CN1308306C - 2-aryl-trisubstituted indole acetamide derivative and medicinal use thereof - Google Patents
2-aryl-trisubstituted indole acetamide derivative and medicinal use thereof Download PDFInfo
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- CN1308306C CN1308306C CNB021213879A CN02121387A CN1308306C CN 1308306 C CN1308306 C CN 1308306C CN B021213879 A CNB021213879 A CN B021213879A CN 02121387 A CN02121387 A CN 02121387A CN 1308306 C CN1308306 C CN 1308306C
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Abstract
The present invention relates to a compound, an optical isomer or pharmaceutical salts thereof. The structure of the compound is disclosed in the following formula. The compound is used for preventing or treating depressive disorder. Each gene definition in the formula is disclosed in the specification.
Description
Invention field
The present invention relates to new formula I 2-aryl 3-substituted indoacetamide derivative.The invention still further relates to formula I compound as for example medicinal use of thymoleptic.
Background technology
People such as Erminio will disclose-have had a bit the indole amides compounds of angst resistance effect in disclosed WO 93/00334A (being called for short R1 from now on) in 1993, disclose similar substituted indole acyl piperazine compounds among the disclosed WO 00/51984 and they have multiple drug action on August 9th, 2000.
People recognize substituted indole amides and MDR receptors bind, thereby the effect of alleviating anxiety is arranged.But its mechanism of action is different from existing antianxiety agent as medicines such as stable, 4-chlorine diazepam, alpidems, stable grade acts directly on the corresponding site of GABA-A acceptor, these known antianxiety agents are except there being the effect of alleviating anxiety, also have other effect such as effect such as anticonvulsion, calm, flesh pine.
Goal of the invention
The objective of the invention is to seek new compound with antidepressant effect.
The inventor has now found that formula I substituted indole amide derivatives demonstrates good antidepressant effect in mouse tail suspension and big mouse forced swimming test model.
The invention summary
First aspect present invention relates to formula (I) compound or its optical isomer or its pharmacologically acceptable salt:
Wherein
M is 0,1,2,3;
R
1, R
2Can be independently selected from hydrogen, C
1-C
12Alkyl, C
2-C
12Unsaturated alkyl, aryl C
1-C
6Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3Alkyl; Wherein alkyl or unsaturated alkyl can be straight or brancheds;
N is 0,1,2,3 or 4;
R ' can be independently selected from hydrogen, C
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3Alkyl, C
1-C
6Alkoxy C
1-C
3Alkyl, C
2-C
6Unsaturated-oxyl C
1-C
3Alkyl, C
1-C
6Carboxylic acid ester groups, hydroxyl, amido, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group or N3; Wherein alkyl or unsaturated alkyl can be straight or brancheds;
The B ring can be the aromatic ring of 6-14 carbon atom or contain 5 Yuans or 6 Yuans rings that are selected from 1-3 heteroatoms such as nitrogen, oxygen or sulphur; Aromatic nucleus also can be replaced by a plurality of substituting groups, wherein
X is 0,1,2,3,4 or 5,
R " can be independently selected from hydrogen, C
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Carboxylic acid ester groups, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3Alkyl, C
1-C
6Alkoxy C
1-C
3Alkyl, C
2-C
6Unsaturated-oxyl C
1-C
3Alkyl, hydroxyl, amido, alkylamino radical, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group; Wherein alkyl or unsaturated alkyl can be straight or brancheds;
Condition is as n=2 on the A ring, 3 or 4 the time, and promptly having more than 2 is during not for the substituting group of hydrogen, x=0,1,2,3,4 or 5 on the B ring;
As x=2,3 on the B ring, 4 or 5 the time, promptly having more than 2 is during not for the substituting group of hydrogen, n=0,1,2,3 or 4.
Further aspect of the present invention relates to pharmaceutical composition, and it contains at least a formula I compound or its optical isomer or its pharmacologically acceptable salt, and pharmaceutical carrier or vehicle.
Further aspect of the present invention relates to formula I compound or its optical isomer or its pharmacologically acceptable salt and is used for prevention or treats depressed medicine purposes in preparation.
Further aspect of the present invention relates to prevention or the depressed method of treatment, and it comprises the patient that the formula I compound of prevention or treatment significant quantity or its optical isomer or its pharmacologically acceptable salt are needed.
Further aspect of the present invention relates to the method for preparation I compound or its optical isomer or its pharmacologically acceptable salt, and it comprises:
(a) with formula 1 compound, R wherein, R ", X, B as above defines
With EtOCOCl and Et
3The N reaction is then with NR
1R
2Reaction, production 2 compounds, R1 wherein, R2, R ", X, B, R as above defines; With
(b) with formula 2 compounds and the reaction of formula 3 compounds,
R1 wherein, n as above defines, production I compound, as needs, formula I compound is converted into another kind of formula I compound or with formula I compound by chromatogram, fractional crystallization, split into its optical isomer or formula I compound be converted into its pharmaceutical salts with medicinal acid with the salifiable method of optically-active acid.
Detailed Description Of The Invention
According to the present invention, preferred formula I compound and optical isomer thereof or its pharmacologically acceptable salt, wherein n=0, i.e. unsubstituted on the A ring; At this moment x=2 on the B ring, 3,4 or 5, R ", m, R
1And R
2By above-mentioned formula I is defined.
According to the present invention, preferred formula I compound and optical isomer thereof or its pharmacologically acceptable salt, wherein n=0, i.e. unsubstituted on the A ring; When B ring is phenyl ring, during x=2, R " two substituting groups can be in 2 ', 3 ' of phenyl ring-, 2 ', 4 '-, 2 ', 5 '-, 2 ', 6 '-, 3 ', 4 '-or 3 ', 5 '-position; Can be respectively C
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Carboxylic acid ester groups, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3Alkyl, C
1-C
6Alkoxy C
1-C
3Alkyl, C
2-C
6Unsaturated-oxyl C
1-C
3Alkyl, hydroxyl, amido, alkylamino radical, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group; Wherein alkyl or unsaturated alkyl can be straight or brancheds; M, R
1And R
2By above-mentioned formula I is defined.
According to the present invention, preferred formula I compound or pharmaceutically acceptable salt thereof, n=0 wherein, unsubstituted on the A ring;
Wherein B ring is phenyl ring, during x=2, two R " can be in 2 ', 3 ' of phenyl ring-, 2 ', 4 '-, 2 ', 5 '-, 2 ', 6 '-, 3 ', 4 '-or 3 ', 5 '-position; Can be respectively C
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Carboxylic acid ester groups, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3Alkyl, C
1-C
6Alkoxy C
1-C
3Alkyl, C
2-C
6Unsaturated-oxyl C
1-C
3Alkyl, hydroxyl, amido, alkylamino radical, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group; Wherein alkyl or unsaturated alkyl can be straight or brancheds;
M=1 wherein, R
1, R
2Can be independently selected from hydrogen, C
1-C
12Alkyl, C
2-C
12Unsaturated alkyl, aryl C
1-C
6Alkyl, C
1-C
6Alkoxy C
1-C
3Alkyl, C
2-C
6Unsaturated-oxyl C
1-C
3Alkyl, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3The C of alkyl, 4-6 person's saturated rings
1-C
6Alkyl, the unsaturated cyclosubstituted C of 4-6 person
1-C
6Alkyl, wherein alkyl or unsaturated alkyl can be straight or brancheds.
