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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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phenyl
tetrazole
hydrocarbyl
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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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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

5- (3-aromatic heterocyclic substituted phenyl) tetrazole compound and application thereof in resisting HIV/AIDS
Technical Field
The invention relates to 5- (3-aromatic heterocycle substituted benzene) -tetrazole compounds, a preparation method thereof, a pharmaceutical composition containing the same and application thereof in preparing medicines for treating or preventing diseases or symptoms related to HIV infection.
Background
AIDS is a serious infectious disease caused by Human Immunodeficiency Virus (HIV). HIV is an RNA retrovirus that selectively infects cells of the human immune system that have CD4 receptors on their surface, such as lymphocytes, monocytes, macrophages, dendritic cells, and the like. The surface of the virus is a double lipid membrane, and two important glycoproteins are arranged on the membrane: gp120 and gp41, gp120 being outside the membrane, for recognizing the CD4 receptor on the cell surface; gp41 crosses the viral membrane and serves primarily to fuse the viral membrane to the cell membrane, thereby releasing the viral internal core material into the host cytoplasm. The viral membrane is enveloped with 2 single-stranded RNAs and some important enzymes (e.g., reverse transcriptase, proteolytic enzyme, integrase) and structural proteins (p24, p17, p7, etc.). HIV cannot reproduce in vitro, and must be replicated and regenerated by human cells, and the replication process is roughly divided into 7 steps: viral attack (binding), fusion (fusing), reverse transcription (reverse transcription), integration (integration), transcription (transcription), translation (translation) and recombination and flooding (assembly & budding) of cells. AIDS virus is continuously replicated in such a cyclic process, so that immune cells of a human body are infected, the immune system of the human body is damaged, and finally, the complete loss of the immune function of the human body is caused, so that patients are in danger of various infections without resistance, and various infectious diseases and tumors are caused, and finally, the patients die. Theoretically, the drug can achieve the purposes of inhibiting virus and treating diseases only by blocking any link in the virus replication process.
To date, there are 20 clinical drugs approved by the FDA for the treatment of aids, which are classified into four categories (Erik dc. antiviral drugs in current clinical use. j Clin Virol, 2004, 30 (2): 115-: (1) nucleoside Reverse Transcriptase Inhibitors (NRTIs), 8; (2) 3 non-nucleoside reverse transcriptase inhibitors (NNRTIs); (3) protease Inhibitors (PIs), 8; (4) fusion Inhibitors (FIs), 1. Different mechanisms of action are most clinically used in combination with drugs, such as two reverse transcriptase inhibitors and one protease inhibitor (Robb's GK, De GV, Shafer RW, et al. Complex of sequence enzyme-primer as primer for HIV-1 primer. N Eng 1J Med, 2003, 349: 2293303. and Shafer RW, Smeaton LM, Robbins GK, et al. Complex of four-primer and pairs of sequence enzyme-primer as primer for HIV-1 primer. N Eng 1J Med, 2003, 349: 230415). The treatment can effectively inhibit the viral load in the body of an infected person and reduce the morbidity and mortality of the infected person, but still has the problems of easy generation of drug resistance, great toxic and side effects and the like. Therefore, it is urgently needed to search for new drug targets in the virus replication process and develop anti-HIV drugs with new action mechanisms.
The existing anti-HIV drugs all play an inhibiting role in the replication process of viruses after entering cells. However, with the progress of the research on the mechanism of fusion between HIV virus and cell, people are paying more attention to the research on drugs which can prevent the virus from invading cells and play an antiviral role in the early stage of virus replication. The medicine can inhibit virus infected cell and virus replication, and is expected to provide effective novel anti-H IV therapeutic medicine with different action mechanisms for patients.
The process of HIV invading cells is mainly composed of 3 steps: adhesion, binding to co-receptors, membrane fusion. The viral envelope glycoprotein GP120 first binds to the cell surface CD4 molecule (GallaherWR, Ball JM, Garry RF, et al. A general model for the surf aceroloproteins of HIV and other retroviruses. AIDS Res Hum Retrovir, 1995, 11: 191-202), changes in conformation and then binds to the co-receptor (chemoattractant, such as CXCR4 or CCR5) (Dragon T, Litwin V, Allaway GP, et al. HIV-1entry into O CD4+ cells is mediated by the chemoattractant CC-CKR-5.Nature, 1996, 381: 66773); then gp41 is inserted into cell membrane to form 6 spirochetes, and the virus membrane is drawn close to the cell membrane to fuse. In this process, gp120 and gp41, the CD4 receptor, and the co-receptors are considered possible drug targets. Of these, gp41 plays a crucial role throughout the fusion process.
The amino acid sequence of Gp41 has four functional regions. The transmembrane domain (TM) at the C-terminus immobilizes gp41 on the viral membrane; CHR segment (C-tertiary header repeat, CHR) and NHR segment (N-tertiary header repeat, NHR) are functional parts of gp41 structure; fusion Peptide (FP) is a highly hydrophobic sequence located at the N-terminus, the main function of which is to insert into the host Cell membrane (Melikyan GB, Markosyn RM, Hemmati H, et al. evaluation which the transition of HIV-1gp41 into a six-helix bundle, not the bundling configuration, indeces membrane fusion. J Cell Biol, 2000, 151: 41323 and Munoz-Barhos I, Salzdel K, Hunter E, et al. roll soft membrane-promoter domain in the interaction stage of a human tissue virus, type 1 expression protein-mediator J, 608992).
