CN101468985A - 5-(3-aromatic heterocyclic substituted phenyl) tetrazole compounds and anti-HIV/AIDS use thereof - Google Patents

5-(3-aromatic heterocyclic substituted phenyl) tetrazole compounds and anti-HIV/AIDS use thereof Download PDF

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CN101468985A
CN101468985A CNA2007103069390A CN200710306939A CN101468985A CN 101468985 A CN101468985 A CN 101468985A CN A2007103069390 A CNA2007103069390 A CN A2007103069390A CN 200710306939 A CN200710306939 A CN 200710306939A CN 101468985 A CN101468985 A CN 101468985A
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coor
alkyl
phenyl
tetrazole
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谢蓝
刘琨
侯岭
姜世勃
陆红
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Institute of Pharmacology and Toxicology of AMMS
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    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D417/10—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 carbon chain containing aromatic rings
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    • 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

Abstract

The invention relates to medical salts for 5-(3-aromic hetero ring substituted benzene)-tetrazole compounds in a formula I, wherein various substituents are defined in the patent claim. The invention also relates to a method for preparing the compounds, a medicine composition containing the compounds, and application of the compounds in preparing medicines for treating or preventing diseases related to HIV infection.

Description

The application of 5-(3-aromatic heterocyclic substituted phenyl base) tetrazole compound and anti-HIV/AIDS thereof
Technical field
The present invention relates to 5-(3-aromatic heterocyclic substituted phenyl)-tetrazole compound, its preparation method, contain their pharmaceutical composition and the application in the medicine of preparation is used for the treatment of or prevention and HIV infect diseases associated or illness thereof.
Background technology
Acquired immune deficiency syndrome (AIDS) is the caused a kind of serious communicable disease of human immunodeficiency virus (HIV).HIV is a kind of RNA retrovirus, and its selectivity infects the surperficial cell that has the CD4 acceptor among the human immune system, as lymphocyte, mononuclear macrophage, dendritic cell etc.This virus surface is the two adipose membrane of layer, and two kinds of important glycoprotein: gp120 and gp41 are arranged on the film, and gp120 is used for the CD4 acceptor on recognizing cells surface in the outside of film; Gp41 is across viromembrane, and main effect is to merge viromembrane and cytolemma, then viral internal core material is discharged in the host cell matter.Be wrapped in 2 single stranded RNAs and some important enzymes (as reversed transcriptive enzyme, proteolytic ferment, intergrase) and structural protein (p24, p17, p7 etc.) in the viromembrane.HIV is external irreproducible, must be by means of human body cell ability reproduction, its reproduction process roughly is divided into 7 steps: viral attack cell (binding), merge (fusing), reverse transcription (reverse transcription), integrate (integration), transcribe (transcription), translate (translation) and reorganization and overflow (assembly﹠amp; Budding) cell.Virus of AIDS constantly duplicates with such working cycle, infect the human immunocyte, destroy the immunity system of human body, finally cause completely losing of immune function of human body, make patient be in all kinds of infection and have no among the danger of defensive ability/resistance ability, thereby cause multiple infectious diseases and tumour, finally cause death.Theoretically, medicine is as long as the arbitrary link in the blocking virus reproduction process all can reach the purpose that suppresses virus and treatment disease.
Up to now, the clinical medicine that the FDA approval is used for the treatment of acquired immune deficiency syndrome (AIDS) has 20, be divided into four classes (Erik DC.Antiviral drugs in current clinical use.J Clin Virol, 2004,30 (2): 115-133): (1) efabirenz (nucleosidereverse trascriptase inhibitors, NRTIs), 8; (2) non-nucleoside reverse transcriptase inhibitor (non-nucleoside reverse trascriptase inhibitors, NNRTIs), 3; (3) proteinase inhibitor (protease inhibitors, PIs), 8; (4) fusion inhibitor (fusion inhibitors, FIs), 1.Clinically medication combined treatments of adopting different mechanism of action more, as two kinds of reverse transcriptase inhibitors and a kind of proteinase inhibitor (Robb ins GK, De GV, Shafer RW, et al.Comparison ofsequential three-drug regimens as initial therapy for HIV-1infection.N Eng1 J Med, 2003,349:2293 303. and Shafer RW, Smeaton LM, Robbins GK, et al.Comparison of four-drug regimensand pairs of sequential three-drug regimens as initial therapy forHIV-1infection.N Eng1 J Med, 2003,349:2304 15).Though this therapy can effectively suppress the intravital virus load of the infected, reduces its M ﹠ M, but still there is problem such as easily develop immunity to drugs, toxic side effect is big.Therefore, seek the novel drugs target spot in the virus replication, and press for the inverase of this development of new mechanism of action.
Existing inverase all is to enter reproduction process performance restraining effect behind the cell at virus.Yet along with deepening continuously of and cytogamy Mechanism Study viral to HIV, people more and more pay close attention to the drug research that can prevent virus intrusion cell, bring into play antivirus action at virus replication in early days.Such medicine both can suppress virus infected cell, can suppress virus replication again, was expected to have different mechanism of action for patient provides, more efficiently novel anti H IV medicine.
The process of HIV invasion cell mainly contains 3 steps: adheres to, combine with accessory receptor, the film fusion.Viral envelope glycoprotein gp120 at first combines (GallaherWR with the CD4 molecule of cell surface, Ball JM, Garry RF, et al.A general model for the surf aceglycoproteins of HIV and other retroviruses.AIDS Res Hum Retrovir, 1995,11:191-202), after structure looks like to change again with accessory receptor (chemokine, as CXCR4 or CCR5) in conjunction with (Dragic T, Litwin V, Allaway GP, et al.HIV-1entry into CD4+ cells is mediated by the chemokine receptorCC-CKR-5.Nature, 1996,381:66773); Insert cytolemma by gp41 subsequently and form 6 spirochetes, viromembrane and cytolemma are furthered makes it fusion.In this process, gp120 and gp41, CD4 acceptor and accessory receptor all are considered possible drug target.Wherein, gp41 plays crucial effects in whole fusion process.