According to the present invention, preferred formula I compound and optical isomer thereof or its pharmacologically acceptable salt, n=0 wherein, unsubstituted on the A ring; When encircling, B is phenyl ring, during x=2, and R on phenyl ring " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH
3, 4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F;
M=1 wherein, R
1, R
2Can be independently selected from hydrogen, C
1-C
12Alkyl, C
2-C
12Unsaturated alkyl, aryl C
1-C
6Alkyl, C
1-C
6Alkoxy C
1-C
3Alkyl, C
2-C
6Unsaturated-oxyl C
1-C
3Alkyl, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3Alkyl, the saturated cyclosubstituted C of 4-6 person
1-C
6Alkyl, the unsaturated cyclosubstituted C of 4-6 person
1-C
6Alkyl; Wherein alkyl or unsaturated alkyl can be straight or brancheds.
According to the present invention, more preferably formula I compound and optical isomer thereof or its pharmacologically acceptable salt, n=0 wherein, unsubstituted on the A ring; When encircling, B is phenyl ring, during x=2, and R on phenyl ring " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH
3, 4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F; M=1 wherein, R
1And R
2Be just-C
3H
7-, positive C
6H
13-, i C
3H
7-;
According to the present invention, more special preferred formula I compound, unsubstituted on the A ring; The B ring, R " be 2 ', 4 '-difluoro; M=1, R
1And R
2Just be-C
3H
7-.
According to the present invention, preferred formula I compound and optical isomer thereof or its pharmacologically acceptable salt, m=1 on the A ring wherein, R ' is 1 and is not the substituting group of hydrogen that this substituting group can be connected in 4,5,6 or 7-position of indole ring, can be C
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3Alkyl, C
1-C
6Alkoxy C
1-C
3Alkyl, C
2-C
6Unsaturated-oxyl C
1-C
3Alkyl, C
1-C
6Carboxylic acid ester groups, hydroxyl, amido, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group or N3; Wherein alkyl or unsaturated alkyl can be straight or brancheds; At this moment x=2 on the B ring, 3,4 or 5, R " be not to be the substituting group of hydrogen more than 2; R ", m, R
1And R
2By above-mentioned formula I is defined.
According to the present invention, preferred formula I compound and optical isomer thereof or its pharmacologically acceptable salt, m=1 on the A ring wherein, R ' is 1 and is not the substituting group of hydrogen that this substituting group can be connected in 4,5,6 or 7-position of indole ring, can be C
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Alkylamino C
1-C
3Alkyl, C
2-C
6The amino C of unsaturated hydrocarbons
1-C
3Alkyl, C
1-C
6Alkoxy C
1-C
3Alkyl, C
2-C
6Unsaturated-oxyl C
1-C
3Alkyl, C
1-C
6Carboxylic acid ester groups, hydroxyl, amido, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group or N3; Wherein alkyl or unsaturated alkyl can be straight or brancheds; Can be connected in 4,5,6 or 7-position of indole ring;
Wherein B is a phenyl ring, x=2,2 R " can be in 2 ', 3 ' of phenyl ring-, 2 ', 4 '-, 2 ', 5 '-, 2 ', 6 '-, 3 ', 4 '-or 3 ', 5 '-position; Can be selected from C respectively
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Carboxylic acid ester groups, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, hydroxyl, amido, alkylamino radical, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group; Wherein alkyl or unsaturated alkyl can be straight or brancheds;
M, R
1And R
2By above-mentioned formula I is defined.
According to the present invention, the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof more, n=1 on the A ring wherein, wherein R ' is 5-F, 5-Cl, 5-Br, 7-F, 7-Cl, 7-Br, 5-CH
3, 5-C
2H
5, 5-OCH
3, 5-NO
2
Wherein B ring is phenyl ring, x=2,2 R " can be in 2 ', 3 ' of phenyl ring-, 2 ', 4 '-, 2 ', 5 '-, 2 ', 6 '-, 3 ', 4 '-or 3 ', 5 '-position; Can be selected from C respectively
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Carboxylic acid ester groups, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, hydroxyl, amido, alkylamino radical, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group; Wherein alkyl or unsaturated alkyl can be straight or brancheds;
M=1 wherein, R
1, R
2Can be independently selected from hydrogen, C
1-C
12Alkyl, C
2-C
12Unsaturated alkyl, aryl C
1-C
6Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3The C of alkyl, 4-6 person's saturated rings
1-C
6Alkyl, the unsaturated cyclosubstituted C of 4-6 person
1-C
6Wherein alkyl or unsaturated alkyl can be straight or brancheds.
According to the present invention, the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof more, n=1 on the A ring wherein, wherein R ' is 5-F, 5-Cl, 5-Br, 7-F, 7-Cl, 7-Br, 5-CH
3, 5-C
2H
5, 5-OCH
3, 5-NO
2
Wherein the B ring is phenyl ring, x=2, R " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH
3, 4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F;
M=1 wherein, R
1, R
2Can be independently selected from hydrogen, C
1-C
12Alkyl, C
2-C
12Unsaturated alkyl, aryl C
1-C
6Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3The C of alkyl, 4-6 person's saturated rings
1-C
6Alkyl, the unsaturated cyclosubstituted C of 4-6 person
1-C
6Alkyl; Wherein alkyl or unsaturated alkyl can be straight or brancheds.
According to the present invention, the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof more, n=1 on the A ring wherein, R ' is 5-F, 5-Cl, 5-Br, 7-F, 7-Cl, 7-Br, 5-CH
3, 5-C
2H
5, 5-OCH
3, 5-NO
2
Wherein the B ring is phenyl ring, x=2, R " be respectively 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH
3, 4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F;
M=1 wherein, R
1And R
2All be just-C
3H
7-, just-C
6H
13-, different C
3H
7-.
According to the present invention, preferred formula I compound especially more, R ' is 5-Br on the A ring, the B ring is phenyl ring, R " and be 3 ', 4 '-dichloro, m=1, R
1And R
2Be nC
3H
7-.
According to the present invention, in the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof, n=2 on the A ring wherein, 3 or 4, R ' is 2,3 or 4 and is not the substituting group of hydrogen, these are several can not to be independently selected from C for the substituting group of hydrogen
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, C
1-C
6Carboxylic acid ester groups, hydroxyl, amido, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group or N3, wherein alkyl or unsaturated alkyl can be straight or brancheds; Can be connected in 4,5,6 or 7-position of indole ring;
Wherein B encircles, and x can be 0,1,2,3, and 4 or 5; B ring, m, R ", R
1And R
2By above-mentioned formula I is defined.
According to the present invention, in the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof, n=2 on the A ring wherein, R ' is 2 and is not the substituting group of hydrogen that these 2 can not be independently selected from C for the substituting group of hydrogen
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, C
1-C
6Carboxylic acid ester groups, hydroxyl, amido, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group or N3, wherein alkyl or unsaturated alkyl can be straight or brancheds; Can be connected in 4,5,6 or 7-position of indole ring;
Wherein B encircles, and x can be 0,1,2,3, and 4 or 5; B ring, m, R ", R
1And R
2By above-mentioned formula I is defined.
According to the present invention, the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof, n=2 on the A ring wherein, R ' is 2 and is not the substituting group of hydrogen, these 2 for the substituting group of hydrogen can not be connected in 4 of indole ring, 5-, 4,6-, 4,7-, 5,6-, 5,7-, 6,7-position; These 2 can not be independently selected from C for the substituting group of hydrogen
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, C
1-C
6Carboxylic acid ester groups, hydroxyl, amido, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group or N3, wherein alkyl or unsaturated alkyl can be straight or brancheds; Can be connected in 4,5,6 or 7-position of indole ring;
Wherein the B ring is a phenyl ring, and x can be 0,1,2,3,4 or 5; M, R ", R
1And R
2By above-mentioned formula I is defined.
According to the present invention, in the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof, n=2 on the A ring wherein, R ' can be 4,7-difluoro, 5,7-difluoro or 4,7-dichloro; R " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH
3, 4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F;
Wherein the B ring is a phenyl ring, and x can be 0,1,2,3,4 or 5; M, R ", R
1And R
2By above-mentioned formula I is defined.