The three NHR helices of gp41 on the surface of the virus were arranged in parallel in the center and the three CHR helices were wrapped around in antiparallel, surrounded by 3 gp 120. When The virus infects cells, The conformation of gp120 on The surface of The virus changes after binding with CD4 receptor and co-receptor on The surface of The cell, and The NHR helix of gp41 extends out from The center, and The N-terminal fusogenic peptide is inserted into The cell membrane (Coleman CI, music BL and Ross J. Enfuvirtide: The first fusion inhibitor for The treatment of diseases with HIV-1infection. formulation, 2003, 38: 204222). Subsequently, NHR and CHR come together and reform into parallel six-membered helical bundles. This conformational change provides the energy required to bring the hydrated surfaces of the viral envelope and host cell membrane into close proximity, thereby drawing the viral membrane and cell membrane together and encouraging fusion to occur. (Cooley LA and Lewis SR, HIV-1 cell entry and development in viral entry therapy. J Clin Virol, 2003, 26: 121132 and Moore JP and Doms RW. the entry of entry inhibition torrs: A fusion of science and medicine. Proc Natl Acad Sci U S A, 2003, 100: 1059810602). The surfaces of the viruses are provided with a plurality of gp41 films to form fusion holes between the two films, the fluidity of the films enables the films to be rapidly expanded, and finally the complete fusion of the HIV envelope and the host cell film is realized, and the virus core substances are released into the cytoplasm of the host.
Both functional regions NHR and CHR of gp41 can be the target of HIV fusion inhibitor. The first fusion inhibitor drug, T-20(Fuzeon), approved by the FDA in the United states is a 36 amino acid polypeptide that mimics the helix structure sequence of the CHR. It blocks the formation of six-membered helix bundle by combining with NHR, thus achieving the purpose of inhibiting the Fusion of virus and cell membrane (Fung HB, BCPS and Guo Y. Enfuvirtide: A Fusion Inhibitor for the Treatment of HIV infection. Clin Ther, 2004, 26 (3): 352-378). Because T20 is a peptide drug and has the defects of poor oral bioavailability, high production cost and the like, the search for a high-efficiency and low-toxicity non-peptide small-molecule HIV fusion inhibitor primer is one of the main directions for the research of new anti-HIV drugs.
By performing targeted activity screening on a small molecule compound library with diversified structures, two N-aryl carboxylic acid Substituted Pyrrole small molecule compounds NB-2 and NB-64(Jiang Sh-B, Lu H, Liu Sh-W, et al.N-understituted Pyrrole Derivatives as Novel Humanimmunity details Virus Type 1Entry inhibition That with gp41 Six-helium Bundle formation and Block Virus fusion. anti-cancer Agents Chemother, 2004, 48: 4349-4359) not only show good anti-HIV replication activity in a cell model (EC-2 and NB-64)50Values of 1.04. mu.M and 2.21. mu.M, respectively), and in the test of fusion of virus with cell membrane (EC)50The values were 6.74. mu. respectivelyM and 29.92. mu.M) and gp41 in six-membered helix bundle formation assay [ IC50(6-HB) values were 13.48. mu.M and 15.69. mu.M, respectively]All have obvious inhibitory activity. The results of these experiments indicate that NB-2 and NB-64 are indeed small molecule active compounds acting on gp 41. Based on the basic principle that the structure is related to the biological activity, the small molecule fusion inhibitor with better activity can be found by modifying the structure of the compound.
Figure A200710306939D00121
Disclosure of Invention
The invention relates to a compound with a 5-substituted phenyl-tetrazole skeleton structure shown in a formula I, which can effectively inhibit the formation of a hexamer of HIV-1 surface glycoprotein gp41, thereby inhibiting HIV replication. The intensive research on the compounds can possibly discover a novel non-peptide small molecule HIV fusion inhibitor, and the inhibitor becomes a novel AI DS resistant medicament.
The first aspect of the invention relates to a tetrazole aryl heterocyclic compound shown in the formula I or a medicinal salt thereof:
Figure A200710306939D00131
wherein,
R1＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6a hydrocarbyl group;
R2-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Alkyl radical, C1-6Alkoxy, -CF3、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
ar is a five membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, selected from:
Figure A200710306939D00132
and
Figure A200710306939D00133
wherein R is3＝CHO、COR’、COOR’、COOH、CF3、CH2R', halogen, C1-6Hydrocarbyl radical, C1-6Alkoxy, -NH2、-OH、-NO2、-CN、-HC＝CH-CN、-CH＝CH2-C ≡ CH, -C ≡ CR ', -CH ═ CHR ', -CH ═ CHCOR ', or optionally bearing an ester group, a carboxyl group, C ≡ C optionally at available positions in its ring structure1-6Hydrocarbyl, phenyl-substituted heterocyclic groups:
Figure A200710306939D00134
wherein X and Y are each independently selected from C, O, S and NH;
R4＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6hydrocarbyl, phenyl;
R5-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Hydrocarbyl radical, C1-6Alkoxy, -CF3、CHO、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
the five-membered heteroaromatic ring optionally carries a substituent selected from the group consisting of aldehyde, ketone, ester, carboxyl, cyano, alpha, beta unsaturated ketone, alkene, alkyne, C, at an available position on the ring1-6Hydrocarbyl radical, C1-6Alkoxy, halogen, -NH2、-OH、-NO2and-CF3A substituent of (1);
R’＝C1-6a hydrocarbyl group; and is
R' is halogen, OH or C1-6An alkoxy group.
The term "hydrocarbyl" as used herein includes alkyl, alkenyl and alkynyl groups.
Para substituent R of the invention3The "following heterocyclic groups" referred to in the description include, but are not limited to, 2, 4-thiazolidinedione, 2-thio-2, 4-thiazolidinedione (Rhodanine), succinimide, 2, 4-imidazolidinedione (hydantoin ), 2-Thiohydantoin (2-Thiohydantoin), Pseudothiohydantoin (Pseudothiohydantoin), and the like.
In a second aspect, the present invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof.
A third aspect of the present invention relates to a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
A fourth aspect of the present invention relates to the use of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition associated with HIV infection.