The aminoacid sequence of Gp41 has four functional zone.(transmembrane domain TM) is fixed on gp41 on the viromembrane to be positioned at the film district of striding of C end; The CHR section (C-terminal heptad repeat, CHR) (N-terminal heptadrepeat NHR) is the funtion part of gp41 structure with the NHR section; Melt film peptide (fusion peptide, FP) be the one section highly hydrophobic sequence that is positioned at the N end, main effect is to insert (Melikyan GB in the host cell membrane, Markosyan RM, Hemmati H, et al.Evidence that thetransition of HIV-1 gp41 into a six-helix bundle, not the bundleconfiguration, induces membrane fusion.J Cell Biol, 2000,151:413 23 and Munoz-Barroso I, Salzwedel K, Hunter E, et al.Role ofthe membrane-proximal domain in the initial stages of humanimmunodeficiency virus type 1 envelope glycoprotein-mediatedmembrane fus ion.J Virol, 1999,73:608992).
Three sections NHR spirals of the gp41 of virus surface are parallel to central authorities, and around being centered around to three sections CHR spiral antiparallels, the outside is surrounded by 3 gp120.When virus infected cell, after combining, the CD4 acceptor of the gp120 of virus surface and cell surface and accessory receptor make its structure look like to change, the NHR spiral of gp41 just stretches out from central authorities, the film peptide that melts of N end is inserted (Coleman CI in the cytolemma, Musial BL and Ross J.Enfuvirtide:The first fusioninhibitor for the treatment of patients with HIV-1 infection.Formulary, 2003,38:204222).Subsequently, NHR and CHR draw close mutually, form parallel hexa-atomic helical bundle again.This conformational change provides energy needed for the aquation surface of peplos and host cell membrane is close mutually, thereby viromembrane and cytolemma are furthered, and impels the generation of fusion.(Cooley LA and Lewin SR, HIV-1 cell entry andadvances in viral entry inhibitor therapy.J Clin Virol, 2003,26:121 132 and Moore JP and Doms RW.The entry of entry inhibi tors:A fusion of science and medicine.Proc Natl Acad Sci U S A, 2003,100:10598 10602).The many gp41 of virus surface make two membranes form intermembranous fusion hole, and the flowability of film makes it rapid expansion, finally realize the fusion fully of HIV coating and host cell membrane, and the nucleoid material is released in the host cell matter.
The two sections functional zone NHR of gp41 and CHR can become the action target spot of HIV fusion inhibitor.First fusion inhibitor medicine T-20 (Fuzeon) of drugs approved by FDA is 36 amino acid whose polypeptide of a simulation CHR spirane structure sequence.It is by combining the formation of blocking hexa-atomic helical bundle with NHR, thereby reach purpose (the Fung HB that suppresses virus and cytolemma fusion, BCPS andGuo Y.Enfuvirtide:A Fusion Inhibitor for the Treatment of HIVInfection.Clin Ther, 2004,26 (3): 352-378).Because T20 is peptide medicament, exist that oral administration biaavailability is poor, the high deficiency of production cost, be one of main direction of studying of anti-HIV new medicament so seek non-peptide micromolecular HIV fusion inhibitor guide thing efficient, low toxicity.
By the target screening active ingredients is carried out in the diversified micromolecular compound of structure storehouse, two N-aryl carboxylic acid substituted azole micromolecular compound N B-2 and NB-64 (Jiang Sh-B, Lu H, Liu Sh-W, et al.N-Substituted Pyrrole Derivatives as Novel HumanImmunodeficiency Virus Type 1 Entry Inhibitors That Interfere withthe gp41 Six-Helix Bundle Format ion and Block Virus Fusion.Antimicrob Agents Chemother, 2004,48:4349-4359) not only in cell model, demonstrate good anti-HIV replication activity (EC 50Value is respectively 1.04 μ M and 2.21 μ M), and at the test for fusion (EC of virus with cytolemma 50Value is respectively 6.74 μ M and 29.92 μ M) and the hexa-atomic helical bundle of gp41 form [IC in the test 50(6-HB) value is respectively 13.48 μ M and 15.69 μ M] all there is obvious inhibition active.These test-results show that NB-2 and NB-64 are really for acting on the small molecule active compound of gp41.Based on the structure ultimate principle relevant,, may search out active better small molecules fusion inhibitor to their structure of modification with biological activity.
Figure A200710306939D00121
Summary of the invention
The present invention relates to the compound with 5-substituted-phenyl-tetrazole skeleton structure of formula I, they can effectively suppress the formation of HIV-1 surface glycoprotein gp41 six aggressiveness, duplicate thereby suppress HIV.To the further investigation of this compounds, might find novel non-peptide micromolecular HIV fusion inhibitor, become new anti-AI DS medicine.
First aspect present invention relates to tetrazole aryl-heterocyclic compounds or its pharmacologically acceptable salt of formula I:
Figure A200710306939D00131
Wherein,
R 1=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl;
R 2=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
Ar contains 1-3 the heteroatomic five yuan of hetero-aromatic rings that are selected from N, O, S, is selected from:
Figure A200710306939D00132
With
Figure A200710306939D00133
R wherein 3=CHO, COR ', COOR ', COOH, CF 3, CH 2R ", halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-OH ,-NO 2,-CN ,-HC=CH-CN ,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', or on the utilized position of its ring structure, have ester group, carboxyl, C for choosing wantonly 1-6The following heterocyclic group that alkyl, phenyl replace:
Figure A200710306939D00134
Wherein, X and Y are selected from C independently of one another, O, S and NH;
R 4=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl, phenyl;
R 5=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, CHO ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
Above-mentioned five yuan of hetero-aromatic rings are chosen wantonly on its ring and can be utilized the position to have to be selected from aldehyde radical, ketone group, ester group, carboxyl, cyano group, α, beta unsaturated ketone, alkene, alkynes, C 1-6Alkyl, C 1-6Alkoxyl group, halogen ,-NH 2,-OH ,-NO 2With-CF 3Substituting group;
R '=C 1-6Alkyl; And
R " be halogen, OH or C 1-6Alkoxyl group.
The term that is adopted among the present invention " alkyl " comprises alkyl, thiazolinyl and alkynyl.
The present invention is to substituent R 3" following heterocyclic group " related in the description includes but not limited to 2,4-thiazolidinedione, 2-sulfo--2,4-thiazolidinedione (rhodanine, Rhodanine), succimide, 2, the 4-imidazolinedione (glycolylurea, glycolylurea, hydantoin), 2-thiohydantoin (2-Thiohydantoin), false thio-hydantoin (Pseudothiohydantoin) etc.
