CN102924443B - 5-hydroxy indole derivative contain heterocyclic ring and applications thereof - Google Patents
5-hydroxy indole derivative contain heterocyclic ring and applications thereof Download PDFInfo
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- CN102924443B CN102924443B CN201210459223.5A CN201210459223A CN102924443B CN 102924443 B CN102924443 B CN 102924443B CN 201210459223 A CN201210459223 A CN 201210459223A CN 102924443 B CN102924443 B CN 102924443B
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- 0 C*C1=**C(C)*1=C Chemical compound C*C1=**C(C)*1=C 0.000 description 6
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a 5-hydroxy indole derivative contain heterocyclic ring as shown in a general formula I. The 5-hydroxy indole derivative contains racemate, an optical isomer and salt and/or hydrate received on the pharmacy, wherein substituent groups R1, R2, X, Y and Z have meanings given in a specification. A compound of the formula I can be used for preparing medicine for curing and/or preventing viral infection and is particularly used for preparing anti-HBV medicine and anti-influenza medicine.
Description
Technical field
The present invention relates to a series of 5-OHi analog derivative containing heterocycle and uses thereof, and with the pharmaceutical composition that this compound is activeconstituents, and it is for the preparation for the treatment of and/or preventing the purposes of viral infection particularly in hepatitis B virus, influenza infection medicine.
Background technology
Virus infection can cause various diseases, the health and lives of the serious harm mankind.The virus that found of the whole world is more than 3000 kinds so far, and new virus is still constantly found.According to statistics, the epidemic infectious diseases of 60-65% is caused by virus infection.Due to the interactional complicacy of virus and host, therefore most of antiviral play therapeutic action time, to human body produce toxicity or antiviral effect lower.This is also that antiviral develops slower reason.With regard to current antiviral breed structure, can be still very deficient for the medicine of Clinical practice, the needs of prevention and therapy virus disease can not be met far away.Research has novel antiviral mechanism, antiviral activity is strong and toxicity is low antiviral is significant.
5-OHi-3-ramification of carboxylic esters is initial to be studied as novel anti-influenza virus medicament.Grinev A.H.,
et al. Khim-Farm Zh, 1987,21 (1), 52; Parisheva E.K.
et al. Khim Farm Zh, 1988,22 (5), 565; Mezentseva M.V.
et al. Khim Farm Zh, 1990,24 (10), 52; Otova S.A.,
et al. Khim Farm Zh, 1992,26 (1), 52; Zotova S.A.
et al. Khim Farm Zh, 1995,29 (1), the synthesis of 51 bibliographical informations such as grade some 5-OHis-3-carboxylic acid ester compound and pharmacology activity research thereof, experiment shows that some of them compound has anti-influenza virus activity, and there is inducing interferon produce, strengthen the pharmacological action of body immunity.
1993, such structural derivative-1-methyl-4-[(dimethylamino) the methyl]-2-(phenylthiomethyl developed by USSR (Union of Soviet Socialist Republics) VNIKhFI company)-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid carbethoxy hydrochloride (Arbidol, PCT Int Appl. WO 9008135 (RUSS), 1990-6-26), in Russia's listing, is used for the treatment of and prevents first, second type influenza virus and acute viral respiratory tract infection.
This seminar, take Arbidol as lead compound, transforms further and optimize its structure, successively obtains the 5-OHi-3-ramification of carboxylic esters of a series of novel structure, and has successively applied for Patents to it.
2003, CN1482118 discloses novel 5-hydroxy-3-carboxylate indole derivatives and preparation method thereof, describe 5-hydroxy-3-carboxylate Benzazole compounds or its pharmaceutically accepted salt, infected by influenza and Respirovirus have significant restraining effect, provide a kind of new and effective anti-influenza virus medicament.
2004, CN1706827 discloses 5-OHi-3-ramification of carboxylic esters and uses thereof, describe 5-OHi-3-ramification of carboxylic esters or its pharmaceutically accepted salt of another structure, can be used for preparation and treat and/or prevent viral infection medicine, in particular for preparing hepatitis B virus resisting and anti human immune deficiency virus medicine.
In the virusology index of HBV,
hBeAg is the important symbol that hbv replication is obvious and infectivity is strong.in HBV infection process, HBeAg can with the immunne response of human leucocyte antigen (HLA) synergic adjustment host, suppress the cytotoxic activity of host T cell, form the immunotolerance to HBV infection, HBV escape from immune is removed, is able to store for a long time in Asymptomatic Carriers colony.The HBeAg Virus mutation occurred after antiviral therapy then has prior meaning compared with reducing with HBV-DNA level
:patient can obtain and continue response, and prognosis improves, and improves the immunizing power of HBV; Show that hbv replication is controlled continuously.
On early stage basis, further investigation is proceeded to 5-OHi compounds, find on 2 of indole ring, to introduce sulfur heterocyclic ring as thiadiazolyl group, thiazolyl, thiazolidone group, the activity that compound is secreted hepatitis B virus HBeAg can be increased substantially.
