201110318467.7A Expired - Fee Related CN103059015B (en) 2011-10-19 2011-10-19 Biphenylylmethylcarbinol derivative, preparation method and the application in treatment autoimmune disorder thereof

Country Status (1)

Country Link
CN (1) CN103059015B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113214299A (en) * 2021-03-01 2021-08-06 重庆西南制药二厂有限责任公司 Gamma-biphenyldicarboxylate intermediate, synthetic method thereof and gamma-biphenyldicarboxylate synthetic method

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH037277A (en) * 1989-06-02 1991-01-14 Tanabe Seiyaku Co Ltd Biphenyl derivative, its production and synthetic intermediate therefor
CN1412185A (en) * 2002-10-11 2003-04-23 常俊标 Production method of halogenated hexahydroxydiphenic derivative and its medicinal application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH037277A (en) * 1989-06-02 1991-01-14 Tanabe Seiyaku Co Ltd Biphenyl derivative, its production and synthetic intermediate therefor
CN1412185A (en) * 2002-10-11 2003-04-23 常俊标 Production method of halogenated hexahydroxydiphenic derivative and its medicinal application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
《European Journal of Medicinal Chemistry》 20111008 Guangcheng Wang, et al Synthesis and biological evaluation of novel dimethyl[1,1'-biphenyl]-2,2'-dicarboxylate derivatives containing thiazolidine-2,4-dione for the treatment of concanavalin A-induced acute liver injury of BALB/c mice 5941-5948 1-12 第46卷, *
GUANGCHENG WANG, ET AL: "Synthesis and biological evaluation of novel dimethyl[1,1’-biphenyl]-2,2’-dicarboxylate derivatives containing thiazolidine-2,4-dione for the treatment of concanavalin A-induced acute liver injury of BALB/c mice", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113214299A (en) * 2021-03-01 2021-08-06 重庆西南制药二厂有限责任公司 Gamma-biphenyldicarboxylate intermediate, synthetic method thereof and gamma-biphenyldicarboxylate synthetic method

Also Published As

Publication number Publication date
CN103059015B (en) 2016-01-13

Similar Documents

Publication Publication Date Title
KR101130380B1 (en) Heterocyclic non-nucleoside compounds, their preparation, pharmaceutical composition and their use as antiviral agents
JP5286087B2 (en) Novel glycyrrhetinic acid-30-amide derivative and use thereof
CN101817833B (en) DPP-IV inhibitor
CN102219725B (en) Benzohetercyclic compound as well as preparation method and applications thereof
CN103145608B (en) Anti-enteric virus71 (EV71) hexanolactam compounds and its production and use
CN102344481A (en) Derivatives of 3-O-caffeoyloleanane type pentacyclic triterpene, preparation method thereof and application thereof
JP7123417B2 (en) Anxiolytic deuterium compound and its medicinal use
CN101362724B (en) Tetramethylpyrazine acidamides derivates, preparation method and medicament composition and application
CN106674176B (en) 7-substituted-4-aryl coumarin compound and preparation method and application thereof
CN103058982A (en) Bifendate derivative containing halogen substituent, preparation method and application
CN107879975A (en) Histon deacetylase (HDAC) inhibitor and its application
CN101633684A (en) Novel tetraterpene derivatives and pharmaceutical use thereof
CN103059015B (en) Biphenylylmethylcarbinol derivative, preparation method and the application in treatment autoimmune disorder thereof
CN101844970B (en) Dibenzocyclooctene lignin derivatives with bioactivity
CN103333216A (en) 5alpha-6-ketone-cholestane analogue and applications thereof
CN107616976A (en) A kind of pharmaceutical composition of Raltitrexed and preparation method thereof
CN111018738A (en) Paeonol derivative, pharmaceutical preparation, preparation method and application
CN110922415A (en) Synthesis and application of novel anti-tumor active compound
CN109503518A (en) A kind of substituted double aromatic radical amide compounds and its preparation method and application
CN104447481B (en) Benzoic acid Thiourea resisiting influenza virus compound and its production and use
CN104817556A (en) 9-O-ibuprofen berberine ester compound as well as preparation method and application of 9-O-ibuprofen berberine ester compound
CN114805141A (en) 4-guanidinobenzoic acid aryl ester compound and application thereof in resisting SARS-CoV-2 virus
CN107400109A (en) The impurity A of Raltitrexed and its preparation and application
CN102391332B (en) Liver protecting compound and preparation method and use thereof
CN103626705A (en) 1-(3-benzoylaminobenzyl)-1H-indazole-3-carboxamide compounds, and preparation method and antiviral use thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160113

Termination date: 20191019

CF01 Termination of patent right due to non-payment of annual fee