According to the present invention, in the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof, n=2 on the A ring wherein, R ' can be 4,7-difluoro, 5,7-difluoro or 4,7-dichloro; R " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH3,4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F;
Wherein B ring is phenyl ring, x be 2, two substituting groups can be in 2 ', 3 ' of phenyl ring-, 2 ', 4 '-, 2 ', 5 '-, 2 ', 6 '-, 3 ', 4 '-or 3 ', 5 '-position; Can be independently selected from C
1-C
6Alkyl, C
2-C
6Unsaturated alkyl, C
1-C
6Alkoxyl group, C
2-C
6Unsaturated-oxyl, C
1-C
6Carboxylic acid ester groups, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, hydroxyl, amido, alkylamino radical, C
1-C
6Alkylthio, difluoromethyl, trifluoromethyl, halogen, nitro, cyano group; Wherein alkyl or unsaturated alkyl can be straight or brancheds;
M, R
1And R
2By above-mentioned formula I is defined.
According to the present invention, the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof, n=2 on the A ring wherein, R ' can be 4,7-difluoro, 5,7-difluoro or 4,7-dichloro; R " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH3,4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F;
Wherein the B ring is phenyl ring, and x is 2, wherein R " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH
3, 4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F;
M=1 wherein, R
1, R
2Can be independently selected from hydrogen, C
1-C
12Alkyl, C
2-C
12Unsaturated alkyl, aryl C
1-C
6Alkyl, C
1-C
6Alcoxyl C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons oxygen C
1-C
3Alkyl, C
1-C
6Alkane ammonia C
1-C
3Alkyl, C
2-C
6Unsaturated hydrocarbons ammonia C
1-C
3The C of alkyl, 4-6 person's saturated rings
1-C
6Alkyl, the unsaturated cyclosubstituted C of 4-6 person
1-C
6Alkyl, R
1, R
2Can form 4-6 person's saturated rings with nitrogen-atoms, or R
1, R
2Can form the unsaturated ring of 4-6 person with nitrogen-atoms; Wherein alkyl or unsaturated alkyl can be straight or brancheds;
According to the present invention, the compound or pharmaceutically acceptable salt thereof of preferred formula I compound and optical isomer thereof, n=2 on the A ring wherein, R ' can be 4,7-difluoro, 5,7-difluoro or 4,7-dichloro;
The B ring is phenyl ring, and x is 2, wherein R " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH
3, 4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F;
M=1, R
1And R
2Be nC
3H
7-, nC
6H
13-, i C
3H
7-.
According to the present invention, special preferred formula I compound, R ' is 5,7-difluoro, R " and be 2 ', 4 '-difluoro, R
1And R
2Be respectively nC
6H
13-.
According to the present invention, formula I compound of the present invention or its optical isomer or its pharmacologically acceptable salt can be by following reaction scheme preparations.
Reaction scheme:
The starting raw material I system that is used for synthetic The compounds of this invention formula I obtains { reference: [1] " Org.Synthesis " coll.vol.II:81～83 by corresponding replacement aromatic ring (benzene or naphthalene nucleus) and succinyl oxide through Fu-Ke prepared in reaction; [2] Li Shuwen, the Fan Rulin compiling, Science and Technology of Shanghai press publishes " practical organic chemistry handbook: 254～257}, or by corresponding replacement aromatic aldehyde under the cryanide ion catalysis through nucleophilic addition to two keys of propylene cyanogen, acidic hydrolysis prepares (Steter H then, Kuhlmann H.The catalyzed nucleophilic addition of aldehydes toelectrophilic double bonds.Org.Reactions:1991,40,407-496).3-replace fragrant carbonylamino propionic acid (1) in the time of-40 ℃ and Vinyl chloroformate in the presence of diethylamine, react and generate the ester that contracts, again in the time of-20 ℃ and corresponding amine reaction generate acid amides (2).Then through the Fischer indole synthesis with 2 and corresponding replace fragrant hydrazine zinc chloride or polyphosphoric acid catalyzed under make target compound, it is formula I compound { reference: [1] Li Shuwen, the Fan Rulin compiling, Science and Technology of Shanghai press publishes " practical organic chemistry handbook: 460～461; [2] " Org.Synthesis " coll.vol.III:725～726; [3] Ishii H, Murakami Y et al.FischerIndolization and Its Related Compounds VIII.Formation of4-Aminoindole Derivatives on the Fischer Indolization of2-Methoxyphenylhydrazone Derivatives.Chem Pharm Bull, 1974,22 (9): 1981～1989}.Gained formula I compound is by with crystallization in acetate ethanol and the normal hexane (1: 1) or with silica gel chromatography (elutriant: ethyl acetate: sherwood oil=5: 1) carry out purifying or separate.Synthetic the obtaining of organic synthesis handbook that it is commercially available replacing aromatic ring and substituted phenylhydrazines or reference is commonly used.
All per-cents cited below are mass percent.
Analytical instrument: ultimate analysis CARLD ERBA-1106 type: IRNicoletmaga-IR
TMSepectromet550 type: NMR JNM-GX400, BRUKER ARX400 and INOVA-600 type instrument; MS Zabspec type instrument; The RY-1 type melting point detector of Tianjin analytical instrument factory is adopted in fusing point test, and thermometer is not calibrated.
The starting raw material and the reagent that are used for synthetic The compounds of this invention are easy to obtain, and promptly buy from market, prepare by the literature method preparation or by the method for enumerating the following embodiment.
According to the present invention, formula I compound of the present invention can give separately or with composition forms.The present invention contains the pharmaceutical composition of formula I compound can oral or non-enteron aisle or topical routes.When pharmaceutical composition during with oral administration, it is tablet, capsule, slow releasing tablet or capsule, granule, pulvis, suspension, solution etc.When pharmaceutical composition during with the parenteral route administration, it is injection, lyophilized injectable powder etc.When present composition topical, can for example be suppository.
The following examples are to further describe of the present invention, but it does not mean that any limitation of the invention.
Biological activity test
The effect that The compounds of this invention shows in the mouse tail suspension test
Experiment content:, observed the oral The compounds of this invention I of mouse with classical mouse tail suspension model
20The back is to the influence of its outstanding tail dead time, to estimate its antidepressant activity.
Experimental technique: male mice in kunming, 18-22g.Connect a clip on the outstanding boot top board axial cord of 25 * 25 * 25cm, it is outstanding that folder mouse tail point 1cm place makes it example, and head is from case bottom surface 4-5cm.Test preceding 60 minutes orally give I
20, outstanding tail 6 minutes, back 4 minutes mouse dead times of accumulative total.Positive control drug imipramine 20mg/kg is at preceding 30 minutes abdominal injections of experiment.
Experimental result: mouse oral administration of compound I
202.5mg/kg after, under 2.5mg/kg dosage, significantly shortening the mouse tail suspension dead time (P＜0.01), the positive control drug imipramine also shows same purpose (the results are shown in Table 1).
The oral I of table 1.
20Influence to the mouse tail suspension dead time
| Medicine | Dosage (mg/kg) | Route of administration | Number of animals | The outstanding tail dead time (sec) |
| Solvent control imipramine solvent control I 20 | - 20 - 2.5 | The abdominal cavity, abdominal cavity is oral | 8 8 12 8 | 57.5±54.4 17.4±21.9 ** 99.0±32.2 59.2±28.6 ** |
Annotate: x ± s,
*Compare with the coordinative solvent control group P＜0.01.