Summary of the invention
The present invention relates to the 5-OHi analog derivative that general formula I contains heterocycle, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
Wherein
R
1for (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, halo;
Y is-NR
3r
4;
R
3and R
4identical or different, be separately selected from (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, optionally by the individual identical or different R of 1-3
8optional replacement;
Or R
3and R
4form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
3and R
4outside the nitrogen-atoms connected, optional 1-4 to be selected from the heteroatoms of N, O and S, described heterocyclic radical and optional 1 ~ 3 the identical or different R of heteroaryl
8replace;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
;
M is 0,1,2;
N is the integer between 0-4;
Q is
,
,
;
R
5for hydrogen, (C
1-C
4) alkyl, C
1-C
4alkoxyl group, hydroxyl, optionally by the (C of hydroxyl, amino or halo
1-C
4) alkyl or (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, free, salify, esterification with amidated carboxyl, halo, (C
1-C
4) alkyl acyl, nitro, cyano group, amino, (C
1-C
4) alkyl amido or coverlet or two [(C
1-C
6) alkyl)] amino that replaces;
Or R
5for (C
6-C
10) aryl or 5-10 unit heteroaryl, they are optionally by R that 1-3 is identical or different
9replace, wherein, described heteroaryl and heterocyclyl contain the heteroatoms that 1-3 is selected from N, O or S;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl,
n-(C
1-C
4) alkyl-carbamoyl,
n, N-two (C
1-C
4) alkyl-carbamoyl, amino-sulfonyl,
n-(C
1-C
4) alkyl amino sulfonyl,
n, N-two (C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
The present invention preferably also relates to the generalformulaⅰcompound be defined as follows, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
Wherein
R
1for (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, halo;
Y is-NR
3r
4;
R
3and R
4identical or different, be separately selected from (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, optionally by the individual identical or different R of 1-3
8optional replacement;
Or R
3and R
4form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
3and R
4outside the nitrogen-atoms connected, optional 1-4 to be selected from the heteroatoms of N, O and S, described heterocyclic radical and optional 1 ~ 3 the identical or different R of heteroaryl
8replace;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
;
M is 0,1,2;
N is the integer between 0-4;
Q is
,
,
;
R
5for hydrogen, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, optionally by (C that (hydroxyl, amino or halogen) replaces
1-C
4) alkyl or (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, (free, salify, esterification or amidated) carboxyl, halo, (C
1-C
4) alkyl acyl, nitro, cyano group, amino, (C
1-C
4) alkylamidoalkyl or coverlet or two (C
1-C
6) alkyl replace amino;
Or R
5for phenyl or 5-6 unit heteroaryl, wherein, described heteroaryl is optionally selected from the heteroatoms of N, O or S containing 1-3, and R
5optionally by the individual identical or different R of 1-3
9replace;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl,
n-(C
1-C
4) alkyl-carbamoyl,
n, N-two (C
1-C
4) alkyl-carbamoyl, amino-sulfonyl,
n-(C
1-C
4) alkyl amino sulfonyl,
n, N-two (C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
The invention still further relates to the compound of Formula I be defined as follows, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
Wherein,
R
1for (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, halo;
Y is-NR
3r
4;
R
3and R
4identical or different, be separately selected from (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, optionally by the individual identical or different R of 1-3
8optional replacement;
Or R
3and R
4form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
3and R
4outside the nitrogen-atoms connected, optional 1-4 to be selected from the heteroatoms of N, O and S, described heterocyclic radical and optional 1 ~ 3 the identical or different R of heteroaryl
8replace;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
;
M is 0,1,2;
N is the integer between 0-4;
Q is
;
R
5for phenyl or 5-6 unit heteroaryl, wherein, described heteroaryl is optionally selected from the heteroatoms of N, O or S containing 1-3, and R
5optionally by the individual identical or different R of 1-3
9replace;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl,
n-(C
1-C
4) alkyl-carbamoyl,
n, N-two (C
1-C
4) alkyl-carbamoyl, amino-sulfonyl,
n-(C
1-C
4) alkyl amino sulfonyl,
n, N-two (C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
The present invention preferably also relates to the generalformulaⅰcompound be defined as follows, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
Wherein
R
1for methyl, ethyl, propyl group, sec.-propyl, cyclopropyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, bromine, fluorine;
Y is-NR
3r
4;
R
3and R
4identical or different, be selected from (C respectively
1-C
4) alkyl, cyclopropyl;
Or R
3and R
4guanidine radicals, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl, 1 is formed together with the nitrogen-atoms connected with them
h-1,2,4-triazole-1-base, 1-imidazolyl, 2-methyl isophthalic acid-imidazolyl and 1
h-tetrazole-1-base;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
;
M is 0,1,2;
N is the integer between 0-4;
Q is
,
;
R
5for hydrogen, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, optionally by (C that (hydroxyl, amino or halogen) replaces
1-C
4) alkyl or (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, (free, salify, esterification with amidated) carboxyl, halo, (C
1-C
4) alkyl acyl, nitro, cyano group, amino, (C
1-C
4) alkylamidoalkyl or coverlet or two (C
1-C
6) alkyl replace amino;
Or R
5for phenyl or 5-6 unit heteroaryl, wherein, described heteroaryl is optionally selected from the heteroatoms of N, O or S containing 1-3, and R
5optionally by the individual identical or different R of 1-3
9replace;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl,
n-(C
1-C
4) alkyl-carbamoyl,
n, N-two (C
1-C
4) alkyl-carbamoyl, amino-sulfonyl,
n-(C
1-C
4) alkyl amino sulfonyl,
n, N-two (C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
The present invention particularly preferably relates to the generalformulaⅰcompound be defined as follows, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
Wherein
R
1for methyl, ethyl, propyl group, sec.-propyl, cyclopropyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, bromine, fluorine;
Y is-NR
3r
4;
R
3and R
4identical or different, be selected from (C respectively
1-C
4) alkyl, cyclopropyl;
Or R
3and R
4guanidine radicals, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl, 1 is formed together with the nitrogen-atoms connected with them
h-1,2,4-triazole-1-base, 1-imidazolyl, 2-methyl isophthalic acid-imidazolyl and 1
h-tetrazole-1-base;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
;
M is 0,1,2;
N is the integer between 0-4;
Q is
,
;
R
5for hydrogen, (C
1-C
4) alkyl, by the identical or different R of 1-3
9the phenyl of optional replacement;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl,
n-(C
1-C
4) alkyl-carbamoyl,
n, N-two (C
1-C
4) alkyl-carbamoyl, amino-sulfonyl,
n-(C
1-C
4) alkyl amino sulfonyl,
n, N-two (C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