Second aspect of the present invention relates to the preparation method of formula I compound or pharmaceutically acceptable salt thereof.
Third aspect of the present invention relates to the pharmaceutical composition that contains at least a formula I compound or pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers or vehicle.
The 4th aspect of the present invention relates to the purposes that above-mentioned formula I compound or pharmaceutically acceptable salt thereof is used to prepare the medicine of diseases associated that treatment and HIV infect or illness.
According to a preferred embodiment of the present invention, Ar is a substituted azole, shown in II:
Figure A200710306939D00141
Wherein,
R 1=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl;
R 2=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R 3=CHO, COR ', COOR ', COOH, CF 3, CH 2R ", halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-OH ,-NO 2,-CN ,-HC=CH-CN ,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', or on its ring structure, have ester group, carboxyl, C for choosing wantonly 1-6The following heterocyclic group that alkyl, phenyl replace:
Figure A200710306939D00151
Wherein, X and Y are selected from C independently of one another, O, S and NH;
R 4=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl, phenyl;
R 5=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, CHO ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R 6=H, CH 3, CF 3, halogen or C 2-4Alkyl;
R '=C 1-6Alkyl; And
R " be halogen, OH or C 1-6Alkoxyl group.
According to another preferred embodiment of the present invention, Ar is 1,2, the 4-oxadiazole, shown in the following formula III:
Figure A200710306939D00152
Wherein,
R 1=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl;
R 2=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R 3=CHO, COR ', COOR ', COOH, CF 3, CH 2R ", halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-OH ,-NO 2,-CN ,-HC=CH-CN ,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', or on its ring structure, have ester group, carboxyl, C for choosing wantonly 1-6The following heterocyclic group that alkyl, phenyl replace:
Wherein, X and Y are selected from C independently of one another, O, S and NH;
R 4=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl, phenyl;
R 5=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, CHO ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R '=C 1-6Alkyl; And
R " be halogen, OH or C 1-6Alkoxyl group.
According to another preferred embodiment of the present invention, Ar is the 5-substituted furan, shown in IV:
Figure A200710306939D00162
Wherein,
R 1=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl;
R 2=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R 3=CHO, COR ', COOR ', COOH, CF 3, CH 2R ", halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-OH ,-NO 2,-CN ,-HC=CH-CN ,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', or on its ring structure, have ester group, carboxyl, C for choosing wantonly 1-6The following heterocyclic group that alkyl, phenyl replace:
Figure A200710306939D00171
Wherein, X and Y are selected from C independently of one another, O, S and NH;
R 4=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl, phenyl;
R 5=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, CHO ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R '=C 1-6Alkyl; And
R " be halogen, OH or C 1-6Alkoxyl group.
The present invention is following compounds more preferably:
5-(3-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1a);
5-(2-hydroxyl-5-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1b);
5-(2-chloro-5-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1c);
5-(3-(3-ethoxycarbonyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1d);
5-(3-(3-carboxyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1e);
5-(3-(1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1f);
1-carboxymethyl-5-(3-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-2b);
1-carboxymethyl-5-(3-(3-carboxyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-2d)
5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole (III-1a);
5-(3-(5-(chloromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole (III-1b);
5-(3-(5-(methylol)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole (III-1c);
1-carboxymethyl-5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole (III-2b);
1-ethyl-5-(3-(5-methyne-(rhodanine-5-yl)-furans-2-yl) phenyl)-1H-tetrazole (IV-2a); With
1-carboxymethyl-5-(3-(5-methyne-(rhodanine-5-yl)-furans-2-yl) phenyl)-1H-tetrazole (IV-2b).
The compounds of this invention can prepare by multiple reaction scheme and method, as shown in the figure:
Route A: universal method:
Figure A200710306939D00181
Reaction conditions: (i) hydrochloride (as ammonia chloride, lithium chloride etc.), DMF is a solvent, room temperature is to refluxing 4-24 hour; (ii) sodium alkoxide is in methyl alcohol or ethanol, room temperature to 100 ℃, 4-32 hour
Route B: for the compound that Ar among the formula I is pyrrole ring:
Figure A200710306939D00182
Reaction conditions: (iii) microwave reaction is a solvent or solvent-free with acetic acid, 120-160 ℃, and 5-20 minute; (ii) with the second step reaction conditions among the route A.
Route C: for the compound of Ar Wei oxadiazole ring among the formula I:
Figure A200710306939D00191
Reaction conditions: (iv) in the presence of the 8-phenopyridine, yellow soda ash or salt of wormwood, 80-100 ℃, 2-8 hour, ethanol was solvent; (v) pyridine or tetrahydrofuran (THF) are solvent, room temperature to 120 ℃, 2-6 hour; (ii) with the second step reaction conditions among the route A.
Route D: for the compound that Ar among the formula I is five-membered ring (as pyrroles, furans etc.) aldehyde:
Figure A200710306939D00192
Reaction conditions: (vi) Suzuki linked reaction, organic boronic reagent, palladium catalyst; (vii) condensation reaction (to that indicated in the drawings or relevant ketone reagent), alkaline condition: organic amine, inorganic strong alkali or weak acid strong alkali salt, the mixed solvent of methyl alcohol, ethanol, acetate, DMF or DMF and water, room temperature-160 ℃, 1-44 hour.
Ar in the above-mentioned reaction scheme, R 1-R 4, R 6The same formula I is described with the definition of X, Y, and U, V, W represent to be selected from the heteroatoms of N, O, S independently of one another or be carbon atom.Specifically,
Synthetic route A: the cyano group of substituted benzene cyanogen compound (A) and sodiumazide effect can be synthesized 1H-tetrazole ring, obtain target compound I-1, and 1 nitrogen hydrogen and halohydrocarbons reaction on the tetrazole ring can obtain Compound I-2.
Synthetic route B: the 5-of replacement (3-amino) phenyl-1H-tetrazole (B) and 2,1 of 5-dimethoxy-tetrahydrofuran or the replacement of β position, the 4-diketone carries out the Paal-Knorr reaction can obtain N-aryl pyrrole compounds (II-1), generates 1H-tetrazole-N-aryl pyrrole compounds (II-2) that 1-replaces with halohydrocarbons reaction again.