According to a preferred embodiment of the invention, Ar is a substituted pyrrole, represented by formula II:
Figure A200710306939D00141
wherein,
R1＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6a hydrocarbyl group;
R2-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Alkyl radical, C1-6Alkoxy, -CF3、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R3＝CHO、COR’、COOR’、COOH、CF3、CH2r', halogen, C1-6Hydrocarbyl radical, C1-6Alkoxy, -NH2、-OH、-NO2、-CN、-HC＝CH-CN、-CH＝CH2-C ≡ CH, -C ≡ CR ', -CH ═ CHR', -CH ═ CHCOR ', or optionally bearing an ester group, a carboxyl group, C ≡ CH', or a cyclic structure thereof1-6Hydrocarbyl, phenyl-substituted heterocyclic groups:
Figure A200710306939D00151
wherein X and Y are each independently selected from C, O, S and NH;
R4＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6hydrocarbyl, phenyl;
R5-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Hydrocarbyl radical, C1-6Alkoxy, -CF3、CHO、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R6＝H、CH3、CF3halogen or C2-4A hydrocarbyl group;
R’＝C1-6a hydrocarbyl group; and is
R' is halogen, OH or C1-6An alkoxy group.
According to another preferred embodiment of the invention, Ar is 1, 2, 4-oxadiazole, as shown in formula III below:
Figure A200710306939D00152
wherein,
R1＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6a hydrocarbyl group;
R2-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Alkyl radical, C1-6Alkoxy, -CF3、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R3＝CHO、COR’、COOR’、COOH、CF3、CH2r', halogen, C1-6Hydrocarbyl radical, C1-6Alkoxy, -NH2、-OH、-NO2、-CN、-HC＝CH-CN、-CH＝CH2-C ≡ CH, -C ≡ CR ', -CH ═ CHR', -CH ═ CHCOR ', or optionally bearing an ester group, a carboxyl group, C ≡ CH', or a cyclic structure thereof1-6Hydrocarbyl, phenyl-substituted heterocyclic groups:
wherein X and Y are each independently selected from C, O, S and NH;
R4＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6hydrocarbyl, phenyl;
R5-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Hydrocarbyl radical, C1-6Alkoxy, -CF3、CHO、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R’＝C1-6a hydrocarbyl group; and is
R' is halogen, OH or C1-6An alkoxy group.
According to another preferred embodiment of the invention, Ar is a 5-substituted furan, as shown in formula IV below:
Figure A200710306939D00162
wherein,
R1＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6a hydrocarbyl group;
R2-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Alkyl radical, C1-6Alkoxy, -CF3、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R3＝CHO、COR’、COOR’、COOH、CF3、CH2r', halogen, C1-6Hydrocarbyl radical, C1-6Alkoxy, -NH2、-OH、-NO2、-CN、-HC＝CH-CN、-CH＝CH2-C ≡ CH, -C ≡ CR ', -CH ═ CHR', -CH ═ CHCOR ', or optionally bearing an ester group, a carboxyl group, C ≡ CH', or a cyclic structure thereof1-6Hydrocarbyl, phenyl-substituted heterocyclic groups:
Figure A200710306939D00171
wherein X and Y are each independently selected from C, O, S and NH;
R4＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6hydrocarbyl, phenyl;
R5-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Hydrocarbyl radical, C1-6Alkoxy, -CF3、CHO、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R’＝C1-6a hydrocarbyl group; and is
R' is halogen, OH or C1-6An alkoxy group.
More preferred in the present invention are the following compounds:
5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole (II-1 a);
5- (2-hydroxy-5- (2, 5-dimethyl-1H-pyrrole-1-yl) phenyl) -1H-tetrazole (II-1 b);
5- (2-chloro-5- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole (II-1 c);
5- (3- (3-ethoxycarbonyl-2, 5-dimethyl-1H-pyrrole-1-yl) phenyl) -1H-tetrazole (II-1 d);
5- (3- (3-carboxy-2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole (II-1 e);
5- (3- (1H-pyrrol-1-yl) phenyl) -1H-tetrazole (II-1 f);
1-carboxymethyl-5- (3- (2, 5-dimethyl-1H-pyrrole-1-yl) phenyl) -1H-tetrazole (II-2 b);
1-carboxymethyl-5- (3- (3-carboxyl-2, 5-dimethyl-1H-pyrrole-1-yl) phenyl) -1H-tetrazole (II-2d)
5- (3- (5- (trifluoromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazole (III-1 a);
5- (3- (5- (chloromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazole (III-1 b);
5- (3- (5- (hydroxymethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazolium (III-1 c);
1-carboxymethyl-5- (3- (5- (trifluoromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazole (III-2 b);
1-ethyl-5- (3- (5-methine- (rhodanin-5-yl) -furan-2-yl) phenyl) -1H-tetrazolium (IV-2 a); and
1-carboxymethyl-5- (3- (5-methine- (rhodanin-5-yl) -furan-2-yl) phenyl) -1H-tetrazole (IV-2 b).
The compounds of the present invention can be prepared by a variety of reaction schemes and methods, as shown in the figure:
route a: the general method comprises the following steps:
Figure A200710306939D00181
reaction conditions are as follows: (i) hydrochloride (such as amine chloride, lithium chloride and the like) and DMF (dimethyl formamide) are taken as a solvent, and the mixture is refluxed at room temperature for 4 to 24 hours; (ii) sodium alkoxide in methanol or ethanol at room temperature to 100 deg.C for 4-32 hr
Route B: for compounds of formula I wherein Ar is a pyrrole ring:
Figure A200710306939D00182
reaction conditions are as follows: (iii) microwave reaction, acetic acid is used as solvent or no solvent, at the temperature of 120 ℃ and 160 ℃, for 5-20 minutes; (ii) the same reaction conditions as in the second step of scheme A.