The present invention preferably also relates to the generalformulaⅰcompound be defined as follows, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
Wherein,
R
1for methyl, ethyl, propyl group, sec.-propyl, cyclopropyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, bromine;
Y is-NR
3r
4;
R
3and R
4identical or different, be selected from (C respectively
1-C
4) alkyl, cyclopropyl;
Or R
3and R
4guanidine radicals, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl, 1 is formed together with the nitrogen-atoms connected with them
h-1,2,4-triazole-1-base, 1-imidazolyl, 2-methyl isophthalic acid-imidazolyl and 1
h-tetrazole-1-base;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
;
M is 0,1,2;
N is the integer between 0-4;
Q is
;
R
5for phenyl or 5-6 unit heteroaryl, wherein, described heteroaryl is optionally selected from the heteroatoms of N, O or S containing 1-3, and R
5optionally by the individual identical or different R of 1-3
9replace;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl,
n-(C
1-C
4) alkyl-carbamoyl,
n, N-two (C
1-C
4) alkyl-carbamoyl, amino-sulfonyl,
n-(C
1-C
4) alkyl amino sulfonyl,
n, N-two (C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
The present invention preferably also relates to the generalformulaⅰcompound be defined as follows, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
Wherein,
R
1for methyl, ethyl, propyl group, sec.-propyl, cyclopropyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, bromine;
R
3and R
4identical or different, be selected from (C respectively
1-C
4) alkyl, cyclopropyl;
Or R
3and R
4guanidine radicals, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl, 1 is formed together with the nitrogen-atoms connected with them
h-1,2,4-triazole-1-base, 1-imidazolyl, 2-methyl isophthalic acid-imidazolyl and 1
h-tetrazole-1-base;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
;
M is 0,1,2;
N is the integer between 0-4;
Q is
;
R
5for phenyl, furyl, pyrryl, thienyl, pyridyl, and R
5by the individual identical or different R of 1-3
9optional replacement;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl,
n-(C
1-C
4) alkyl-carbamoyl,
n, N-two (C
1-C
4) alkyl-carbamoyl, amino-sulfonyl,
n-(C
1-C
4) alkyl amino sulfonyl,
n, N-two (C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
The present invention preferably also relates to the generalformulaⅰcompound be defined as follows, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
Wherein,
R
1for methyl, ethyl, propyl group, sec.-propyl, cyclopropyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, bromine;
R
3and R
4identical or different, be selected from (C respectively
1-C
4) alkyl, cyclopropyl;
Or R
3and R
4guanidine radicals, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl, 1 is formed together with the nitrogen-atoms connected with them
h-1,2,4-triazole-1-base, 1-imidazolyl, 2-methyl isophthalic acid-imidazolyl and 1
h-tetrazole-1-base;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
;
M is 0,1,2;
N is the integer between 0-4;
Q is
;
R
5for furans-2-base, pyridine-2-base, thiophene-2-base;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl,
n-(C
1-C
4) alkyl-carbamoyl,
n, N-two (C
1-C
4) alkyl-carbamoyl, amino-sulfonyl,
n-(C
1-C
4) alkyl amino sulfonyl,
n, N-two (C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
The present invention's following formula I derivative very particularly preferably, comprises its raceme or optically active isomer, and pharmacy acceptable salt and/or hydrate:
1-cyclopropyl-4-[(dimethylamino) methyl]-2-[(4-phenyl thiazole-2-base) thiomethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(morpholine-4-base) methyl]-2-[(4-phenyl thiazole-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(dimethylamino) methyl]-2-[(4-phenyl thiazole-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(dimethylamino) methyl]-2-[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(Pyrrolidine-1-base) methyl]-2-[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(4-phenyl thiazole-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(4-phenyl thiazole-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(thiazol-2-yl) thiomethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(thiazol-2-yl) thiomethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(imidazoles-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(thiazol-2-yl) sulfonymethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(thiazol-2-yl) sulfonymethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(dimethylamino) methyl]-2-[(4-methylthiazol-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(glyoxal ethyline-1-base) methyl]-2-[thiazol-2-yl) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester.
1-methyl-4-[(Pyrrolidine-1-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(morpholine-4-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(dimethylamino) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(4-methylpiperazine-1-yl) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(4-methylpiperazine-1-yl) methyl]-2-[[2-[2-(3-trifluoromethyl)-4-oxothiazoiium quinoline-3-base] ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(diethylin) methyl]-2-[[2-[2-(4-p-methoxy-phenyl)-4-oxothiazoiium quinoline-3-base] ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(dimethylamino) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylsulfinyl] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(morpholine-4-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylsulfinyl] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(dimethylamino) methyl]-2-[[2-[2-(pyridin-4-yl)-4-oxothiazoiium quinoline-3-base] ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(imidazoles-1-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(glyoxal ethyline-1-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(imidazoles-1-base) methyl]-2-[[2-[2-(3-trifluoromethyl)-4-oxothiazoiium quinoline-3-base] ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(glyoxal ethyline-1-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylsulfinyl] methyl]-5-hydroxyl-6-bromo-1
h-Indole-3-Carboxylic Acid ethyl ester.
And according to some usual methods in field belonging to the present invention, the 5-OHi analog derivative containing heterocycle of formula I of the present invention can generate its pharmacy acceptable salt with acid.Acid can comprise mineral acid or organic acid, and the salt formed with following acid is particularly preferred: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, toxilic acid, citric acid, fumaric acid, Tartaric acid, Phenylsulfonic acid, phenylformic acid or tosic acid etc.
The compounds of this invention can exist with stereoisomer form, and these stereoisomeric forms in any ratio can be enantiomorph or diastereomer.The present invention had both related to enantiomorph or diastereomer, also related to their respective mixtures, as diastereomer, according to self known method, racemic form can be separated into stereomeric one-component.
In addition, the present invention also comprises the prodrug of the compounds of this invention.According to the present invention, prodrug is the derivative of generalformulaⅰcompound, they self may have more weak activity or even not have activity, but upon administration, (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form in physiological conditions.