Synthetic route C: make raw material with 5-(3-cyano group) phenyl-1H-tetrazole (C) that replaces; generate amino oxime intermediate (D) with the oxammonium hydrochloride reaction; can obtain 3-aryl-1 with the acylating reagent effect again; 2; 4-oxadiazole compounds (III-1), the halogenating reaction of nitrogen can get target compound III-2 then.
Synthetic route D: the 5-of replacement (3-bromine) phenyl-1H-tetrazole (E) reacts by Suzuki with fragrant heterocyclic boric acid compound, and coupling generates and contains fragrant heterocyclic target compound IV-1.When fragrant heterocycle contains aldehyde radical, can obtain target compound IV-2 through condensation, halo.
The 5-of the replacement that the present invention relates to (3-aromatic heterocyclic substituted phenyl base) tetrazole compound (formula I) is the HIV (human immunodeficiency virus)-resistant activity compound that a class has new skeleton structure.They act on HIV-1gp41, will be expected to develop into the novel inverase that a class has particular target: non-peptide micromolecular fusion inhibitor.Test-results of the present invention shows: Compound I I-1a suppresses 6-HB bonded IC 50Value is 25.61 μ M, is higher than positive control compound N B-64 (IC used in the identical test 50=58.74 μ M).This compound in test cell line (MT-2 lymphocyte) to the active EC of the inhibition of wild-type HIV 50Value is 7.70 μ M (SI〉32), and duplicating of clinical isolating eurypalynous HIV virus strain all had suppresses active, obviously is better than known activity compound N B-64.The activity data of part correlation compound sees Table 1-2.Result of the present invention shows with II-1a to be that the compound of representative is effect HIV-1 gp41 target spot, has a class novel anti HIV active compound of antiviral spectrum widely, can develop into the inhibitor that the anti-HIV of non-peptide micromolecular merges.
The compounds of this invention both can itself also can its pharmacologically acceptable salt or solvate forms use.The pharmacologically acceptable salt of formula I compound comprises the conventional salt with pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases formation.The example of suitable acid salt comprises with hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, pounces on the salt that acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, tannic acid etc. form.The example of suitable base addition salt comprises and sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, the salt that N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethanolamine, quadrol, N-methylglucosamine and PROCAINE HCL, PHARMA GRADE etc. form.When relating to The compounds of this invention herein, comprise formula I compound and pharmacologically acceptable salt thereof or solvate.
According to the present invention, formula I compound of the present invention can become pharmaceutical composition with conventional pharmaceutical carrier or vehicle group.This pharmaceutical composition can be by oral or parenteral route administration.Pharmaceutical composition of the present invention can be prepared into various formulations by this area ordinary method, includes but not limited to tablet, capsule, solution, suspension, granule or injection etc., oral administration or parenteral route administration.
It may be noted that in addition, The compounds of this invention using dosage and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～100mg/kg body weight/day.
Embodiment
The following examples are used to further specify the present invention, but it does not mean that the present invention only limits to this.
Embodiment 1:5-(3-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1a) (synthetic route B)
2,5-hexanedione (0.13mL) is added in Glacial acetic acid (3mL) solution that contains 3-(1H-tetrazole-5-yl) aniline (1mmol), and under the microwave condition, 150 ℃ were reacted 10 minutes.Be chilled to room temperature, reactant is poured in the frozen water, collects solid, is washed to neutrality, separates (petrol ether/ethyl acetate/acetate) with preparative chromatography and gets white solid 124mg, yield 52%, mp147-148 ℃; 1H NMR (DMSO-D 6) δ ppm 8.14 (1H, d, J=8.4Hz, ArH-6), 7.87 (1H, s, ArH-2), 7.76 (1H, t, J=8.4Hz, ArH-5), 7.53 (1H, d, J=8.4Hz, ArH-4), 5.85 (2H, s, PyH), 2.02 (6H, s, Py-CH 3* 2). mass spectrum (EI-MS): m/z (%) 239 (M +, 76), 211 (M-2 * N, 100).
Embodiment 2:5-(3-(1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1f)
The same II-1a of preparation method (route B).3-(1H-tetrazole-5-yl) aniline (1mmo l) and 2,5-dimethoxy-tetrahydrofuran (0.14mL) react Compound I I-1f, white solid 186mg, yield 88%, mp 210-212 ℃; 1H NMR (DMSO-D 6) δ ppm 8.19 (1H, d, J=2.0Hz, ArH-2), 7.92 (1H, d, J=8.4Hz, ArH-6), 7.83 (1H, dd, J=8.4 ﹠amp; 2.0Hz, ArH-4), 7.71 (1H, t, J=8.4Hz, ArH-5), 7.47 (2H, m, PyH-2,5), 6.35 (2H, t, J=2.2Hz, PyH-3,4); Mass spectrum (EI-MS): m/z (%) 211 (M +, 100), 183 (M-2 * N, 98), 168 (M-2 * N-NH, 37).
Embodiment 3:5-(3-(3-ethoxycarbonyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1d) (synthetic route B)
With sodium methylate (1.65g, 30.6mmol) gradation join 0 ℃ methyl aceto acetate (4g, in anhydrous methanol 30.6mmol) (20mL) solution, insulation reaction 30 minutes, slowly splash into then martonite (2.2mL, 25.5mmol), in room temperature reaction 10 hours.With aqueous hydrochloric acid accent pH value is neutral, uses ethyl acetate extraction, and drying is removed the back of desolvating and got 3-ethoxycarbonyl-2,5-hexanedione, weak yellow liquid 2.9g, product yield 61% with chromatographic column separation (petrol ether/ethyl acetate=8: 1).
Freshly prepd 3-ethoxycarbonyl-2,5-hexanedione (205mg) and 3-(1H-tetrazole-5-yl) aniline (1mmol) under the condition identical, react with preparation II-1a product II-1d, pale yellow oily liquid body 256mg, yield 78%, mp121-123 ℃. 1H-NMR(CDCl 3)δppm?11.66(1H，br，Tetrazole-H)，8.33(1H，d，J＝8.0Hz，ArH-6)，7.99(1H，s，ArH-2)，7.68(1H，t，J＝8.0Hz，ArH-5)，7.34(1H，d，J＝8.0Hz，ArH-4)，6.36(1H，s，Py-H)，4.29(2H，q，-O CH 2 CH 3)，2.24(3H，s，Py-CH 3)，1.97(3H，s，Py-CH 3)，1.35(3H，t，-CH 2 CH 3 ).