The effect of The compounds of this invention in mouse forced swimming experimental model
Experiment content:, observed the oral or abdominal injection various dose The compounds of this invention I of mouse with the classical mandatory swimming model of mouse
20The back is to the influence of its forced swimming dead time, to estimate the antidepressant activity of this medicine.
Experimental technique: male mice in kunming, body weight 18-22g.Mouse placed fill 25 ℃ of tap water, the depth of water is glass jar (the diameter 10cm of 10cm, high 20cm) in, swam 6 minutes, dead time of animal in 4 minutes behind the cumulative observation (be animal hind leg attonity or hind leg fine motion but keep personal floatation motionless time), test preceding 60 minutes (oral) or 30 minutes (abdominal injection) gives Compound I
20The positive control drug imipramine is at preceding 30 minutes abdominal injections of experiment.
Experimental result: mouse peritoneal injection Compound I
201.25, behind 2.5mg/kg or the oral 5.0mg/kg, significantly reducing the forced swimming dead time, the positive control drug imipramine also shows same purpose (the results are shown in Table 2).
Table 2. abdominal injection or oral administration of compound I
20Influence to the mouse forced swimming dead time
| Medicine | Dosage (mg/kg) | Route of administration | Number of animals | The forced swimming dead time (sec) |
| Solvent control imipramine solvent control I 20Solvent control I 20 | - 20 - 1.25 2.5 - 2.5 5.0 | Abdominal cavity, abdominal cavity, abdominal cavity, abdominal cavity is oral | 15 10 10 10 10 8 8 8 | 80.5±49.6 43.7±39.7 ** 92.5±62.4 39.5±26.5 * 29.4±35.2 ** 111.8±28.8 89.4±61.0 60.1±44.6 ** |
Annotate: x ± s,
*P＜0.05,
*Compare with the coordinative solvent control group P＜0.01.
The compounds of this invention I
20Effect in rat forced swimming experimental model
Experiment content has been observed the oral or abdominal injection The compounds of this invention I of animal with classical depression model rat forced swimming experiment
20The back is to the influence of rat forced swimming dead time, to estimate its antidepressant activity.
The experimental technique male Wistar rat, body weight 220-260g.Rat is placed in the glass jar (diameter 18cm, high 40cm) of the tap water that fills, depth of water 23cm, 25 ℃ of water temperatures, swimming after 15 minutes to take out places the infrared ray electric heating stokehold, dries after with the moisture wiping on the animal health with dried cloth.Next day, 9:00am began administration, and 60min (oral) or 30min (abdominal injection) give Compound I before experiment respectively
20, once more rat is put into the water vat of above-mentioned equal conditions, the dead time (be the time of animal hind leg attonity) of cumulative observation rat in 5 minutes.The positive control drug imipramine is the 30min abdominal injection before experiment.
Experimental result rats by intraperitoneal injection Compound I
200.5, behind 1.0mg/kg or the oral 1.0mg/kg, significantly reducing the forced swimming dead time, positive control drug imipramine 15mg/kg also demonstrates same purpose (the results are shown in Table 3).
Oral or the abdominal injection Compound I of table 3.
20Influence to the rat forced swimming dead time
| Medicine | Dosage (mg/kg) | Route of administration | Number of animals | The forced swimming dead time (sec) |
| Solvent control imipramine solvent control I 20Solvent control I 20 | - 15 - 0.5 1.0 - 1.0 | Abdominal cavity, abdominal cavity, abdominal cavity, abdominal cavity is oral | 16 8 8 8 8 8 8 | 147.1±38.8 83.7±51.2 ** 145.9±30.8 78.9±26.8 ** 96.4±30.9 ** 122.5±14.3 81.1±48.1 * |
Annotate: x ± s,
*P＜0.05,
*Compare with the coordinative solvent control group P＜0.01.
Embodiment 1
N, N-two-n-propyl-1H-2-(2 ', 4 '-difluoro) phenyl-3-indoleacetamide (I
1) preparation
Get 3-(2,4 difluorobenzene formyl radical) propionic acid 2.14g (0.01mol) and triethylamine 3g (0.03mol, commercially available) and be dissolved among the tetrahydrofuran (THF) 25ml, stir and be chilled to-40 ℃.Stir and drip Vinyl chloroformate 1.1g (0.01mol is commercially available) down, continue reaction 0.5 hour down at-20 ℃ then, add di-n-propylamine 1g (0.01mol, commercially available) subsequently, at room temperature continued stirring reaction 1 hour.The gained suspension liquid carries out chromatographic separation with silica gel, and (chromatographic solution: ethyl acetate: sherwood oil=2: 1), remove elutriant under reduced pressure, evaporate to dryness obtains acid amides.Add phenylhydrazine 2.2g (0.02mol, commercially available), polyphosphoric acid 5 gram mixing in the acid amides, stir with thermometer, slowly heat in 120 ℃ of oil baths of temperature outside, interior temperature rose suddenly when reaction took place, and had gas to produce, and was stirred to react in heating bath and calmed down, and is cold
The back adds 50ml water, and filter collection solid separates (chromatographic solution: ethyl acetate: sherwood oil=5: 1), get product I with re-crystallizing in ethyl acetate or with silicagel column
1, be white solid.
I
1142～143 ℃ of fusing points; Ultimate analysis (C
22H
24F
2N
2O): calculated value (%): C71.35, H6.53, N7.56, experimental value (%): C71.18, H6.43, N7.47; IR (KBr): 3220,2966,1626,1260cm
-1 1HNMR (CDCl
3, 300MHz): 8.28 (s, 1H), 7.67 (d, 1H), 7.61 (q, 1H), 7.36 (d, 1H), 7.28 (t, 1H), 7.15 (t, 1H), 6.97 (m, 2H), 3.84 (s, 2H), 3.26,3.13 (tt, 4H), 1.65 (b, 4H), 0.819,0.713 (tt, 6H); MS (m/z): 471 (M
++ 1).
Make Compound I with sample preparation method
2, I
5, I
6, I
7, I
8, I
9, I
10The part physicochemical data sees Table 8.
Table 8 physicochemical data table
| Numbering | NR 1R 2 | (R’)n | (R”)x | Mp(℃) | Molecular formula | M.W. | MS |
| I 1 I 2 I 5 I 6 I 7 I 8 I 9 I 10 | N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 6H 13) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N[CH(CH 3) 2] 2 N[CH(CH 3) 2] 2 | H H H H H H H H | 2 ', 4 '-difluoro, 2 ', 4 '-difluoro, 2 '-Cl, 4 '-CH 3 2’-CH 3，4’-Cl 2’-Cl，4’-CH 3 2’-CH 3，4’-Cl 2’-Cl，4’-CH 3 2’-CH 3，4’-Cl | 142～143 132～134 112～114 124～125 171～172 174 237～238 265～266 | C 22H 24F 2N 2O C 28H 36F 2N 2O C 29H 39ClN 2O C 29H 39ClN 2O C 23H 27ClN 2O C 23H 27ClN 2O C 23H 27ClN 2O C 23H 27ClN 2O | 370 454 466 466 382 382 382 382 | 371(M ++1) 455(M ++1) 467(M ++1) 467(M ++1) 383(M ++l) 383(M ++1) 383(M ++1) 383(M ++1) |
N, N-two-n-hexyl-1H-2-(2 ', 4 '-difluoro) phenyl-3-indoleacetamide (I
2) preparation
Press embodiment 1 described same procedure, the cold back of question response mixture adds 50ml water, and filter collection solid gets I with re-crystallizing in ethyl acetate
2White solid, 132～134 ℃ of fusing points; Ultimate analysis (C
28H
36F
2N
2O): calculated value (%): C74.01, H7.93, N6.17, experimental value (%): C74.11, H7.95, N6.22; IR (KBr) 3250,2940,1620cm
-1 1HNMR (CDCl
3, 400MHz): 8.34 (s, 1H), 7.66 (d, 1H), 7.57 (q, 1H), 7.32 (d, 1H), 7.19 (t, 1H), 7.11 (t, 1H), 6.95 (m, 2H), 3.8 (s, 2H), 3.27,3.13 (tt, 4H), 1.43-0.83 (m, 22H); MS (m/z): 455 (M
++ 1).