Unless otherwise noted, term used herein " halo " refers to fluoro, chloro, bromo or iodo, " alkyl " refers to the alkyl of straight or branched, " cycloalkyl " refers to substituted or unsubstituted cycloalkyl, " thiazolinyl " refers to the thiazolinyl of straight or branched, " alkynyl " refers to the alkynyl of straight or branched, " aryl " refers to a hydrogen atom in removing aromatic hydrocarbons and the organic group that obtains, as phenyl, naphthyl, 5-10 unit heteroaryl comprises and is selected from N containing one or more, the heteroatoms of O and S, wherein the ring-type system of each heteroaryl can be monocycle or many rings, ring-type system is aromaticity, altogether containing 5-10 atom, such as imidazolyl can be enumerated, pyridyl, pyrimidyl, pyrazolyl, (1, 2, 3)-and (1, 2, 4)-triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrryl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl-, benzothiazolyl, indyl, quinolyl etc., 5-10 unit heterocyclic radical comprises containing one or more heteroatoms being selected from N, O and S, wherein the ring-type system of each heteroaryl can be monocycle or many rings, but be nonaromatic, ring-type system is altogether containing 5-10 atom, optionally can comprise 1 or 2 carbon-carbon double bond or carbon-carbon triple bond, such as pyrrolidyl, morpholinyl, piperazinyl, piperidyl, thiazolinyl etc. can be enumerated.
Specific compound of the present invention can have asymmetric center, therefore exists with the form of different enantiomorphs and diastereomer.The present invention relates to all optically active isomers, raceme and composition thereof of the compounds of this invention." raceme " refers to the mixture of a pair enantiomer containing equivalent.
Because the 5-OHi compounds leading to I according to above formula of the present invention has antivirus action, the particularly activity of Anti-HBV activity and resisiting influenza virus, therefore, it can be used as the medicine that preparation treats and/or prevents viral infection, the infection particularly caused as HBV, influenza A virus, Influenza B virus, respiratory syncytial virus, parainfluenza virus, rhinovirus and adenovirus etc. by following virus.
Compound according to the present invention can be used as activeconstituents for the preparation for the treatment of and/or preventing hepatitis B, influenza, acute viral respiratory tract infection and influenza, the present invention also provides treatment or prevents the method for above-mentioned disease, comprise the patient significant quantity suffering from or easily suffer from this disease according to compound of the present invention.
The present invention includes pharmaceutical composition, said composition contains the 5-OHi compounds of formula I or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable excipient.Described pharmaceutically acceptable excipient refers to any thinner, auxiliary and/or the carrier that can be used for pharmaceutical field.Compound of the present invention can use with other active ingredient combinations, such as, as long as they do not produce other disadvantageous effect, anaphylaxis.
Pharmaceutical composition of the present invention can be mixed with several formulation, wherein containing some vehicle conventional in pharmaceutical field; Such as, oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding water for injection before the injection can use immediately); Topical formulations (such as ointment or solution).
Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, comprising: the tackiness agent, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc. of oral preparations; The sanitas, solubilizing agent, stablizer etc. of injectable formulation; The matrix, thinner, lubricant, sanitas etc. of topical formulations.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
And, the 5-OHi compounds of formula I is used for the clinical dosage of patient can basis: the age of activeconstituents therapeutic efficiency in vivo and bioavailability, their metabolism and discharge rate and patient, sex, disease phase suitably adjust, but every per daily dose of adult generally should be 10-500mg, is preferably 50-300mg.Therefore, when pharmaceutical composition of the present invention is made into unit dosage, consider above-mentioned effective dose, per unit preparation should lead to the 5-OHi compounds of I containing 10-500mg above formula, be preferably 50-300mg.According to the guidance of doctor or pharmacist, these preparations can divide several times administration (being preferably to six time) at certain intervals.
Synthetic route A-C describes the preparation of generalformulaⅰcompound of the present invention below, and all raw materials are all methods by describing in these schematic diagram, prepared by the method known by organic chemistry filed those of ordinary skill or commercially available.Whole finalization compound of the present invention is all method by describing in these schematic diagram or is prepared by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.The whole variable factors applied in these schematic diagram are as definition hereafter or as the definition in claim.
According to formula I of the present invention or formula II compound, in route A, Y is-NR
3r
4, wherein, R
3, R
4identical or different, be selected from hydrogen, amino, C respectively
1-C
10alkyl, C
3-C
7cycloalkyl, C
2-C
10thiazolinyl and C
2-C
10alkynyl, they can by 1-3 R
8optional replacement; Or R
3, R
4form 5-10 unit heterocyclic radical together with the nitrogen-atoms connected with them, described heterocyclic radical except with R
3and R
4outside the nitrogen-atoms connected, the heteroatoms of N, O and S can be selected from containing 1-4, except R
3and R
4outside the nitrogen-atoms connected, described heterocyclyl comprises 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical can by 1-3 R
8optional replacement; Q is
,
; Substituent R
1, R
2and R
5as summary of the invention part define.
Route A
According to generalformulaⅰcompound of the present invention, in route B, substituent X, R
1, R
2as defined in the claims; Q, R
3and R
4as compound substituent in route A define.
Route B
The synthetic method that compd B-1 can provide according to route A obtain, compd B-1 in glacial acetic acid with Sodium peroxoborate (NaBO
3) be oxygenant, 40 DEG C ~ 60 DEG C reactions, by changing proportioning and the reaction times of oxygenant, can obtain single oxide compound B-2 and double oxide B-3, then carry out the Mannich reaction i.e. compd B-4 of obtained formula I or formula II and B-5.
According to formula I of the present invention or formula II compound, in route C, Y is-NR
3r
4,-S (CH
2)
rr
8, r is the integer between 1-4, R
1, R
2with Z as claim Chinese style II compound define, R
3, R
4and form guanidine radicals or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heteroaryl except with R
3and R
4outside the nitrogen-atoms connected, can be selected from the heteroatoms of N, O and S containing 1-4, described heteroaryl can by the individual identical or different R of 1-3
8optional replacement; Other substituting groups as claim formula II compound define.