Route C: for compounds of formula I wherein Ar is an oxadiazole ring:
Figure A200710306939D00191
reaction conditions are as follows: (iv) in the presence of 8-hydroxyquinoline, sodium carbonate or potassium carbonate is added at 80-100 ℃ for 2-8 hours, and ethanol is used as a solvent; (v) pyridine or tetrahydrofuran as solvent at room temperature to 120 deg.c for 2-6 hr; (ii) the same reaction conditions as in the second step of scheme A.
Route D: for compounds of formula I wherein Ar is a five-membered heterocyclic (e.g., pyrrole, furan, etc.) aldehyde:
Figure A200710306939D00192
reaction conditions are as follows: (vi) suzuki coupling reaction, organic boric acid reagent and palladium catalyst; (vii) condensation reaction (with ketone reagents shown or related in the figure), alkaline conditions: organic amine, inorganic strong base or weak acid strong base salt, and mixed solvent of methanol, ethanol, acetic acid, DMF or DMF and water at room temperature of-160 deg.C for 1-44 hr.
Ar and R in the above reaction scheme1-R4、R6And X, Y are as previously described for formula I, each U, V, W independently represents a heteroatom selected from N, O, S or is a carbon atom. In particular, the present invention relates to a method for producing,
scheme a: the cyano group of the substituted benzonitrile compound (A) can react with sodium azide to synthesize a 1H-tetrazole ring to obtain a target compound I-1, and the 1-site nitrogen hydrogen on the tetrazole ring reacts with halohydrocarbon to obtain a compound I-2.
Scheme B: the substituted 5- (3-amino) phenyl-1H-tetrazole (B) and 2, 5-dimethoxytetrahydrofuran or beta-substituted 1, 4-diketone are subjected to Paal-Knorr reaction to obtain an N-arylpyrrole compound (II-1), and then the N-arylpyrrole compound (II-1) is reacted with halogenated hydrocarbon to generate a 1-substituted 1H-tetrazole-N-arylpyrrole compound (II-2).
Scheme C: substituted 5- (3-cyano) phenyl-1H-tetrazole (C) is used as a raw material, reacts with hydroxylamine hydrochloride to generate an amino oxime intermediate (D), then reacts with an acylation reagent to obtain a 3-aryl-1, 2, 4-oxadiazole compound (III-1), and then undergoes a nitrogen halogenation reaction to obtain a target compound III-2.
Scheme D: the substituted 5- (3-bromine) phenyl-1H-tetrazole (E) and the aromatic heterocyclic boric acid compound are coupled to generate the target compound IV-1 containing the aromatic heterocyclic through Suzuki reaction. When the aromatic heterocycle contains aldehyde group, the target compound IV-2 can be obtained by condensation and halogenation.
The invention relates to a substituted 5- (3-aromatic heterocycle substituted phenyl) tetrazole compound (formula I), which is an anti-HIV active compound with a novel skeleton structure. The compounds act on HIV-1gp41, and are expected to be developed into a novel anti-HIV drug with a specific target: non-peptide small molecule fusion inhibitors. The test results of the invention show that: IC for inhibiting 6-HB binding by Compound II-1a50The value was 25.61. mu.M, which is higher than that of the positive control compound NB-64 (IC) used in the same assay5058.74 μ M). The inhibitory Activity of this Compound against wild type HIV in a cellular assay (MT-2 lymphocytes), EC50The value was 7.70. mu.M (SI)>32) And has inhibitory activity on replication of various clinically isolated HIV strains, which is obviously superior to the known active compound NB-64. The activity data for some of the related compounds are shown in tables 1-2. The result of the invention shows that the compound represented by II-1a is used as HIV-1gp41 target, has a wide antiviral spectrum and is a novel anti-HIV active compound, and can be developed into a non-peptide small molecule anti-HIV fusion inhibitor.
The compounds of the present invention may be used either as such or in the form of their pharmaceutically acceptable salts or solvates. Pharmaceutically acceptable salts of the compounds of formula I include conventional salts with pharmaceutically acceptable inorganic or organic acids or bases. Examples of suitable acid addition salts include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid, and the like. Examples of suitable base addition salts include salts with sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine, and the like. Reference herein to the compounds of the present invention includes compounds of formula I and pharmaceutically acceptable salts or solvates thereof.
According to the invention, the compounds of formula I according to the invention can be combined with customary pharmaceutical carriers or excipients to form pharmaceutical compositions. The pharmaceutical composition can be administered by oral or parenteral route. The pharmaceutical composition of the present invention can be prepared into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, etc. according to conventional methods in the art, and can be administered orally or parenterally.
It is further noted that the dosage and method of administration of the compounds of the present invention will depend upon a variety of factors including the age, weight, sex, physical condition, nutritional status, the activity level of the compound, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The preferable dosage is 0.01-100 mg/kg body weight/day.
Detailed Description
The following examples are intended to further illustrate the invention, but are not intended to limit the invention thereto.
Example 1: 5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazol (II-1a) (scheme B)
2, 5-hexanedione (0.13mL) was added to a solution of 3- (1H-tetrazol-5-yl) aniline (1mmol) in glacial acetic acid (3mL) and reacted at 150 ℃ for 10 minutes under microwave conditions. Cooling to room temperature, pouring the reaction product into ice water, and collecting solidWashing with water to neutrality, and separating with preparative chromatography (petroleum ether/ethyl acetate/acetic acid) to obtain white solid 124mg with yield of 52%, mp147-148 deg.C;1H NMR(DMSO-D6)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-CH3x 2) mass spectrum (EI-MS): m/z (%) 239 (M)+，76)，211(M-2×N，100).
Example 2: 5- (3- (1H-pyrrole-1-yl) phenyl) -1H-tetrazole (II-1f)
The preparation method is the same as II-1a (route B). 3- (1H-tetrazol-5-yl) aniline (1mmo l) and 2, 5-dimethoxy tetrahydrofuran (0.14mL) react to obtain a compound II-1f, white solid 186mg, yield 88%, mp 210-;1H NMR(DMSO-D6)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 &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).