N, N-two-n-hexyl-1H-2-(2 '-chlorine, 4 '-methyl) phenyl-3-indoleacetamide (I
5) preparation
Press embodiment 1 described same procedure, (chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
5White solid, through re-crystallizing in ethyl acetate, 112～114 ℃ of fusing points; Ultimate analysis (C
29H
39ClN
2O): calculated value (%): C74.57, H8.42, N6.00, experimental value (%): C74.86, H8.58, N5.89; IR (KBr): 3210,2927,1619,1456cm
-1 1HNMR (CDCl
3, 400MHz) 7.95 (s, 1H), 7.76 (d, 1H), 7.35～7.12 (m, 6H), 3.65 (s, 2H), 3.23 (s, 2H), 3.01 (s, 2H), 2.26 (s, 3H), 1.39～0.84 (m, 24H); MS (m/z): 467 (M
++ 1).
N, N-two-n-hexyl-1H-2-(2 '-methyl, 4 '-chlorine) phenyl-3-indoleacetamide (I
6) preparation
Press embodiment 1 described same procedure, (chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
6White solid, through re-crystallizing in ethyl acetate, 124～125 ℃ of fusing points; Ultimate analysis (C
29H
39ClN
2O): calculated value (%): C74.57, H8.42, N6.00, experimental value (%): C74.71, H8.67, N5.70; IR (KBr): 3209,2927,1618,1456cm
-1 1HNMR (CDCl
3, 400MHz): 8.15 (s, 1H), 7.76 (d, 1H), 7.35～7.12 (m, 6H), 3.65 (s, 2H), 3.23 (s, 2H), 3.01 (s, 2H), 2.26 (s, 3H), 1.39～0.84 (m, 24H); MS (m/z): 467 (M
++ 1).
N, N-two-n-propyl-1H-2-(2 '-chlorine, 4 '-methyl) phenyl-3-indoleacetamide (I
7) preparation
Press embodiment 1 described same procedure, (chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
7White solid, through re-crystallizing in ethyl acetate, 171～172 ℃ of fusing points; Ultimate analysis (C
23H
27ClN
2O): calculated value (%): C72.14, H7.11, N7.32, experimental value (%): C72.04, H7.08, N7.23; IR (KBr): 3205,2960,1614,1456cm
-1 1HNMR (CDCl
3, 400MHz, ppm): 8.12 (s, 1H), 7.54 (d, 1H), 7.33～7.12 (m, 6H), 3.63 (s, 2H), 3.23 (t, 2H), 3.02 (t, 2H), 2.25 (s, 3H), 1.41 (m, 4H), 0.82 (t, 3H), 0.67 (t, 3H); MS (m/z): 383 (M
++ 1).
N, N-two-n-propyl-1H-2-(2 '-methyl, 4 '-chlorine) phenyl-3-indoleacetamide (I
8) preparation
Press embodiment 1 described same procedure, (chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
8White solid, through re-crystallizing in ethyl acetate, 174 ℃ of fusing points; Ultimate analysis (C
23H
27ClN
2O): calculated value (%): C72.14, H7.11, N7.32, experimental value (%): C72.10, H7.18, N7.35; IR (KBr): 3236,2967,1616,1456cm
-1 1HNMR (CDCl
3, 400MHz, ppm): 8.23 (s, 1H), 7.79 (d, 1H), 7.42～7.11 (m, 6H), 3.76 (s, 2H) 3.24 (t, 2H), 3.05 (t, 2H), 2.41 (s, 3H), 1.44 (q, 2H), 1.40 (q, 2H), 0.82 (t, 3H), 0.67 (t, 3H); MS (m/z): 383 (M
++ 1).
N, N-two-sec.-propyl-1H-2-(2 '-chlorine, 4 '-methyl) phenyl-3-indoleacetamide (I
9) preparation
Press embodiment 1 described same procedure, (chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
9White solid, 237～238 ℃ of fusing points; IR (KBr): 3237,2929,1616,1448;
1HNMR (CDCl
3, 400MHz, ppm): 7.92 (s, 1H), 7.78 (d, 1H), 7.34～7.10 (m, 6H), 3.65 (s, 2H) 3.77 (m, 1H), 3.25 (m, 1H), 2.25 (s, 3H), 1.33 (d, 3H), 0.83 (s, 3H); MS (m/z): 383 (M
++ 1).
N, N-two-n-propyl-1H-2-(2 '-methyl, 4 '-chlorine) phenyl-3-indoleacetamide (I
10) preparation
Press embodiment 1 described same procedure, (chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
10White solid, 265～266 ℃ of fusing points; IR (KBr): 3224,2966,1615,1456cm
-1 1HNMR (CDCl
3, 400MHz, ppm): 8.21 (s, 1H), 7.77 (d, 1H), 7.38～7.10 (m, 6H), 3.96 (s, 2H) 3.83 (m, 1H), 3.28 (m, 1H), 2.40 (s, 3H), 1.33 (d, 3H), 0.82 (s, 3H); MS (m/z): 383 (M
++ 1).
Embodiment 2
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-3-indoleacetamide (I
17) preparation:
Get 3-(3,4-dichlorobenzene acyl group) propionic acid 2.5g (0.01mol) and triethylamine 3g (0.03mol) and be dissolved in the tetrahydrofuran (THF) of 25ml, be cooled to-40 ℃.Splash into Vinyl chloroformate 1.1g (0.01mol) under stirring, solution continues down to react half an hour at-20 ℃, adds two normal hexyl Amine 1g (0.01mol) subsequently, at room temperature continues to stir one hour.The gained suspension liquid carries out chromatographic separation with silica gel, and (chromatographic solution: ethyl acetate: sherwood oil=2: 1), collect elutriant, evaporate to dryness obtains acid amides.Add phenylhydrazine 2.2g (0.02mol) in the acid amides, zinc chloride 10 grams mix, stir with thermometer, outside 170 ℃ of temperature quick stirring reaction 5 minutes down.Cold back adds 50ml water, and filter collection solid separates (chromatographic solution: ethyl acetate: sherwood oil=5: 1), get product I with re-crystallizing in ethyl acetate or with silicagel column
17, be white solid.
I
1779～80 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.366 (s, 1H), 7.585 (s, 1H), 7.480 (s, 2H), 7.392 (d, 1H), 7.262 (d, 1H), 7.235～7.077 (m, 3H), 3.839 (s, 2H), 3.344 (t, 2H), 3.224 (t, 2H), 1.599～0.852 (m, 22H); MS (m/z): 487 (M
++ 1).
Get Compound I with legal system
22-I
25, I
28-I
33, I
37-I
39, I
41-I
42, I
46-I
47, I
49-I
56, I
58-I
61, I
64-I
66, I
69-I
78, I
82-I
84, I
86-I
89, I
92, I
94-I
96And I
98Crystallization (corresponding phenylhydrazine is commercially available).Physicochemical data sees Table 9.