Route C
The synthetic method that Compound C-1 can provide according to route A and B obtains, by Compound C-1 and compound H NR
3r
4or HS (CH
2) mR
8reaction, the organic solvent that reaction uses is alcohol-water (1:1) solvent, and temperature of reaction is 60-80 DEG C, and the reaction times is 4-12 h, reaction is finished, concentration of reaction solution, dichloromethane extraction, merges, dry, evaporate to dryness, with ethanol or recrystallizing methanol or through column chromatography, obtains the Compound C-2 of formula I or formula II.
Embodiment
Embodiment is intended to set forth instead of limit the scope of the invention.The proton nmr spectra of compound measures with Bruker ARX-300, and mass spectrum Agilent 1100 LC/MSD measures; Agents useful for same is analytical pure or chemical pure.
The preparation of mercaptan or thiophenol intermediate
Part mercaptan or thiophenol can commercially be buied; The preparation method of other mercaptan or thiophenol is as follows:
Method 1:
preparation
By dithiocarbonic anhydride 100 mL(1.6 mole) add in three-necked bottle, be cooled to-5 DEG C, drip ammonia-ethanolic soln 300 mL of 15%, drip and finish, continue at-5 DEG C and stir 4 h.Suction filtration, ether is washed, dry, obtains yellow crystals ammonium dithiocarbamate 152 g, yield 86%.
By methyl phenyl ketone 100 mL(0.85 mol) add in 150 mL ethanol, keep temperature not add tribromide phenyltrimethyammonium (phenyl trimethylammonium tribromide higher than-5 DEG C in batches, PTT) 320 g (0.85 mol), finish, continue stirring 30 min, suction filtration, filtrate reduced in volume, obtain the alpha-brominated methyl phenyl ketone 164g of colourless liquid, content 95%, yield 92%.
By 40% monochloroacetaldehyde 100 mL(0.61 mol) add in 100 mL water, control temperature is lower than 5 DEG C, add ammonium dithiocarbamate 67 g(0.61 mol in batches), finish, rise to room temperature and continue stirring 2 h, separate out white solid, suction filtration, uses a small amount of ethanol and water washing filter cake respectively, dry, obtain white solid thiazol-2-thiol 66.2 g, yield 93%.
According to the preparation method of thiazol-2-thiol, with monochloroacetone and ammonium dithiocarbamate for raw material, take ethanol as solvent, obtained white solid 4-methylthiazol-2-mercaptan, yield 87%.
According to the preparation method of 4-methylthiazol-2-mercaptan, with alpha-brominated methyl phenyl ketone and ammonium dithiocarbamate for raw material, obtained white solid 4-phenyl thiazole-2-mercaptan, yield 91%.
The logical method 1 (route A) of preparation:
Steps A: the preparation of 3-alkyl amido-2-butylene acid esters (A-1)
Installing gas generating unit, 50% sodium hydroxide solution 300 mL is added in three-necked bottle, under stirring low-grade fever, drip methylamine solution or ethylamine solution (1.4 mol), the methylamine occurred or ethamine gas are imported in acetylacetic ester (1.3 mol), exothermic heat of reaction, stir, water-bath cooling reaction solution, temperature of reaction maintains 35-40 DEG C, after ventilation, stirring at room temperature 17 h.In reaction solution, add ether 300 mL, separate organic layer, it is 8 that organic layer is washed to pH, anhydrous sodium sulfate drying, evaporated under reduced pressure, and obtain 3-methylamino (ethylamino-)-2-butylene acid esters, yield 70 ~ 90%, gained concentrated solution is directly used in the next step.
Be C for alkyl
3~ C
6alkyl, C
3-C
7the alkyl of cycloalkyl and replacement, the 3-alkyl amido-2-butylene acid esters of cycloalkyl, do not need gas generating unit, in the amine instillation acetylacetic ester that can directly be replaced by alkyl, standby according to upper legal system.
Step B:1-alkyl-2-methyl-5-hydroxyl-
1Hthe preparation of-Indole-3-Carboxylic Acid ester (A-2)
Para benzoquinone (0.096 mol) is dissolved in 1,2-ethylene dichloride 100 mL, is heated to 60 DEG C, be stirred to and dissolve completely, drip compd A-1, drip and finish, back flow reaction 8 h, reaction solution is naturally cooled to room temperature, and placement is spent the night, separate out solid, suction filtration, cold acetone is washed, dry, acetone recrystallization obtains compd A-2, yield: 40 ~ 60 %.
Step C:1-alkyl-2-methyl-5-acetoxyl group-1
h-Indole-3-Carboxylic Acid ester (A-3)
Compd A-2 (0.05 mol) is joined in acetone 80 mL, adds pyridine 10 mL (0.1 mol), be stirred to entirely molten, drip Acetyl Chloride 98Min. 5.5 mL (0.075 mol), control temperature of reaction lower than 30 DEG C, drip and finish, stirring at room temperature reacts 4 h, and by reaction solution impouring frozen water under stirring, placement is spent the night, separate out solid, suction filtration, washing, dry, obtain compd A-3, yield 75-90%.
Step D:1-alkyl-2-brooethyl-5-acetoxyl group-6-bromo-1
hthe preparation of-Indole-3-Carboxylic Acid ester (A-4)
Joined in tetracol phenixin 50 mL by compd A-3 (0.04 mol), reflux is entirely molten to solid.Add the benzoyl peroxide of catalytic amount, reflux downhill reaction drop adds dry bromine 5.1 mL (0.1 mol), and drip and finish, reflux 5 h, and reaction is finished, and leaves standstill, cooling, suction filtration, and washing, methanol wash column, obtains compound V, and yield is 65%-85%.
Step e: 1-alkyl-2-(thiomethyl of replacement)-5-hydroxyl-6-bromo-1
hthe preparation of-Indole-3-Carboxylic Acid ester (A-5)
In methyl alcohol 40mL, add thiophenol or the mercaptan (0.03 mol) of potassium hydroxide 5 g (0.09 mol) and replacement, after stirring at room temperature 2 h, gradation adds compd A-4 (0.03 mol), stirring at room temperature 6-8 h, and dilute hydrochloric acid neutralization reaction liquid is to neutral, separate out a large amount of solid, suction filtration, washing, methanol wash column, ethyl acetate is washed, ethyl alcohol recrystallization, obtains white solid, dry compd A-5, yield: 60%-90%.