Embodiment 4:5-(3-(3-carboxyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1e) (synthetic route B)
II-1d (100mg, 0.32mmol) room temperature reaction 48 hours in the 1N NaOH aqueous solution (6mL) is 3 with the aqueous hydrochloric acid adjust pH, collect solid, be washed to neutrality, separate (petrol ether/ethyl acetate/acetate) with preparative chromatography and get white solid 63mg, yield 69%, 250 ℃ of decomposition of mp. 1H-NMR(CDCl 3)δ?ppm?11.77(1H，br，Tetrazole-H)，8.16(1H，d，J＝8.0Hz，ArH-6)，7.86(1H，s，ArH-2)，7.78(1H，t，J＝8.0Hz，ArH-5)，7.55(1H，d，J＝8.0Hz，ArH-4)，6.24(1H，s，Py-H)，2.21(3H，s，Py-CH 3)，1.87(3H，s，Py-CH 3).
Embodiment 5:1-methoxycarbonyl methyl-5-(3-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-2a) (synthetic route B or A)
With sodium methylate (270mg, 5mmol) and methyl bromoacetate (0.3mL, 3.3mmol) join II-1a (231mg, in methyl alcohol 1mmol) (10mL) solution, back flow reaction 27 hours.Boil off solvent, residue is dissolved in the ethyl acetate, washing, dry, concentrated, and crude product separates (petrol ether/ethyl acetate/acetate) with preparative chromatography and gets white solid 205mg, productive rate 68%, mp 128-130 ℃. 1H?NMR(DMSO-D 6)δ?ppm?8.15(1H，d，J＝8.0Hz，ArH-6)，7.83(1H，s，ArH-2)，7.74(1H，t，J＝8.0Hz，ArH-5)，7.50(1H，d，J＝8.0Hz，ArH-4)，5.94(2H，s，CH 2)，5.85(2H，s，Py-H)，3.76(3H，s，OCH 3)，2.00(6H，s，Py-CH 3×2).
Embodiment 6:1-carboxymethyl-5-(3-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-2b) (synthetic route B)
With the 10%NaOH aqueous solution (1mL) join II-2a (40mg, in methyl alcohol 0.13mmol) (2mL) solution, room temperature reaction 6 hours.Reaction solution is poured in the frozen water, transferred PH to acid, collect solid, wash with water, get product II-2b34mg, yield 87%, mp 158-160 ℃ after the drying to neutrality with 10% aqueous hydrochloric acid. 1H-NMR (DMSO-D 6) δ ppm:8.15 (1H, d, J=8.0Hz, ArH-6), 7.83 (1H, s, ArH-2), 7.74 (1H, t, J=8.0Hz, ArH-5), 7.50 (1H, d, J=8.0Hz, ArH-4), 5.84 (2H, s, CH 2), 5.78 (2H, s, Py-H), 2.00 (6H, s, Py-CH 3* 2). mass spectrum (ESI-MS): m/z (%) 296 (M-H, 43), 252 (M-COOH, 31), 195 (M-H-CH 2COOH-3 * N, 100).
Embodiment 7:1-ethoxycarbonylmethyl group-5-(3-(3-ethoxycarbonyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-2c) (synthetic route A or B)
With sodium ethylate (61mg, 0.9mmol) and methyl bromoacetate (0.06mL, 0.6mmol) join II-1d (93mg, in ethanol 0.3mmol) (5mL) solution, back flow reaction 4 hours.Boil off solvent, residue is dissolved in the ethyl acetate, washing, dry, concentrated, and crude product separates (petrol ether/ethyl acetate) with preparative chromatography and gets II-2c, white oily matter 71mg, productive rate 60%. 1H?NMR(CDCl 3)δ?ppm?8.28(1H，d，J＝8.0Hz，ArH-6)，8.01(1H，s，ArH-2)，7.64(1H，t，J＝8.0Hz，ArH-5)，7.32(1H，d，J＝8.0Hz，ArH-4)，6.39(1H，s，Py-H)，5.47(2H，s，CH 2)，4.31(4H，m，-O CH 2 CH 3×2)，2.33(3H，s，Py-CH 3)，2.02(3H，s，Py-CH 3)，1.34(6H，m，-CH 2 CH 3 ×2).
Embodiment 8:5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole (III-1a) (synthetic route C)
(966mg, hydrochloride solution (7mL) 6mmol) is cooled to 0～5 ℃, drips Sodium Nitrite (434mg, the 6.3mmol) aqueous solution (4mL), generation diazonium salt with 3-(1H-tetrazole-5-yl) aniline.In addition with sodium cyanide solution (2mL, 17.2mmol) join cuprous cyanide (592mg, 6.6mmol) and in the mixture of water (4mL), formation NaCu (CN) 3Complex salt solution is heated to 60 ℃.Diazonium salt solution slowly is added to NaCu (CN) 3In the solution, insulated and stirred is 2 hours then, is chilled to room temperature.Reaction system is slowly poured in the cold concentrated hydrochloric acid, use ethyl acetate extraction, dry, remove desolvate the back with preparative chromatography separate (petrol ether/ethyl acetate/Glacial acetic acid=7:3:0.03) 5-(3-cyano group) phenyl-1H-tetrazole (C), white solid 626mg, product yield 61%, mp 145-147 ℃.
With oxine (1mg, (513mg is in ethanolic soln 3mmol) (30mL) 0.0075mmol) to join C, add oxammonium hydrochloride (446mg more successively, 6.4mmol) and yellow soda ash (515mg, aqueous solution 4.9mmol) (each 5mL), reflux 4 hours.Boil off ethanol, residue adds water (30mL) dissolving, transfers PH to acid with aqueous hydrochloric acid, collect solid, wash with water, get (Z)-5-(the amino oxime of 3-) phenyl-1H-tetrazole (D) after the drying to neutrality, white solid 465mg, product yield 76%, mp194-196 ℃.
Trifluoroacetic anhydride (TFAA) (0.21mL, 1.5mmol) join D (102mg, in the anhydrous pyridine solution (3mL) 0.5mmol), reflux 2 hours.Reactant is poured in the frozen water after being chilled to room temperature, transfers PH to acid with aqueous hydrochloric acid, collects solid, washes with water to neutrality, gets III-1a, white solid 121mg, product yield 86%, mp 146-148 ℃ after the drying. 1H-NMR (DMSO-D 6) δ ppm:8.75 (1H, s, ArH-2), 8.36 (1H, d, J=8.0Hz, ArH-6), 8.30 (1H, d, J=8.0Hz, ArH-4), 7.88 (1H, t, J=8.0Hz, ArH-5). mass spectrum (ESI-MS): m/z (%) 281 (M-H, 100), 137 (M-tetrazole-phenyl, 23).