Table 9 physicochemical data table
| Numbering | NR 1R 2 | (R’)n | (R”)x | Mp(℃) | Molecular formula | M.W. | MS |
| I 17 I 22 I 23 I 24 I 25 I 28 I 29 I 30 I 31 I 32 I 33 I 37 I 38 I 39 I 41 I 42 I 46 I 47 I 49 I 50 I 51 I 52 I 53 I 54 I 55 I 56 I 58 I 59 | N(n-C 6H 13) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 | H 5-F 5-F 5-F 5-F 5-F 5-F 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Br 5-Br 5-Br 7-F 7-F 7-F 7-F 7-F 7-Cl 7-Cl 7-Cl 7-Cl 7-Cl 7-Br | 3 ', 4 '-dichloro 2 ', 4 '-difluoro, 2 ', 4 '-difluoro, 2 '-Cl, 4 '-CH 3 2’-Cl，4’-CH 33 ', 4 '-dichloro 3 ', 4 '-dichloro 2 ', 4 '-difluoro 2 ', 4 '-difluoro 3 ', 4 '-dichloro 3 ', 4 '-dichloro 2 '-F, 4 '-CH 3 2’-F，4’-CH 3 2’-Cl，4’-CH 32 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-CH 34 '-Cl 2 ', 4 '-difluoro 3 ', 4 '-dichloro 3 ', 4 '-dichloro 2 '-Cl, 4 '-CH 3 2’-Cl，4’-CH 32 ', 4 '-difluoro 2 ', 4 '-difluoro 3 ', 4 '-dichloro 3 ', 4 '-dichloro 2 '-Cl, 4 '-CH 32 ', 4 '-difluoro | 79～80 175～176 145～146 85～86 158～159 75～76 174～175 70～71 141～142 71～72 178～179 81～82 122～123 165～166 74～75 110～111 173～174 69～70 186～187 108～109 68 121～122 85～86 87～88 184～185 88～89 143～144 69～70 | C 28H 36Cl 2N 2O C 28H 35F 3N 2O C 22H 23F 3N 2O C 29H 38ClFN 2O C 23H 26ClFN 2O C 28H 35FCl 2N 2O C 22H 23FCl 2N 2O C 28H 35ClF 2N 2O C 22H 23ClF 2N 2O C 28H 35Cl 3N 2O C 22H 23Cl 3N 2O C 29H 38ClFN 2O C 23H 26FClN 2O C 23H 26Cl 2N 2O C 28H 35BrF 2N 2O C 28H 35BrCl 2N 2O C 23H 26BrClN 2O C 28H 35F 3N 2O C 22H 23Cl 2FN 2O C 28H 35Cl 2FN 2O C 29H 38ClFN 2O C 23H 26ClFN 2O C 28H 35ClF 2N 2O C 22H 23ClF 2N 2O C 22H 23Cl 3N 2O C 28H 35Cl 3N 2O C 23H 26Cl 2N 2O C 28H 35BrF 2N 2O | 486 472 388 484 400 504 420 488 404 520 436 484 400 416 532 566 460 472 420 504 484 400 488 404 520 416 532 | 487(M ++1) 473(M ++1) 389(M ++1) 485(M ++1) 401(M ++1) 505(M ++1) 421(M ++1) 489(M ++1) 405(M ++1) 521(M ++1) 437(M ++1) 485(M ++1) 401(M ++1) 417(M ++1) 532.9* 567 463* 473(M ++1) 421(M ++1) 505(M ++1) 485(M ++1) 401(M ++1) 489(M ++1) 405(M ++1) 521(M ++1) 416.9 533(M ++1) |
| I 60 I 61 I 64 I 65 I 66 I 69 I 70 I 71 I 72 I 73 I 74 I 75 I 76 I 77 I 78 I 82 I 83 I 84 I 86 I 87 I 88 I 89 I 92 I 94 I 96 I 96 I 98 | N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 6H 13) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 | 7-Br 7-Br 7-Br 5-CH 3 5-CH 3 5-OCH 3 5-NO 2 7-C 2H 5 7-C 2H 54,7-difluoro 4,7-difluoro 4, the 7-dichloro-4,4, the 7-dichloro-4,4, the 7-dichloro-4,4, the 7-dichloro-4,4, the 7-dichloro-4,4,7-dichloro 5,7-difluoro 5,7-difluoro H 5-F 7-F 7-Cl 5-Br 7-Br 5,7-difluoro 4, the 7-dichloro | 3 ', 4 '-dichloro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH 33 ', 4 '-dichloro 3 ', 4 '-dichloro 3 ', 4 '-dichloro 2 ', 4 '-difluoro 3 ', 4 '-dichloro 3 ', 4 '-dichloro 3 ', 4 '-dichloro 3 ', 4 '-dichloro 2 ', 4 '-difluoro 2 ', 4 '-difluoro 3 ', 4 '-dichloro 3 ', 4 '-dichloro 2 '-Cl, 4 '-CH 3 2’-Cl，4’-CH 32 ', 4 '-difluoro 2 '-Cl, 4 '-CH 3 2’-CH3，4’-F 2’-F，4’-CH 3 2’-CH 3，4’-F 2’-CH 3，4’-F 2’-CH 3，4’-F 2’-CH 3，4’-F 2’-CH 3，4’-F 2’-CH 3，4’-F | 97～98 170～171 152 74 175～176 98～99 146～147.5 70～71 119～120 90～91 185～186 89～90 110～111 120～121 222～223 125～126 181～182 67～68 107～108 153～155 148～149 147～148 141～143 132～133 130～131 188～190 190～191 | C 28H 35BrCl 2N 2O C 22H 23BrCl 2N 2O C 23H 26BrClN 2O C 29H 38Cl 2N 2O C 23H 26Cl 2N 2O C 29H 38Cl 2N 2O 2 C 22H 23F 2N 3O 3 C 30H 40Cl 2N 2O C 24H 28Cl 2N 2O C 28H 34Cl 2F 2N 2O C 22H 22Cl 2F 2N 2O C 22H 22Cl 2F 2N 2O C 28H 34Cl 2F 2N 2O C 28H 34Cl 4N 2O C 22H 22Cl 4N 2O C 29H 37Cl 3N 2O C 23H 25Cl 3N 2O C 28H 34F 4N 2O C 23H 25ClF 2N 2O C 23H 27FN 2O C 23H 26F 2N 2O C 23H 26F 2N 2O C 23H 26ClFN 2O C 23H 26BrFN 2O C 23H 26BrFN 2O C 23H 25F 3N 2O C 23H 25Cl 2FN 2O | 566 482 460 500 416 516 415 514 430 522 438 438 522 554 470 534 450 490 418 366 384 384 400 444 444 402 434 | 567(M ++1) 483(M ++1) 462.9* 501(M ++1) 417(M ++1) 517(M ++1) 416(M ++1) 515(M ++1) 431(M ++1) 523(M ++1) 439(M ++1) 439(M ++1) 523(M ++1) 556(M ++1) 473* 535(M ++1) 450.9 491(M ++1) 419(M ++1) 367(M ++1) 385(M ++1) 385(M ++1) 401(M ++1) 445(M ++1) 445(M ++1) 403(M ++1) 435(M ++1) |
* the MS value is isotope value and M
++ 1 peak
N, N-two-n-hexyl-1H-2-(2 ', 4 '-difluoro) phenyl-5-fluoro-3-indoleacetamide (I
22) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
22White solid, 175～176 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 9.213 (s, 1H), 7.346 (d, 1H), 7.315 (d, 1H), 7.169 (d, 1H), 7.020 (t, 1H), 6.799 (m, 1H), 6.664 (m, 1H), 3.721 (s, 2H), 3.457 (t, 2H), 3.355 (t, 2H), 1.709～0.920 (m, 10H); MS (m/z): 473 (M
++ 1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-5-fluoro-3-indoleacetamide (I
28) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
28White solid, 75～76 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 9.063 (s, 1H), 7.381 (m, 3H), 7.222 (d, 1H), 6.928 (t, 1H), 6.872 (d, 1H), 3.728 (s, 2H), 3.428 (t, 2H), 3.330 (t, 2H), 1.622～0.868 (m, 22H); MS (m/z): 505 (M
++ 1).