Step H:1-alkyl-4-[(fatty amido) methyl]-2-(thiomethyl of replacement)-5-hydroxyl-6-bromo-1
hthe preparation of-Indole-3-Carboxylic Acid ester (A-6)
Aliphatic amide (0.032 mol), 37% formaldehyde solution 1.1 mL (0.014 mol) and compd A-5 (0.013 mol) are added in Glacial acetic acid 50 mL successively, in 50-55 DEG C of reaction 6 ~ 8 h, remove acetic acid under reduced pressure, concentrated solution is poured in water 20 mL, add 20% sodium hydroxide solution and adjust pH to 10, dichloromethane extraction water layer, merge organic layer, anhydrous magnesium sulfate drying, evaporate to dryness, obtains oily matter.
Be dissolved in by gained oily matter in acetone 30 mL, drip appropriate ether, leave standstill crystallization, filter, wash with a small amount of acetone, ether washes, obtain A-6, yield is 40 ~ 70%;
Or oily matter is dissolved in acetone 30 mL, drip ethanol solution hydrochloride to pH 1-2, drip a small amount of ether to muddy, leave standstill, spend the night, crystallization obtains A-6 hydrochloride, and yield is 40 ~ 70%.
According to the logical method 1 of preparation, respectively obtained embodiment 1-27 compound (see table one).
Table one:
The logical method 2 of preparation
Steps A: the thiomethyl-5-hydroxyl-6-that 1-alkyl-2-replaces replaces (hydrogen)-1
hthe preparation of-Indole-3-Carboxylic Acid ethyl ester (B-1)
The preparation of compd B-1 can prepare according to the synthetic method of the logical method 1 and 2 of preparation.
Sulfinyl methyl-5-hydroxyl-the 6-that step B:1-alkyl-2-replaces replaces (hydrogen)-1
hthe preparation of-Indole-3-Carboxylic Acid ethyl ester (B-2)
In glacial acetic acid 50 mL, add compd B-1 (0.01 mol) and sodium perborate tetrahydrate (NaBO
3.4H
2o) 1.85g (0.012 mol), stirs, reaction solution is warming up to 40-60 DEG C, reaction 1-2 h, thin-layer chromatography monitoring reaction times.Reaction is finished, and evaporate to dryness, adds water 25 mL, with NaOH (10%) solution adjust pH to 10, and dichloromethane extraction, united extraction liquid, washing, anhydrous sodium sulfate drying, filters, evaporate to dryness, add ether, separate out solid, with ether/acetone recrystallization, obtain compd B-2, yield 60-80 %.
Sulfonymethyl-5-hydroxyl-the 6-that step C:1-alkyl-2-replaces replaces (hydrogen)-1
hthe preparation of-Indole-3-Carboxylic Acid ethyl ester (B-3)
In glacial acetic acid 50 mL, add compd B-1 (0.01 mol) and sodium perborate tetrahydrate (NaBO
3.4H
2o) 3.85 g (0.025 mol), stir, reaction solution are warming up to 40-60 DEG C, reaction 24-36 h, thin-layer chromatography monitoring reaction times.Reaction is finished, and evaporate to dryness, adds water 25 mL, and with NaOH (10%) solution adjust pH to 10, dichloromethane extraction, united extraction liquid, saturated sodium-chloride water solution is washed, washing, anhydrous sodium sulfate drying.Filter, evaporate to dryness, recrystallizing methanol, obtains compd B-3, yield 50-80 %.
Sulfinyl methyl (sulfonymethyl of the replacement)-5-hydroxyl-6-that the amine methyl-2-that step D:1-alkyl-4-replaces replaces replaces (hydrogen)-1
hthe preparation of-Indole-3-Carboxylic Acid ethyl ester (B4 or B-5)
Operate according to preparation logical method 1 step H, compd B-2 or B-3 and applicable aliphatic amide, 37% formaldehyde solution are reacted and are prepared target product B-4 or B-5.
According to the logical method 2 of preparation, respectively obtained embodiment 29-34 compound (see table two).
table two:
The logical method 3 of preparation:
The preparation of Compound C-1:
Compound C-1 can obtain according to the logical method 1 or 2 of preparation.
The preparation of Compound C-2
Compound C-1 (0.02 mol) is added to ethanol: in water (1:1) 80mL, add HNR
3r
4(guanidine, aromatic amine or nitrogenous fragrant heterocycle) or HS (CH
2)
rr
8(0.05 mol), is warming up to 80 DEG C by reaction solution, reaction 6-8 h, concentrating under reduced pressure, and dichloromethane extraction, merges, dry, evaporate to dryness, with applicable solvent recrystallization, or is separated with silica gel column chromatography, obtains Compound C-2, yield: 50-80%.
According to the logical method 3 of preparation, respectively obtained embodiment 35 ~ 65 compound (see table three).
table three:
The pharmacological research of product of the present invention
Below, the screening of In Vitro Anti hepatitis B virus activity and anti-HIV-1-protease activity screening have been carried out to the thiazole-5-OHi analog derivative according to above formula I of the present invention or formula II.
One, In Vitro Anti hepatitis B virus activity screening
With 2.2.15 cell for hepatitis B poisonous carrier, working sample suppresses hepatitis B virus to carry out DNA replication dna and produces the ability of HBsAg, HBeAg.
Test material and method:
1, cell strain: 2.2.15 cell;
2, sample preparation: sample is dissolved in DMSO and is made into proper concn, each sample nutrient solution does 3 times of dilutions, totally 8 extent of dilution.
3, positive control drug: lamivudine (3TC), company produces by Glaxo Wellcome.