Example 3: 5- (3- (3-ethoxycarbonyl-2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazol (II-1d) (scheme B)
Sodium methoxide (1.65g, 30.6mmol) was added in portions to a 0 ℃ solution of ethyl acetoacetate (4g, 30.6mmol) in anhydrous methanol (20mL), the mixture was allowed to react for 30 minutes while maintaining the temperature, and bromoacetone (2.2mL, 25.5mmol) was slowly added dropwise to the mixture, followed by reaction at room temperature for 10 hours. Adjusting pH to neutral with hydrochloric acid aqueous solution, extracting with ethyl acetate, drying, removing solvent, separating with chromatographic column (petroleum ether/ethyl acetate ratio is 8: 1) to obtain 3-ethoxycarbonyl-2, 5-hexanedione as light yellow liquid 2.9g, and obtaining product yield of 61%.
The newly prepared 3-ethoxycarbonyl-2, 5-hexanedione (205mg) and 3- (1H-tetrazol-5-yl) aniline (1mmol) react under the same conditions as in the preparation of II-1a to obtain a product II-1d, which is 256mg of light yellow oily liquid with yield of 78%, mp121-123℃。1H-NMR(CDCl3)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，-OCH 2 CH3)，2.24(3H，s，Py-CH3)，1.97(3H，s，Py-CH3)，1.35(3H，t，-CH2 CH 3 ).
Example 4: 5- (3- (3-carboxy-2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazol-e (II-1e) (scheme B)
II-1d (100mg, 0.32mmol) was reacted in 1N aqueous NaOH (6mL) for 48 h at room temperature, adjusted to pH 3 with aqueous hydrochloric acid, the solid was collected, washed to neutrality with water and separated by preparative chromatography (petroleum ether/ethyl acetate/acetic acid) to give 63mg of white solid in 69% yield, decomposed at mp 250 ℃.1H-NMR(CDCl3)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-CH3)，1.87(3H，s，Py-CH3).
Example 5: 1-methoxycarbonylmethyl-5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazolium (II-2a) (synthetic route B or A)
Sodium methoxide (270mg, 5mmol) and methyl bromoacetate (0.3mL, 3.3mmol) were added to a solution of II-1a (231mg, 1mmol) in methanol (10mL), and the reaction was refluxed for 27 hours. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water, dried and concentrated, and the crude product was separated by preparative chromatography (petroleum ether/ethyl acetate/acetic acid) to give 205mg of a white solid in 68% yield, mp 128-.1H NMR(DMSO-D6)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，CH2)，5.85(2H，s，Py-H)，3.76(3H，s，OCH3)，2.00(6H，s，Py-CH3×2).
Example 6: 1-carboxymethyl-5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazolium (II-2B) (scheme B)
A10% aqueous NaOH solution (1mL) was added to a solution of II-2a (40mg, 0.13mmol) in methanol (2mL) and reacted at room temperature for 6 hours. Pouring the reaction solution into ice water, adjusting the pH value to acidity by using 10% hydrochloric acid aqueous solution, collecting the solid, washing the solid to neutrality by using water, and drying to obtain the product II-2b34mg with the yield of 87% and the temperature of mp 158-.1H-NMR(DMSO-D6)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，CH2)，5.78(2H，s，Py-H)，2.00(6H，s，Py-CH3X 2) mass spectrum (ESI-MS): m/z (%) 296(M-H, 43), 252(M-COOH, 31), 195 (M-H-CH)2COOH-3×N，100).
Example 7: 1-ethoxycarbonylmethyl-5- (3- (3-ethoxycarbonyl-2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole (II-2c) (synthetic route A or B)
Sodium ethoxide (61mg, 0.9mmol) and methyl bromoacetate (0.06mL, 0.6mmol) were added to a solution of II-1d (93mg, 0.3mmol) in ethanol (5mL), and the reaction was refluxed for 4 hours. The solvent was evaporated and the residue dissolved in ethyl acetate, washed with water, dried, concentrated and the crude product was chromatographed (petroleum ether/ethyl acetate) to give II-2c as a white oil 71mg, 60% yield.1H NMR(CDCl3)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，CH2)，4.31(4H，m，-OCH 2 CH3×2)，2.33(3H，s，Py-CH3)，2.02(3H，s，Py-CH3)，1.34(6H，m，-CH2 CH 3 ×2).
Example 8: 5- (3- (5- (trifluoromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazol-e (III-1a) (scheme C)
And (2) cooling a hydrochloride solution (7mL) of 3- (1H-tetrazole-5-yl) aniline (966mg, 6mmol) to 0-5 ℃, and dropwise adding an aqueous solution (4mL) of sodium nitrite (434mg, 6.3mmol) to generate the diazonium salt. An additional aqueous sodium cyanide solution (2mL, 17.2mmol) was added to a mixture of cuprous cyanide (592mg, 6.6mmol) and water (4mL) to form NaCu (CN)3The double salt solution is heated to 60 ℃. The diazonium salt solution was slowly added to the NaCu (CN)3The solution was then stirred for 2 hours at room temperature and cooled to room temperature. The reaction system was slowly poured into cold concentrated hydrochloric acid, extracted with ethyl acetate, dried, and the solvent was removed and separated by preparative chromatography (petroleum ether/ethyl acetate/glacial acetic acid 7:3:0.03) to give 5- (3-cyano) phenyl-1H-tetrazole (C) as a white solid 626mg with a product yield of 61% and mp 145-.