N, N-two-n-propyl-1H-2-(3 ', 4 '-dichloro) phenyl-5-fluoro-3-indoleacetamide (I
29) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
29White solid, 174～175 ℃ of fusing points; Ultimate analysis (C
22H
23Cl
2FN
2O): calculated value (%) C62.71 H5.50 N6.65, experimental value (%) C62.52 H5.26 N6.40;
1HNMR (CDCl
3, 600MHz): 9.213 (s, 1H), 7.341 (d, 1H), 7.308 (d, 1H), 7.160 (q, 1H), 6.875 (q, 1H), 6.648 (t, 1H), 3.721 (s, 2H), 3.745,3.343 (tt, 4H), 1.685 (m, 4H), 0.984,0.933 (tt, 6H); MS (m/z): 421 (M+1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-5-chloro-3-indoleacetamide (I
32) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
32White solid, 71～72 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 9.242 (s, 1H), 7.339 (d, 3H), 7.186 (d, 1H), 6.885 (d, 1H), 6.800 (d, 1H), 3.717 (s, 2H), 3.470 (t, 2H), 3.347 (t, 2H), 1.644～0.882 (m, 22H); MS (m/z): 521 (M
++ 1).
N, N-two-n-propyl-1H-2-(3 ', 4 '-dichloro) phenyl-7-fluoro-3-indoleacetamide (1
49) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
49White solid, 186～187 ℃ of fusing points;
1HNMR (CDCl
3, 600MIz, ppm): 8.897 (s, 1H), 7.545 (d, 1H), 7.423 (d, 2H), 7.279 (d, 1H), 6.965 (m, 1H), 6.772 (m, 1H), 3.792 (s, 2H), 3.382 (t, 2H), 3.288 (t, 2H), 1.640～0.879 (m, 10H); MS (m/z): 421 (M
++ 1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-7-fluoro-3-indoleacetamide (I
50) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
50White solid, 108～109 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.646 (s, 1H), 7.584 (s, 1H), 7.483 (d, 1H), 7.379 (d, 1H), 7.335 (t, 1H), 7.260 (m, 1H), 6.989 (m, 1H), 3.859 (s, 2H), 3.345 (t, 2H), 3.210 (t, 2H), 1.874～0.850 (m, 22H); MS (m/z): 505 (M
++ 1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-7-chloro-3-indoleacetamide (I
56) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
56White solid, 88～89 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.389 (s, 1H), 7.646 (d, 1H), 7.531 (d, 1H), 7.444 (m, 1H), 7.258 (t, 1H), 7.184 (m, 1H), 7.062 (m, 1H), 3.836 (s, 2H), 3.331 (t, 2H), 3.194 (t, 2H), 1.479～0.837 (m, 22H); MS (m/z): 521 (M
++ 1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-7-bromo-3-indoleacetamide (I
60) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
60White solid, 97～98 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.346 (s, 1H), 7.644 (d, 1H), 7.574 (m, 1H), 7.439 (m, 1H), 7.334 (t, 1H), 7.254 (m, 1H), 6.996 (m, 1H), 3.818 (s, 2H), 3.329 (t, 2H), 3.192 (t, 2H), 1.480～0.836 (m, 22H); MS (m/z): 567 (M
++ 1).
N, N-two-n-propyl-1H-2-(3 ', 4 '-dichloro) phenyl-7-bromo-3-indoleacetamide (I
61) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
61White solid, 170～171 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.330 (s, 1H), 7.646 (s, 1H), 7.557 (t, 1H), 7.445 (m, 1H), 7.341 (d, 1H), 7.255 (m, 1H), 6.994 (s, 1H), 3.869 (s, 2H), 3.312 (d, 2H), 3.193 (s, 2H), 1.875～0.796 (m, 22H); MS (m/z): 483 (M
++ 1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-5-methyl-3-indoleacetamide (I
65) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
65White solid, 74 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.146 (s, 1H), 7.586 (d, 1H), 7.494 (d, 1H), 7.395 (d, 1H), 7.262 (t, 1H), 7.181 (m, 1H), 6.997 (m, 1H), 3.837 (s, 2H), 3.349 (t, 2H), 3.213 (t, 2H), 1.502～0.857 (m, 20H); MS (m/z): 501 (M
++ 1).
N, N-two-n-propyl-1H-2-(3 ', 4 '-dichloro) phenyl-5-methyl-3-indoleacetamide (I
66) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
66White solid, 175～176 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.274 (s, 1H), 7.564 (d, 1H), 7.470 (m, 1H), 7.370 (d, 1H), 7.268 (t, 1H), 7.132 (d, 1H), 6.964 (m, 1H), 3.832 (s, 2H), 3.361 (t, 2H), 3.253 (t, 2H), 1.606～0.813 (m, 10H); MS (m/z): 417 (M
++ 1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-5-methoxyl group-3-indoleacetamide (I
69) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
69White solid, 98～99 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.243 (s, 1H), 7.559 (s, 1H), 7.479 (d, 1H), 7.362 (m, 1H), 7.141 (t, 1H), 7.054 (m, and 1H) 6.807 (m, 1H), 3.815 (s, 2H), 3.347 (t, 2H), 3.192 (t, 2H), 1.650～0.851 (m, 22H); MS (m/z): 517 (M
++ 1).
N, N-two-n-propyl-1H-2-(2 ', 4 '-difluoro) phenyl-5-nitro-3-indoleacetamide (I
70) preparation
Press embodiment 2 described method preparations.After the question response mixture is cold, add 50m1 water, filter collection solid gets I with re-crystallizing in ethyl acetate
70Orange solids, 146～147.5 ℃ of fusing points; Ultimate analysis (C
22H
23F
2N
3O
3): calculated value (%): C63.61, H5.54, N10.12, experimental value (%): C63.43, H5.26, N10.02; IR (KBr) 3250,2950,1630,1260cm
-1 1HNMR (CDCl
3, 400MHz): 9.34 (s, 1H), 8.42 (d, 1H), 7.7 (q, 1H), 7.24 (m, 1H), 7.07 (d, 1H), 6.85 (m, 2H), 3.77 (s, 2H), 3.6 (tt, 4H), 1.627 (m, 4H), 0.92 (t, 6H); MS (m/z): 416 (M
++ 1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-7-ethyl-3-indoleacetamide (I
71) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
71White solid, 70～71 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.126 (s, 1H), 7.622 (d, 1H), 7.508 (d, 1H), 7.494 (d, 1H), 7.259 (m, 2H), 7.081 (m, 1H), 3.855 (s, 2H), 3.327 (t, 2H), 3.213 (t, 2H), 1.874～0.834 (m, 10H); MS (m/z): 515 (M
++ 1).
N, N-two-n-propyl-1H-2-(3 ', 4 '-dichloro) phenyl-7-ethyl-3-indoleacetamide (I
72) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
72White solid, 119～120 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.519 (s, 1H), 7.563 (d, 1H), 7.438 (d, 1H), 7.378 (d, 1H), 7.268 (s, 1H), 7.040 (m, 1H), 6.930 (d, 1H), 3.830 (s, 2H), 3.375 (t, 2H), 3.293 (t, 2H), 1.633～0.843 (m, 10H); MS (m/z): 431 (M
++ 1).
N, N-two-n-hexyl-1H-2-(3 ', 4 '-dichloro) phenyl-4,7-two fluoro-3-indoleacetamide (I
73) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
73White solid, 90～91 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 8.944 (s, 1H), 7.512 (s, 1H), 7.435 (d, 1H), 7.327 (m, 1H), 7.316 (t, 1H), 7.269 (m, 1H), 3.737 (s, 2H), 3.400 (t, 2H), 3.279 (t, 2H), 1.803～0.863 (m, 22H); MS (m/z): 523 (M
++ 1).