4, main agents: HBeAg and s antigen are put and exempted from detection kit, and Beijing North Institute of Biological Technology provides; α
32pdCTP, Chinese Fu Rui biotechnology company limited provides.
5, testing method: 2.2.15 cell kind 96 well culture plate, sample and positive control drug is added respectively by above extent of dilution after 36 hours, establish cell control well simultaneously, the sample cultivation liquid containing different weaker concn is changed respectively after 96 hours, in kind of plate the 8th day difference collecting cell supernatant and 2.2.15 cell, adopt RIA method to detect the secretory volume of HBsAg, HBeAg in cell conditioned medium, dot blot method detects HBV DNA replication dna degree in cell, calculates IC respectively
50and SI.
Test result is as table four.
Table four compound In Vitro Anti hepatitis B virus activity the selection result
"/" represents does not survey activity
two, anti-influenza virus activity screening
With MDCK (suslik kidney) cell for virus host, working sample suppresses influenza virus A type to cause mdck cell lesion degree.
Test material and method:
1, virus strain: first 3 C-type virus C 90-15 strain.
2, sample preparation: sample is dissolved in DMSO before use and is made into proper concn, does 2 times of dilutions with nutrient solution during detection, totally 8 extent of dilution.
3, positive control drug: ribavirin (RBV), is produced by Hubei Ke Yi pharmaceutical factory.
4, testing method: mdck cell kind 96 well culture plate, 24 hours postoperative infection A/ help and prevent/90-15 strain 10
-3adsorb 3 hours, abandon virus liquid, sample and positive control drug is added by above extent of dilution, establish cell control well and virus control wells simultaneously, 30 hours observation of cell lesion degrees (CPE), with the half-inhibition concentration (IC of Reed-Muench method difference calculation sample infected by influenza A type
50).
Measurement result is in table five.
table five Compound ira vitro anti-influenza virus activity the selection result
Claims (10)
1. the compound of formula I, or its pharmacy acceptable salt,
Wherein,
R
1for (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl;
R
2for (C
1-C
6) alkyl;
X is hydrogen, halo;
Y is-NR
3r
4;
R
3and R
4identical or different, be separately selected from (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, optionally by the individual identical or different R of 1-3
8optional replacement;
Or R
3and R
4form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl together with the nitrogen-atoms connected with them, described heterocyclic radical and heteroaryl except with R
3and R
4outside the nitrogen-atoms connected, optional 1-4 to be selected from the heteroatoms of N, O and S, described heterocyclic radical and optional 1 ~ 3 the identical or different R of heteroaryl
8replace;
R
8representative (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group, nitro;
Z is
M is 0,1,2;
N is the integer between 0-4;
Q is
R
5for hydrogen, (C
1-C
4) alkyl, C
1-C
4alkoxyl group, hydroxyl, optionally by the (C of hydroxyl, amino or halo
1-C
4) alkyl or (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, free, salify, esterification or amidated carboxyl, halo, (C
1-C
4) alkyl acyl, nitro, cyano group, amino, (C
1-C
4) alkyl amido or coverlet or two [(C
1-C
6) alkyl)] amino that replaces;
Or R
5for (C
6-C
10) aryl or 5-10 unit heteroaryl, they are optionally by R that 1-3 is identical or different
9replace, wherein, described heteroaryl and heterocyclyl contain the heteroatoms that 1-3 is selected from N, O or S;
R
9for (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, carboxyl, amino, nitro, cyano group, sulfydryl, (C
1-C
4) thiazolinyl, (C
1-C
4) alkynyl, (C
1-C
4) alkylthio, hydroxyl (C
1-C
4) alkyl, amino (C
1-C
4) alkyl, allyl group, (2-methyl) allyl group, (3-methyl) allyl group, (2-methyl)-2-alkene butyl, (C
1-C
4) alkyl amido, (C
1-C
4) alkyl sulphinyl, (C
1-C
4) alkyl sulphonyl, (C
1-C
4) alkoxy methyl, (C
1-C
4) alkyl acyl, formamyl, N-(C
1-C
4) alkyl-carbamoyl, N, N-bis-(C
1-C
4) alkyl-carbamoyl, amino-sulfonyl, N-(C
1-C
4) alkyl amino sulfonyl, N, N-bis-(C
1-C
4) alkyl amino sulfonyl and (C
1-C
3) alkylenedioxy group.
2. the generalformulaⅰcompound of claim 1, or its pharmacy acceptable salt,
Wherein
Q is
R
5for hydrogen, (C
1-C
4) alkyl, (C
1-C
4) alkoxyl group, hydroxyl, optionally by (C that (hydroxyl, amino or halogen) replaces
1-C
4) alkyl or (C
1-C
4) alkoxyl group, (C
1-C
4) alkylthio, (free, salify, esterification or amidated) carboxyl, halo, (C
1-C
4) alkyl acyl, nitro, cyano group, amino, (C
1-C
4) alkylamidoalkyl or coverlet or two (C
1-C
6) alkyl replace amino; Or R
5for phenyl or 5-6 unit heteroaryl, wherein, described heteroaryl is optionally selected from the heteroatoms of N, O or S containing 1-3, and R
5optionally by the individual identical or different R of 1-3
9replace.
3. the generalformulaⅰcompound of claim 2, or its pharmacy acceptable salt,
Wherein,
R
1for methyl, ethyl, propyl group, sec.-propyl, cyclopropyl;
X is hydrogen, bromine, fluorine;
Y is-NR
3r
4;
R
3and R
4identical or different, be selected from (C respectively
1-C
4) alkyl, cyclopropyl;
Or R
3and R
4guanidine radicals, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, piperidino, 1-pyrrolidyl, 1H-1,2,4-triazole-1-base, 1-imidazolyl, 2-methyl isophthalic acid-imidazolyl and 1H-tetrazole-1-base is formed together with the nitrogen-atoms connected with them;
Q is
4. the generalformulaⅰcompound of claim 3, or its pharmacy acceptable salt,
Wherein,
R
5for hydrogen, (C
1-C
4) alkyl, by the identical or different R of 1-3
9the phenyl of optional replacement.