8-Hydroxyquinoline (1mg, 0.0075mmol) was added to a solution of C (513mg, 3mmol) in ethanol (30mL), and then hydroxylamine hydrochloride (446mg, 6.4mmol) and an aqueous solution (5mL each) of sodium carbonate (515mg, 4.9mmol) were added in this order, followed by heating and refluxing for 4 hours. The ethanol is evaporated, the residue is dissolved by adding water (30mL), the pH value is adjusted to acidity by hydrochloric acid aqueous solution, solid is collected, washed to neutrality by water and dried to obtain (Z) -5- (3-amino oxime) phenyl-1H-tetrazole (D), white solid is 465mg, the product yield is 76%, and the temperature is mp194-196 ℃.
Trifluoroacetic anhydride (0.21mL, 1.5mmol) was added to a solution of D (102mg, 0.5mmol) in anhydrous pyridine (3mL) and heated under reflux for 2 h. The reaction was cooled to room temperature and poured into ice water, the pH was adjusted to acidity with aqueous hydrochloric acid, the solid was collected, washed with water to neutrality and dried to give III-1a as a white solid at 121mg, yield 86%, mp 146-.1H-NMR(DMSO-D6) 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 spectrometry (ESI-MS): m/z (%) 281(M-H, 100), 137 (M-tetrazol-phenyl, 23).
Example 9: 5- (3- (5- (chloromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazol-e (III-1b) (scheme C)
Chloroacetyl chloride (0.1mL, 1.2mmol) was added toD (204mg, 1mmol) in THF (10mL) was heated under reflux for 4 hours. The reaction was cooled to room temperature and poured into ice water, the solid was collected and washed with water to neutrality and separated by preparative chromatography (petroleum ether/ethyl acetate/glacial acetic acid) to give III-1b as a white solid 176mg in 67% yield, mp 160-.1H-NMR(DMSO-D6)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，CH2) Mass spectrum (ESI-MS): m/z (%) 261(M-H, 100), 263(M-H +2, 28), 117 (M-tetrazolo-phenyl, 35).
Example 10: 5- (3- (5- (hydroxymethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazolium (III-1C) (scheme C)
III-1b (76mg, 0.29mmol) was reacted in 10% aqueous NaOH (2mL) at room temperature for 1.5 h. The reaction solution was poured into ice water, adjusted to acidic pH with 10% aqueous hydrochloric acid, extracted with ethyl acetate, dried, and the solvent was removed and separated by preparative TLC (petroleum ether/ethyl acetate 3:2) to give III-1c as a white solid 39mg in 55% yield, mp 120-.1H-NMR(DMSO-D6)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，CH2) Mass spectrum (ESI-MS): m/z (%) 243(M-H, 100), 215(M-H-2 XN, 34).
Example 11: 1-ethoxycarbonylmethyl-5- (3- (5- (trifluoromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazol (III-2a) (scheme C or A)
The preparation method is the same as II-2 c. III-1a (50mg, 0.18mmol) and methyl bromoacetate (0.02mL, 0.22mmol) were reacted to give III-2a as an off-white solid, 35mg, yield 54%, mp 78-81 ℃.1H NMR(CDCl3)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，CH2)，4.31(2H，q，-OCH 2 CH3)，1.32(3H，t，-CH2 CH 3 ).
Example 12: 1-Ethyl-5- (3- (5-formyl-furan-2-yl) phenyl) -1H-tetrazolium (IV-1a) (scheme D)
A hydrobromic acid solution (40%, 2mL) of 3- (1H-tetrazol-5-yl) aniline (322mg, 2mmol) was cooled to 0-5 ℃, and an aqueous solution (2mL) of sodium nitrite (166mg, 2.4mmol) was added dropwise to generate the diazonium salt. This diazonium salt solution was slowly added to a solution of cuprous bromide (344mg, 2.4mmol) in hydrobromic acid (40%, 1mL) and reacted overnight at room temperature. The reaction system was slowly poured into ice water, the solid was collected, washed with water to neutrality, and dried to obtain 5- (3-bromo) phenyl-1H-tetrazole as a yellow solid (362 mg, yield 80%). The intermediate (113mg, 0.5mmol) and iodoethane (0.14mL, 1.75mmol) were reacted according to II-2c preparation to give 113mg of 1-ethyl-5- (3-bromophenyl) -1H-tetrazole as an oily substance in 89% yield.
Pd (PPh) under nitrogen protection3)4(22mg, 0.02mmol) was added to a DMF solution (5mL) of 1-ethyl-5- (3-bromophenyl) -1H-tetrazole (113mg, 0.45mmol), followed by addition of an aqueous solution (10mL) of diisopropylethylamine (0.22mL, 1.35mmol) and a DMF solution (5mL) of 5-formyl-2-furanboronic acid (75mg, 0.54mmol), respectively, and reaction at 100 ℃ for 4 hours. The reaction was poured into ice water, extracted with ethyl acetate, dried, and the solvent removed and chromatographed using preparative chromatography (petroleum ether/ethyl acetate 3:1) to give 88mg of a yellow solid, 73% yield, mp77-80 ℃.1H NMR(CDCl3)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，-NCH 2 CH3)，1.72(3H，t，-CH2 CH 3 ).
Example 13: 1-Ethyl-5- (3- (5-methylidene- (rhodanin-5-yl) -furan-2-yl) phenyl) -1H-tetrazol (IV-2a) (scheme D)
IV-1a (46mg, 0.17mmol), woundTannin (37mg, 0.28mmol) and anhydrous sodium acetate (42mg, 0.51mmol) were reacted in anhydrous methanol (5mL) at reflux for 13 hours. After removal of the solvent, preparative TLC (petroleum ether/ethyl acetate) was used to obtain IV-2a as a red solid mg, yield%, mp ℃.1H NMR(CDCl3)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，-NCH 2 CH3)，1.72(3H，t，-CH2 CH 3 ).
Example 14: anti-HIV Activity assay (cell model) with EC50Indicates the activity.
Reference documents to which the assay can be referred are Jiang, s., et al.