N, N-two-n-propyl-1H-2-(3 ', 4 '-dichloro) phenyl-4,7-two fluoro-3-indoleacetamide (I
74) preparation
Press embodiment 2 described method preparations.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in the cold back of question response mixture
74White solid, 185～186 ℃ of fusing points;
1HNMR (CDCl
3, 600MHz, ppm): 9.479 (s, 1H), 7.425 (s, 1H), 7.341 (d, 1H), 7.255 (m, 1H), 6.884 (t, 1H), 6.482 (m, 1H), 3.697 (s, 2H), 3.439 (t, 2H), 3.339 (t, 2H), 1.693～0.837 (m, 10H); MS (m/z): 439 (M
++ 1).
Embodiment 3
N, N-two-n-propyl-1H-2-(3 ', 4 '-dichloro) phenyl-3-indoleacetamide (I
16) preparation:
Get 3-(3, the 4-dichloro) benzoyl group-propionic acid 2.5g (0.01mol) and triethylamine 3g (0.03mol) and be dissolved in the tetrahydrofuran (THF) of 25ml, be cooled to-40 ℃.Splash into Vinyl chloroformate 1.1g (0.01mol) under stirring, solution continues down to react half an hour at-20 ℃, adds di-n-propylamine 1g (0.01mol) then, at room temperature continues to stir one hour.The gained suspension liquid carries out chromatographic separation with silicagel column, and (chromatographic solution: ethyl acetate: sherwood oil=2: 1), collect elutriant, evaporated under reduced pressure obtains acid amides.Add phenylhydrazine 2.2g (0.02mol) in the acid amides,, added the 40ml alcohol reflux one hour with 15 gram Zinc Chloride Anhydrous powder mixes.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I is separated with silicagel column in cold back
16White solid.
I
16185～186 ℃ of fusing points; Ultimate analysis (C
22H
23ClN
2O): calculated value (%): C65.68, H5.76, N6.96, experimental value (%): C65.59, H5.75, N6.86; IR (KBr): 3268,2962,1625,1457cm
-1 1HNMR (CDCl
3, 400MHz, ppm): 8.67 (s, 1H), 7.50 (s, 1H), 7.49～7.01 (m, 6H), 3.83 (s, 2H) 3.36 (t, 2H), 3.26 (t, 2H), 1.60 (m, 4H), 0.88 (m, 6H); MS (m/z): 403 (M+1).
Get I with legal system
20, I
21Crystallization (corresponding phenylhydrazine is commercially available).The part physicochemical data sees Table 10.
Table 10 physicochemical data table
| Numbering | NR 1R 2 | R 3、R 4、R 5Or R 6 | R’ | Mp ℃ | Molecular formula | M.W. | MS |
| I 16 I 20 I 21 | N(n-C 3H 7) 2 N(n-C 3H 7) 2 N(n-C 3H 7) 2 | H 5-Br 5-Br | 3 ', 4 '-dichloro, 3 ', 4 '-dichloro, 2 ', 4 '-difluoro | 185～186 115～116 132～133 | C 22H 24Cl 2N 2O C 22H 23BrCl 2N 2O C 22H 23BrF 2N 2O | 402 480 448 | 403(M ++1) 483* 449(M ++1) |
* the MS value is isotope value and M
++ 1 peak
N, N-two-n-propyl-1H-2-(3 ', 4 '-dichloro) phenyl-5-bromo-3-indoleacetamide (I
20) preparation
Undertaken by embodiment 3 described same procedure.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I through re-crystallizing in ethyl acetate is separated with silicagel column in the cold back of question response mixture
20White solid, 115～116 ℃ of fusing points; Ultimate analysis (C
22H
23BrCl
2N
2O): calculated value (%) C65.68 H5.76N6.96, experimental value (%) C65.59 H5.75 N6.86; IR (KBr): 3268,2929,1625,1457;
1HNMR (CDCl
3, 400MHz, ppm): 9.43 (s, 1H), 7.45 (s, 1H), 7.23～6.67 (m, 6H), 3.72 (s, 2H) 3.46 (t, 2H), 3.35 (t, 2H), 1.72 (m, 4H), 0.96 (m, 6H); MS (m/z): 483 (Br isotropic substance M
++ 1).
N, N-two-n-propyl-1H-2-(2 ', 4 '-difluoro) phenyl-5-bromo-3-indoleacetamide (I
21) preparation
Undertaken by embodiment 3 described same procedure.(chromatographic solution: ethyl acetate: sherwood oil=5: 1), get I through re-crystallizing in ethyl acetate is separated with silicagel column in the cold back of question response mixture
21White solid, 132～133 ℃ of fusing points; Ultimate analysis (C
22H
23BrFl
2N
2O): calculated value (%): C58.81, H5.16, N6.23, experimental value (%): C59.20, H5.15, N5.98; IR (KBr): 3253,2964,1625,1450;
1HNMR (CDCl
3, 400MHz, ppm): 9.43 (s, 1H), 7.45 (s, 1H), 7.23～6.67 (m, 6H), 3.72 (s, 2H) 3.46 (t, 2H), 3.35 (t, 2H), 1.72 (m, 4H), 0.96 (m, 6H); MS (m/z): 449 (Br isotropic substance M
++ 1).
Claims (4)
1. formula (I) compound, its optical isomer or its pharmacologically acceptable salt are used for prevention or treatment antidepressant drug purposes in preparation,
Wherein
N=0,1 or 2, R ' is a hydrogen or halogen; The B ring is phenyl ring, x=2, wherein R " be 2 ', 4 '-difluoro, 3 ', 4 '-dichloro, 2 '-Cl, 4 '-CH
3, 2 '-CH
3, 4 '-Cl, 2 '-F, 4 '-CH
3, 2 '-CH
3, 4 '-F; M=1, R
1And R
2Be nC
3H
7-, nC
6H
13-, i-C
3H
7-.
2. according to the purposes of claim 1, R wherein " be 2 ', 4 '-difluoro, R
1And R
2Be respectively nC
3H
7-.
3. according to the purposes of claim 1, wherein R ' is 5-Br, R " be 3 ', 4 '-dichloro, R
1And R
2Be respectively nC
3H
7-.
4. according to the purposes of claim 1, wherein R ' is 5,7-difluoro, R " be 2 ', 4 '-difluoro, R
1And R
2Be respectively n
C6H
13-.
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| CNB021213879A CN1308306C (en) | 2002-06-18 | 2002-06-18 | 2-aryl-trisubstituted indole acetamide derivative and medicinal use thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993000334A1 (en) * | 1991-06-27 | 1993-01-07 | Fidia - Georgetown Institute For The Neurosciences | Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders |
| WO2000051984A1 (en) * | 1999-03-04 | 2000-09-08 | Merck Sharp & Dohme Limited | 2-aryl indole derivatives as antagonists of tachykinins |
-
2002
- 2002-06-18 CN CNB021213879A patent/CN1308306C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993000334A1 (en) * | 1991-06-27 | 1993-01-07 | Fidia - Georgetown Institute For The Neurosciences | Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders |
| WO2000051984A1 (en) * | 1999-03-04 | 2000-09-08 | Merck Sharp & Dohme Limited | 2-aryl indole derivatives as antagonists of tachykinins |
Non-Patent Citations (1)
| Title |
|---|
| 恽榴红2-芳基-3-吲哚取代乙酰胺类衍生物的合成及抗焦虑活性 周勇 杨洪菊 殷明昭 姚霞君，药学学报，第36卷第12期 2001 * |
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