5. the generalformulaⅰcompound of claim 3, or its raceme or optically active isomer, or its pharmacy acceptable salt and/or hydrate,
X is hydrogen, bromine;
Q is
R
5for phenyl or 5-6 unit heteroaryl, wherein, described heteroaryl is optionally selected from the heteroatoms of N, O or S containing 1-3, and R
5optionally by the individual identical or different R of 1-3
9replace.
6. the generalformulaⅰcompound of claim 5, or its pharmacy acceptable salt,
Wherein, R
5for phenyl, furyl, pyrryl, thienyl, pyridyl, and R
5by the individual identical or different R of 1-3
9optional replacement.
7. the generalformulaⅰcompound of claim 6, or its pharmacy acceptable salt,
Wherein, R
5for furans-2-base, pyridine-2-base, thiophene-2-base.
8. following formula I derivative, or its pharmacy acceptable salt:
1-cyclopropyl-4-[(dimethylamino) methyl]-2-[(4-phenyl thiazole-2-base) thiomethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(morpholine-4-base) methyl]-2-[(4-phenyl thiazole-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(dimethylamino) methyl]-2-[(4-phenyl thiazole-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(dimethylamino) methyl]-2-[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(Pyrrolidine-1-base) methyl]-2-[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(4-phenyl thiazole-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(4-phenyl thiazole-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(thiazol-2-yl) thiomethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(thiazol-2-yl) thiomethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(imidazoles-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(thiazol-2-yl) sulfonymethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(thiazol-2-yl) sulfonymethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(dimethylamino) methyl]-2-[(4-methylthiazol-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(glyoxal ethyline-1-base) methyl]-2-[thiazol-2-yl) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(4-methylthiazol-2-base) sulfonymethyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(imidazoles-1-base) methyl]-2-[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(glyoxal ethyline-1-base) methyl]-2-[(5-methyl isophthalic acid, 3,4-thiadiazoles-2-base) sulfinyl methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(Pyrrolidine-1-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(morpholine-4-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(dimethylamino) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(4-methylpiperazine-1-yl) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(4-methylpiperazine-1-yl) methyl]-2-[[2-[2-(3-trifluoromethyl)-4-oxothiazoiium quinoline-3-base] ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(diethylin) methyl]-2-[[2-[2-(4-p-methoxy-phenyl)-4-oxothiazoiium quinoline-3-base] ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(dimethylamino) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylsulfinyl] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(morpholine-4-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylsulfinyl] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(dimethylamino) methyl]-2-[[2-[2-(pyridin-4-yl)-4-oxothiazoiium quinoline-3-base] ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(imidazoles-1-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(glyoxal ethyline-1-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-methyl-4-[(imidazoles-1-base) methyl]-2-[[2-[2-(3-trifluoromethyl)-4-oxothiazoiium quinoline-3-base] ethylmercapto group] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester;
1-cyclopropyl-4-[(glyoxal ethyline-1-base) methyl]-2-[[2-(2-phenyl-4-oxothiazoiium quinoline-3-base) ethylsulfinyl] methyl]-5-hydroxyl-6-bromo-1H-Indole-3-Carboxylic Acid ethyl ester.
9. a medicinal compositions, to comprise in claim 1-8 any one compound or its pharmacy acceptable salt as activeconstituents and pharmaceutically acceptable excipient.
10. in claim 1-8, any one compound or its pharmacy acceptable salt or pharmaceutical composition according to claim 9 are preparing the application treated and/or prevented in hepatitis B virus medicaments.
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| TW102140944A TWI609015B (en) | 2012-11-15 | 2013-11-11 | 5-Hydroxyindan derivatives containing heterocyclic rings and uses thereof |
| PCT/CN2013/087136 WO2014075618A1 (en) | 2012-11-15 | 2013-11-14 | Heterocyclic ring-containing 5-hydroxy indole derivative and use thereof |
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| CN106608874B (en) * | 2015-10-22 | 2019-04-12 | 湖南大学 | 2- [5- (nitrogen azoles -1- base) thiazole -2- imino group] thiazolinone and the preparation method and application thereof |
| WO2018112128A1 (en) * | 2016-12-16 | 2018-06-21 | The Scripps Research Institute | Arbidol analogs with improved influenza hemagglutinin potency |
| CN112972466B (en) * | 2019-12-16 | 2022-09-09 | 沈阳药科大学 | Application of 5-hydroxyindole-3-carboxylate compound in inhibiting peripheral inflammation and central nervous system inflammation |
| CN111358786A (en) * | 2020-05-15 | 2020-07-03 | 淮安市厚沐医疗技术咨询中心 | Application of Gab1 inhibitor in treatment of bile duct cancer |
| CN111529525A (en) * | 2020-05-15 | 2020-08-14 | 淮安市厚沐医疗技术咨询中心 | Application of Gab1 inhibitor in treatment of bile duct cancer |
| CN114380770B (en) * | 2021-12-24 | 2022-12-09 | 山东艾孚特科技有限公司 | Synthesis process of methyl mercapto thiadiazole catalyzed by solid superacid |
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| CN100519523C (en) * | 2004-03-12 | 2009-07-29 | 沈阳药科大学 | 5-hydroxyindole-3-carboxylate derivative and its use |
| CN101190913A (en) * | 2006-12-01 | 2008-06-04 | 黄振华 | Novel compound with antiviral activity |
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| Title |
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| 《Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 5-hydroxy-1H-indole-3-carboxylates》;Chunshen Zhao;《Bioorganic & Medicinal Chemistry》;20051001;第14卷;2552-2558 * |
| 《Synthesis and in vitro anti-hepatitis B virus activities of some ethyl 6-bromo-5-hydroxy-1H-indole-3-carboxylates》;Huifang Chai et al.;《Bioorganic & Medicinal Chemistry》;20050923;第14卷;911-917 * |
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