50 μ L of compound solutions of different concentrations were mixed with equal volumes of HIV-1in 96 well cell culture platesIIIBVirus strain (100 TCID)50) Mixing, incubating at 37 ℃ for 30 min, and adding 100. mu.L of MT-2 cells (1X 10)5mL, RPIM 1640 medium with 10% serum), mixed well and incubated overnight at 37 ℃. On day 2, 150. mu.L of supernatant was aspirated, an equal volume of fresh medium was replenished, incubation was continued at 37 ℃ for 3 additional days, and Cytopathic (CPE) effects were recorded on day four. Then, 100. mu.L of the culture supernatant was aspirated, and the viral particles were lysed with 5% Triton X-100 to detect p24 antigen by ELISA. Briefly, the ELISA plates were coated with HIVIG (2. mu.g/mL), blocked with 1% nonfat milk, and the viral lysates were added and incubated at 37 ℃ for 60 min. After the plate is fully washed, anti-p 24 monoclonal antibody-183-12H-5C, biotin-labeled goat anti-mouse antibody and avidin-labeled horseradish peroxidase are added in sequence. Then, color was developed with TMB, and the optical density was measured at 450 nm. Calcusyn software was used to calculate half the viral inhibitory concentration (EC) of compounds50)。
TABLE 1 Activity data for inhibition of HIV replication and formation of the target molecule gp41-6 mer
And (3) SI: selection index CC50/EC50(ii) a ND: is under test
TABLE 2 Activity data (cell model) for inhibition of replication of HIV primary strains
Example 15: cytotoxicity assay of Compounds with CC50And (4) showing.
Reference documents to which the assay can be referred are Jiang, s., et al, antimicrob, Agents Chemother.2004, 48, 4349-.
In 96-well cell culture plates, 50. mu.L of different concentrations of compound solutions were mixed with an equal volume of PBS, incubated at 37 ℃ for 30 minutes, and then 100. mu.L of MT-2 cells (1X 10)5mL, RPIM 1640 medium with 10% serum), mixed well and incubated overnight at 37 ℃. After sucking off 150. mu.L of the supernatant on day 2, supplementing an equal volume of fresh medium and further incubating at 37 ℃ for 3 days, 50. mu.L of freshly prepared XTT solution containing PMS (1mg/mL) was added on day four and the optical density at 450nm was measured after 4 h. Calcusyn software was used to calculate half the Cytotoxic Concentration (CC) of the compound50). The results are shown in Table 1.
Example 16: inhibition of gp41 formation of six-membered helix bundle (6-HB), IC for inhibition of Activity50And (4) showing.
References to which assays can be referred are Jiang, S., et al.J.Virol. methods, 1999, 80, 85-96. The results are shown in Table 1.
The existing results show that: the compound of formula I is a non-peptide small molecule inhibitor with a novel framework structure and acting on HIV-1gp 41. They can effectively inhibit the formation of HIV-1gp41 six-membered helix bundle body (6-HB), thereby inhibiting the replication of HIV. The compounds also have inhibitory activity on various types of HIV virus strains clinically isolated, and have wide antiviral spectrum. The compound related by the invention is expected to be developed into a novel anti-HIV drug: a non-peptide small molecule HIV-1 fusion inhibitor taking gp41 as a target.

Claims (8)

1. Tetrazole aryl heterocyclic compounds of formula I:
Figure A200710306939C00021
wherein,
R1＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6a hydrocarbyl group;
R2-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Alkyl radical, C1-6Alkoxy, -CF3、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
ar is a five membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, selected from:
Figure A200710306939C00022
and
Figure A200710306939C00023
wherein R is3＝CHO、COR’、COOR’、COOH、CF3、CH2R', halogen, C1-6Hydrocarbyl radical, C1-6Alkoxy, -NH2、-OH、-NO2、-CN、-HC＝CH-CN、-CH＝CH2-C ≡ CH, -C ≡ CR ', -CH ═ CHR ', -CH ═ CHCOR ', or optionally bearing an ester group, a carboxyl group, C ≡ C optionally at available positions in its ring structure1-6Hydrocarbyl, phenyl-substituted heterocyclic groups:
Figure A200710306939C00024
wherein X and Y are each independently selected from C, O, S and NH;
R4＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6hydrocarbyl, phenyl;
R5-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Hydrocarbyl radical, C1-6Alkoxy, -CF3、CHO、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
the five-membered heteroaromatic ring optionally carries an unsaturation selected from the group consisting of aldehyde, keto, ester, carboxyl, cyano, alpha, beta, unsaturated, etc. at an available position on the ringKetones, alkenes, alkynes, C1-6Hydrocarbyl radical, C1-6Alkoxy, halogen, -NH2、-OH、-NO2and-CF3A substituent of (1);
R’＝C1-6a hydrocarbyl group; and is
R' is halogen, OH or C1-6An alkoxy group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula II:
Figure A200710306939C00031
wherein,
R1＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6a hydrocarbyl group;
R2-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Alkyl radical, C1-6Alkoxy, -CF3、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R3＝CHO、COR’、COOR’、COOH、CF3、CH2r', halogen, C1-6Hydrocarbyl radical, C1-6Alkoxy, -NH2、-OH、-NO2、-CN、-HC＝CH-CN、-CH＝CH2-C ≡ CH, -C ≡ CR ', -CH ═ CHR', -CH ═ CHCOR ', or optionally bearing an ester group, a carboxyl group, C ≡ CH', or a cyclic structure thereof1-6Hydrocarbyl, phenyl-substituted heterocyclic groups:
Figure A200710306939C00032
wherein X and Y are each independently selected from C, O, S and NH;
R4＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6hydrocarbyl, phenyl;
R5-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Hydrocarbyl radical, C1-6Alkoxy, -CF3、CHO、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R6＝H、CH3、CF3halogen or C2-4A hydrocarbyl group;