Embodiment 9:5-(3-(5-(chloromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole (III-1b) (synthetic route C)
Chloroacetyl chloride (0.1mL, 1.2mmol) join D (204mg, in the THF solution (10mL) 1mmol), reflux 4 hours.Reactant is poured in the frozen water after being chilled to room temperature, collects solid, is washed to neutrality, separates (petrol ether/ethyl acetate/Glacial acetic acid) with preparative chromatography and gets III-1b, white solid 176mg, product yield 67%, mp 160-162 ℃. 1H-NMR (DMSO-D 6) δ ppm:8.71 (1H, s, ArH-2), 8.30 (1H, d, J=8.0Hz, ArH-6), 8.24 (1H, d, J=8.0Hz, ArH-4), 7.84 (1H, t, J=8.0Hz, ArH-5), 5.24 (2H, s, CH 2). mass spectrum (ESI-MS): m/z (%) 261 (M-H, 100), 263 (M-H+2,28), 117 (M-tetrazole-phenyl, 35).
Embodiment 10:5-(3-(5-(methylol)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole (III-1c) (synthetic route C)
III-1b (76mg, 0.29mmol) in the 10% NaOH aqueous solution (2mL) in room temperature reaction 1.5 hours.Reaction solution is poured in the frozen water, transferred PH to acid with 10% aqueous hydrochloric acid, use ethyl acetate extraction, drying is removed the back of desolvating and is separated with preparation type TLC that (petrol ether/ethyl acetate=3:2) gets III-1c, white solid 39mg, yield 55%, mp 120-122 ℃. 1H-NMR (DMSO-D 6) δ ppm:11.60 (1H, s, OH), 8.47 (1H, s, ArH-2), 8.22 (1H, d, J=8.0Hz, ArH-6), 7.96 (1H, d, J=8.0Hz, ArH-4), 7.75 (1H, t, J=8.0Hz, ArH-5), 4.44 (2H, s, CH 2). mass spectrum (ESI-MS): m/z (%) 243 (M-H, 100), 215 (M-H-2 * N, 34).
Embodiment 11:1-ethoxycarbonylmethyl group-5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole (III-2a) (synthetic route C or A)
The same II-2c of preparation method.With III-1a (50mg, 0.18mmol) and methyl bromoacetate (0.02mL, 0.22mmol) react III-2a, white-yellowish solid 35mg, yield 54%, mp 78-81 ℃. 1H?NMR(CDCl 3)δ?ppm?8.94(1H，s，ArH-2)，8.41(1H，d，J＝8.0Hz，ArH-6)，8.26(1H，d，J＝8.0Hz，ArH-4)，7.69(1H，t，J＝8.0Hz，ArH-5)，5.49(2H，s，CH 2)，4.31(2H，q，-O CH 2 CH 3)，1.32(3H，t，-CH 2 CH 3 ).
Embodiment 12:1-ethyl-5-(3-(5-aldehyde radical-furans-2-yl) phenyl)-1H-tetrazole (IV-1a) (synthetic route D)
With 3-(1H-tetrazole-5-yl) aniline (322mg, hydrobromic acid solution 2mmol) (40%, 2mL) be cooled to 0～5 ℃, (166mg, aqueous solution 2.4mmol) (2mL) generate diazonium salt to drip Sodium Nitrite.With this diazonium salt solution slowly be added to cuprous bromide (344mg, hydrobromic acid solution 2.4mmol) (40%, 1mL) in, room temperature reaction spends the night.Reaction system is slowly poured in the frozen water, collects solid, is washed to neutrality, gets 5-(3-bromine) phenyl-1H-tetrazole, yellow solid 362mg (yield 80%) after the drying.With this intermediate (113mg, 0.5mmol) and iodoethane (0.14mL, 1.75mmol) according to the preparation method of II-2c react 1-ethyl-5-(3-bromophenyl)-1H-tetrazole, oily matter 113mg, yield 89%.
Under the nitrogen protection, with Pd (PPh 3) 4(22mg; 0.02mmol) be added to 1-ethyl-5-(3-bromophenyl)-1H-tetrazole (113mg; 0.45mmol) DMF solution (5mL) in; add diisopropyl ethyl amine (0.22mL more respectively; 1.35mmol) the aqueous solution (10mL) and 5-formyl radical-2-furans boric acid (75mg; 0.54mmol) DMF solution (5mL), 100 ℃ the reaction 4 hours.Reaction system is introduced in the frozen water, uses ethyl acetate extraction, drying, remove desolvate the back with preparative chromatography separate (petrol ether/ethyl acetate=3:1) yellow solid 88mg, yield 73%, mp77-80 ℃. 1H?NMR(CDCl 3)δ?ppm：9.70(1H，s，CHO)，8.59(1H，s，ArH-2)，8.20(1H，d，J＝8.0Hz，ArH-6)，7.96(1H，d，J＝8.0Hz，ArH-4)，7.59(1H，t，J＝8.0Hz，ArH-5)，7.37&6.6.98(each1H，d，J＝4.0Hz，FuranH-4′or-3′)，4.74(2H，q，-N CH 2 CH 3)，1.72(3H，t，-CH 2 CH 3 ).
Embodiment 13:1-ethyl-5-(3-(5-methyne-(rhodanine-5-yl)-furans-2-yl) phenyl)-1H-tetrazole (IV-2a) (synthetic route D)
IV-1a (46mg, 0.17mmol), rhodanine (37mg, 0.28mmol) and anhydrous sodium acetate (42mg, 0.51mmol) back flow reaction 13 hours in anhydrous methanol (5mL).Remove the back of desolvating and get IV-2a, red solid mg, yield %, mp ℃ with preparation type TLC separation (petrol ether/ethyl acetate). 1H?NMR(CDCl 3)δ?ppm：9.70(1H，s，CHO)，8.59(1H，s，ArH-2)，8.20(1H，d，J＝8.0Hz，ArH-6)，7.96(1H，d，J＝8.0Hz，ArH-4)，7.59(1H，t，J＝8.0Hz，ArH-5)，7.58(1H，s，C＝C-H)，7.37?&?6.6.98(each1H，d，J＝4.0Hz，FuranH-4′or-3′)，4.74(2H，q，-N CH 2 CH 3)，1.72(3H，t，-CH 2 CH 3 ).