R’＝C1-6a hydrocarbyl group; and is
R' is halogen, OH or C1-6An alkoxy group.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula III:
Figure A200710306939C00041
wherein,
R1＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6a hydrocarbyl group;
R2-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Alkyl radical, C1-6Alkoxy, -CF3、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R3＝CHO、COR’、COOR’、COOH、CF3、CH2r', halogen, C1-6Hydrocarbyl radical, C1-6Alkoxy, -NH2、-OH、-NO2、-CN、-HC＝CH-CN、-CH＝CH2-C ≡ CH, -C ≡ CR ', -CH ═ CHR', -CH ═ CHCOR ', or optionally bearing an ester group, a carboxyl group, C ≡ CH', or a cyclic structure thereof1-6Hydrocarbyl, phenyl-substituted heterocyclic groups:
Figure A200710306939C00042
wherein X and Y are each independently selected from C, O, S and NH;
R4＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6hydrocarbyl, phenyl;
R5-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Hydrocarbyl radical, C1-6Alkoxy, -CF3、CHO、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R’＝C1-6a hydrocarbyl group; and is
R' is halogen, OH or C1-6An alkoxy group.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula IV:
wherein,
R1＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6a hydrocarbyl group;
R2-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Alkyl radical, C1-6Alkoxy, -CF3、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R3＝CHO、COR’、COOR’、COOH、CF3、CH2r', halogen, C1-6Hydrocarbyl radical, C1-6Alkoxy, -NH2、-OH、-NO2、-CN、-HC＝CH-CN、-CH＝CH2、-C≡CH、-C≡CR’、-CH＝CHR ', -CH ═ CHCOR', or optionally having an ester group, carboxyl group, C on the ring structure1-6Hydrocarbyl, phenyl-substituted heterocyclic groups:
Figure A200710306939C00052
wherein X and Y are each independently selected from C, O, S and NH;
R4＝-H、-CH2COOH、-CH2CH2COOH、-CH＝CH-COOH、-CH2COOR’、-CH2CH2COOR’、-CH＝CH-COOR’、C1-6hydrocarbyl, phenyl;
R5-H, halogen, -NO2、-NH2、-NHR’、-N(R’)2、-CN、-OH、C1-6Hydrocarbyl radical, C1-6Alkoxy, -CF3、CHO、-COOH、-SO3H、-CONH2-CONHR 'or-COOR';
R’＝C1-6a hydrocarbyl group; and is
R' is halogen, OH or C1-6An alkoxy group.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:
5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole;
5- (2-hydroxy-5- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole;
5- (2-chloro-5- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole;
5- (3- (3-ethoxycarbonyl-2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole;
5- (3- (3-carboxy-2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole;
5- (3- (1H-pyrrole-1-yl) phenyl) -1H-tetrazole (II-1f)
1-carboxymethyl-5- (3- (2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole;
1-carboxymethyl-5- (3- (3-carboxy-2, 5-dimethyl-1H-pyrrol-1-yl) phenyl) -1H-tetrazole;
5- (3- (5- (trifluoromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazole;
5- (3- (5- (chloromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazole;
5- (3- (5- (hydroxymethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazole;
1-carboxymethyl-5- (3- (5- (trifluoromethyl) -1, 2, 4-oxadiazol-3-yl) phenyl) -1H-tetrazole;
1-ethyl-5- (3- (5-methine- (rhodanin-5-yl) -furan-2-yl) phenyl) -1H-tetrazole; and
1-carboxymethyl-5- (3- (5-methine- (rhodanin-5-yl) -furan-2-yl) phenyl) -1H-tetrazole.
6. A process for preparing a compound according to claim 1, or a pharmaceutically acceptable salt thereof, which comprises:
route a: general procedure
Figure A200710306939C00061
The cyano group of the substituted benzonitrile compound (A) can react with sodium azide to synthesize a 1H-tetrazole ring to obtain a target compound I-1, and the 1-site nitrogen hydrogen on the tetrazole ring reacts with halohydrocarbon to obtain a compound I-2;
or,
route B: for compounds of formula I wherein Ar is a pyrrole ring:
Figure A200710306939C00071
carrying out Paal-Knorr reaction on substituted 5- (3-amino) phenyl-1H-tetrazole (B) and 2, 5-dimethoxytetrahydrofuran or beta-substituted 1, 4-diketone to obtain an N-arylpyrrole compound (II-1), and reacting with halogenated hydrocarbon to generate a 1-substituted 1H-tetrazole-N-arylpyrrole compound (II-2);
or,
route C: for compounds of formula I wherein Ar is an oxadiazole ring:
Figure A200710306939C00072
substituted 5- (3-cyano) phenyl-1H-tetrazole (C) is used as a raw material, the substituted 5- (3-cyano) phenyl-1H-tetrazole (C) reacts with hydroxylamine hydrochloride to generate an amino oxime intermediate (D), the amino oxime intermediate (D) reacts with an acylation reagent to obtain a 3-aryl-1, 2, 4-oxadiazole compound (III-1), and then a target compound III-2 is obtained through a nitrogen halogenation reaction;
or,
route D: for compounds of formula I wherein Ar is a five-membered heterocyclic (e.g., pyrrole, furan, etc.) aldehyde:
the substituted 5- (3-bromine) phenyl-1H-tetrazole (E) and the aromatic heterocyclic boric acid compound are coupled to generate the target compound IV-1 containing the aromatic heterocyclic through Suzuki reaction. When the aromatic heterocycle contains aldehyde group, a target compound IV-2 can be obtained through condensation and halogenation;
r in the reaction scheme1-R4、R6And X, Y are as previously described for formula I, each U, V, W independently represents a heteroatom selected from N, O, S or is a carbon atom.
7. A pharmaceutical composition comprising at least one compound of formula I as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients.
8. Use of a compound of formula I as described in any one of claims 1-5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with HIV infection.
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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