Embodiment 14: HIV (human immunodeficiency virus)-resistant activity test (cell model), use EC 50Expression is active.
Mensuration can reference reference literature be Jiang, S., et al.Antimicrob.AgentsChemother.2004,48,4349-4359.
In 96 porocyte culture plates, with compound solution and isopyknic HIV-1 of 50 μ L different concns IIIBVirus strain (100 TCID 50) mix, in 37 ℃ of incubations 30 minutes, add 100 μ L MT-2 cells (1 * 10 then 5/ mL contains the RPIM RPMI-1640 of 10% serum), mix, 37 ℃ are incubated overnight.Inhaled in the 2nd day and remove 150 μ L supernatant liquors, mend the equal-volume fresh medium, 37 ℃ were continued incubation 3 days, in the 4th day record cytopathy (CPE) effect.Draw the culture supernatant night of 100 μ L then, the Triton X-100 lytic virus particle with 5% adopts the ELISA method to detect wherein p24 antigen.In brief,, seal with 1% nonfat milk again, successively add employing virus cracking liquid, 37 ℃ of incubations 60 minutes with HIVIG (2 μ g/mL) coated elisa plate.After fully washing plate, successively add anti-p24 monoclonal antibody-183-12H-5C, the horseradish peroxidase of biotin labeled sheep anti-mouse antibody and avidin mark.With the TMB colour developing, detect optical density(OD) at the 450nm place then.Half virus inhibition concentration (EC with CalcuSyn computed in software compound 50).
Table 1. suppresses HIV and duplicates the activity data that forms with target molecule gp41-6 aggressiveness
SI: selectivity index CC 50/ EC 50ND: test
Table 2. suppresses the activity data (cell model) that HIV virus strain of former generation is duplicated
Embodiment 15: the cell toxicity test of compound, use CC 50Expression.
Mensuration can reference reference literature be Jiang, S., et al.Antimicrob.Agents Chemother.2004,48,4349-4359.
In 96 porocyte culture plates, the compound solution of 50 μ L different concns is mixed with isopyknic PBS, in 37 ℃ of incubations 30 minutes, add 100 μ L MT-2 cells (1 * 10 then 5/ mL contains the RPIM RPMI-1640 of 10% serum), mix, 37 ℃ are incubated overnight.Inhaled in the 2nd day and remove 150 μ L supernatant liquors, mend the equal-volume fresh medium, 37 ℃ were continued incubation after 3 days, added the freshly prepared XTT solution (1mg/mL) that contains PMS of 50 μ L in the 4th day, detected the optical density(OD) at 450nm place behind the 4h.Half cytotoxicity concentration (CC with CalcuSyn computed in software compound 50).The results are shown in Table 1.
Embodiment 16: suppress the hexa-atomic helical bundle of gp41 (6-HB) and form experiment, suppress activity IC 50Expression.
Mensuration can reference reference literature be Jiang, S., et al.J.Virol.Methods, 1999,80,85-96.The results are shown in Table 1.
Existing result shows: formula I compound of the present invention is that a class has novel skeleton structure, acts on the non-peptide type small molecular inhibitor of HIV-1 gp41.They can effectively suppress the formation of the hexa-atomic helical bundle body of HIV-1gp41 (6-HB), thereby suppress duplicating of HIV.This compounds also all has the activity of inhibition to clinical isolating eurypalynous HIV virus strain, has antiviral spectrum widely.The compound that the present invention relates to will be expected to develop into the novel inverase of a class: the non-peptide micromolecular HIV-1 fusion inhibitor that with gp41 is target spot.

Claims (8)

1. the tetrazole aryl-heterocyclic compounds of formula I or its pharmacologically acceptable salt:
Figure A200710306939C00021
Wherein,
R 1=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl;
R 2=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
Ar contains 1-3 the heteroatomic five yuan of hetero-aromatic rings that are selected from N, O, S, is selected from:
Figure A200710306939C00022
With
Figure A200710306939C00023
R wherein 3=CHO, COR ', COOR ', COOH, CF 3, CH 2R ", halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-OH ,-NO 2,-CN ,-HC=CH-CN ,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', or on the utilized position of its ring structure, have ester group, carboxyl, C for choosing wantonly 1-6The following heterocyclic group that alkyl, phenyl replace:
Figure A200710306939C00024
Wherein, X and Y are selected from C independently of one another, O, S and NH;
R 4=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl, phenyl;
R 5=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, CHO ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
Above-mentioned five yuan of hetero-aromatic rings are chosen wantonly on its ring and can be utilized the position to have to be selected from aldehyde radical, ketone group, ester group, carboxyl, cyano group, α, beta unsaturated ketone, alkene, alkynes, C 1-6Alkyl, C 1-6Alkoxyl group, halogen ,-NH 2,-OH ,-NO 2With-CF 3Substituting group;
R '=C 1-6Alkyl; And
R " be halogen, OH or C 1-6Alkoxyl group.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, it has formula II:
Figure A200710306939C00031
Wherein,
R 1=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl;
R 2=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R 3=CHO, COR ', COOR ', COOH, CF 3, CH 2R ", halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-OH ,-NO 2,-CN ,-HC=CH-CN ,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', or on its ring structure, have ester group, carboxyl, C for choosing wantonly 1-6The following heterocyclic group that alkyl, phenyl replace:
Figure A200710306939C00032
Wherein, X and Y are selected from C independently of one another, O, S and NH;
R 4=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl, phenyl;
R 5=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, CHO ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R 6=H, CH 3, CF 3, halogen or C 2-4Alkyl;
R '=C 1-6Alkyl; And
R " be halogen, OH or C 1-6Alkoxyl group.
3. the compound or pharmaceutically acceptable salt thereof of claim 1, it has formula III:
Figure A200710306939C00041
Wherein,
R 1=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl;
R 2=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R 3=CHO, COR ', COOR ', COOH, CF 3, CH 2R ", halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-OH ,-NO 2,-CN ,-HC=CH-CN ,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', or on its ring structure, have ester group, carboxyl, C for choosing wantonly 1-6The following heterocyclic group that alkyl, phenyl replace:
Figure A200710306939C00042
Wherein, X and Y are selected from C independently of one another, O, S and NH;
R 4=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl, phenyl;
R 5=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, CHO ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R '=C 1-6Alkyl; And
R " be halogen, OH or C 1-6Alkoxyl group.
4. the compound or pharmaceutically acceptable salt thereof of claim 1, it has formula IV:
Wherein,
R 1=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl;
R 2=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R 3=CHO, COR ', COOR ', COOH, CF 3, CH 2R ", halogen, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-OH ,-NO 2,-CN ,-HC=CH-CN ,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', or on its ring structure, have ester group, carboxyl, C for choosing wantonly 1-6The following heterocyclic group that alkyl, phenyl replace:
Figure A200710306939C00052
Wherein, X and Y are selected from C independently of one another, O, S and NH;
R 4=-H ,-CH 2COOH ,-CH 2CH 2COOH ,-CH=CH-COOH ,-CH 2COOR ' ,-CH 2CH 2COOR ' ,-CH=CH-COOR ', C 1-6Alkyl, phenyl;
R 5=-H, halogen ,-NO 2,-NH 2,-NHR ' ,-N (R ') 2,-CN ,-OH, C 1-6Alkyl, C 1-6Alkoxyl group ,-CF 3, CHO ,-COOH ,-SO 3H ,-CONH 2,-CONHR ' or-COOR ';
R '=C 1-6Alkyl; And
R " be halogen, OH or C 1-6Alkoxyl group.
5. the compound or pharmaceutically acceptable salt thereof of claim 1 is selected from:
5-(3-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole;
5-(2-hydroxyl-5-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole;
5-(2-chloro-5-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole;
5-(3-(3-ethoxycarbonyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole;
5-(3-(3-carboxyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole;
5-(3-(1H-pyrroles-1-yl) phenyl)-1H-tetrazole (II-1f)
1-carboxymethyl-5-(3-(2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole;
1-carboxymethyl-5-(3-(3-carboxyl-2,5-dimethyl-1H-pyrroles-1-yl) phenyl)-1H-tetrazole;
5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole;
5-(3-(5-(chloromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole;
5-(3-(5-(methylol)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole;
1-carboxymethyl-5-(3-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl) phenyl)-1H-tetrazole;
1-ethyl-5-(3-(5-methyne-(rhodanine-5-yl)-furans-2-yl) phenyl)-1H-tetrazole; With
1-carboxymethyl-5-(3-(5-methyne-(rhodanine-5-yl)-furans-2-yl) phenyl)-1H-tetrazole.
6. compound or pharmaceutically acceptable salt thereof preparation method as claimed in claim 1, it comprises:
Route A: universal method
Figure A200710306939C00061
The cyano group of substituted benzene cyanogen compound (A) and sodiumazide effect can be synthesized 1H-tetrazole ring, obtain target compound I-1, and 1 nitrogen hydrogen and halohydrocarbons reaction on the tetrazole ring can obtain Compound I-2;
Perhaps,
Route B: for the compound that Ar among the formula I is pyrrole ring:
Figure A200710306939C00071
5-(3-amino) phenyl-1H-tetrazole (B) and 2 that replaces, 1 of 5-dimethoxy-tetrahydrofuran or the replacement of β position, the 4-diketone carries out the Paal-Knorr reaction can obtain N-aryl pyrrole compounds (II-1), generates 1H-tetrazole-N-aryl pyrrole compounds (II-2) that 1-replaces with halohydrocarbons reaction again;
Perhaps,
Route C: for the compound of Ar Wei oxadiazole ring among the formula I:
Figure A200710306939C00072
Make raw material with 5-(3-cyano group) phenyl-1H-tetrazole (C) that replaces, generate amino oxime intermediate (D) with the oxammonium hydrochloride reaction, can obtain 3-aryl-1,2 with the acylating reagent effect again, 4-oxadiazole compounds (III-1), the halogenating reaction of nitrogen can get target compound III-2 then;
Perhaps,
Route D: for the compound that Ar among the formula I is five-membered ring (as pyrroles, furans etc.) aldehyde:
5-(3-bromine) phenyl-1H-tetrazole (E) that replaces reacts by Suzuki with fragrant heterocyclic boric acid compound, and coupling generates and contains fragrant heterocyclic target compound IV-1.When fragrant heterocycle contains aldehyde radical, can obtain target compound IV-2 through condensation, halo;
R in the reaction scheme 1-R 4, R 6The same formula I is described with the definition of X, Y, and U, V, W represent to be selected from the heteroatoms of N, O, S independently of one another or be carbon atom.
7. pharmaceutical composition, it contains each described formula I compound or pharmaceutically acceptable salt thereof of at least a claim 1-5, and one or more pharmaceutical carriers or vehicle.
8. each described formula I compound or pharmaceutically acceptable salt thereof of claim 1-5 is used to prepare the purposes of the medicine of diseases associated that treatment or prevention and HIV infect or illness.
CNA2007103069390A 2007-12-28 2007-12-28 5-(3-aromatic heterocyclic substituted phenyl) tetrazole compounds and anti-HIV/AIDS use thereof Pending CN101468985A (en)

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US7053085B2 (en) * 2003-03-26 2006-05-30 Merck & Co. Inc. EP4 receptor agonist, compositions and methods thereof
JP2005225819A (en) * 2004-02-13 2005-08-25 Orient Chem Ind Ltd Azole compound having pyrrole ring and its production method
US7517998B2 (en) * 2004-06-01 2009-04-14 Boehringer Ingelheim International Gmbh Non nucleoside reverse transcriptase inhibitors

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WO2010081387A1 (en) * 2009-01-13 2010-07-22 中国人民解放军军事医学科学院毒物药物研究所 N-substituted phenyl-3-methylene heterocyclic aryl-2,5-dimethylpyrrole compounds and anti-hiv/aids uses thereof
WO2017076740A1 (en) 2015-11-04 2017-05-11 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10492494B2 (en) 2015-11-13 2019-12-03 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10687532B2 (en) 2015-11-13 2020-06-23 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10674727B2 (en) 2015-11-19 2020-06-09 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10986839B2 (en) 2016-04-11 2021-04-27 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi

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