CN101717364B - Paradoximes as HIV reverse transcriptase inhibitor as well as preparation method and purpose thereof - Google Patents

Paradoximes as HIV reverse transcriptase inhibitor as well as preparation method and purpose thereof Download PDF

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Publication number
CN101717364B
CN101717364B CN200910177472.3A CN200910177472A CN101717364B CN 101717364 B CN101717364 B CN 101717364B CN 200910177472 A CN200910177472 A CN 200910177472A CN 101717364 B CN101717364 B CN 101717364B
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alkyl
compound
cyano
halogen
arh
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CN101717364A (en
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谢蓝
田兴涛
李国雄
姜世勃
陆虹
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

The invention relates to 2-(4-substituted phenylamino group) polysubstitution paradoximes as HIV reverse transcriptase inhibitors, and a preparation method and purpose thereof, in particular to I type compounds or medicinal salt thereof, wherein the definitions of the R1, R2, R3, R4, R5, R6, R7 and X are stated as the specification. The I type compounds of the invention are anti-HIV activity compounds having a novel framework structure.

Description

As pyridine compounds and their of hiv reverse transcriptase inhibitor and its production and use
Technical field
The present invention relates to have 2-(4-substituted anilinic) the polysubstituted pyridine compounds, its preparation method, the pharmaceutical composition that contains them of HIV (human immunodeficiency virus)-resistant activity and for the preparation of the purposes of the medicine of anti-HIV.
background technology
Virus of AIDS (HIV) is a kind of RNA viruses.The surface of this virus is the two adipose membrane of layer.In film, 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.).There are two very important glycoprotein gp120 and gp41 in the film surface of virus.Gp120 is in the outside of film, and gp41 forms a complex body across two adipose membranes and with gp120.Their major function is in identification and attack human immune system, to have the cell of CD4 surface receptor, as lymphocyte (T cell), scavenger cell etc.HIV is irreproducible in vitro, must be by means of human body cell ability reproduction.The reproduction process of HIV was broadly divided into the next stage: the combination of virus and host cell and fusion, the reverse transcription of virogene, integrates, and transcribes, and translates, assembling and the release of virus.Virus of AIDS constantly copies with such working cycle, infects human immunocyte, destroys the immunity system of human body, finally causes completely losing of immune function of human body, and patient is had no among the danger of defensive ability/resistance ability in all kinds of infection.Theoretically, medicine is as long as the arbitrary link in blocking virus reproduction process all can reach the object that suppresses virus and treatment disease.
Up to the present, approval listing infects and treats the chemicals of acquired immune deficiency syndrome (AIDS) and combine existing kind more than 30 for clinical anti-HIV.Existing medicine is divided into five classes by its mechanism of action: efabirenz (NRTIs), non-nucleoside reverse transcriptase inhibitor (NNRTIs), proteinase inhibitor (PIs), fusion inhibitor (Enfuvirtide) and entry inhibitor (Maraviroc).Existing medicine is used alone or in combination and can effectively suppresses virus copying in vivo, but the subject matter of jointly facing is resistance.HIV virus can produce certain variation with drug effect after for some time.The virus of variation can no longer be subject to the inhibition of medicine, still as before medication, continues to copy in vivo a large amount of virus.Therefore, find and exploitation has new texture type novel mechanism, new role target spot or the drug-fast virus of tool is had to strong inhibiting anti-AIDS drug of new generation is a focus in drug research field in recent years always.
At present, the non-nucleoside reverse transcriptase inhibitor [nevirapine (Nevirapine), Delavirdine (Delavirdine), efavirenz (Efavirenz), etravirine (Entravine)] that has 4 listings.Such medicine has superior part such as structure diversity, high-efficiency low-toxicity, target spot and clear mechanism and noncompetitive inhibitor etc., in anti-HIV combination treatment (HAART), occupies critical positions.But the main problem existing is easily to produce resistance or day medicining times is more.For overcoming the drawback of existing medicine, need to find and can effectively suppress the non-nucleoside reverse transcriptase inhibitor medicine of new generation that wild-type and several drug resistance HIV virus strain copy.
Summary of the invention
Summary of the invention
First aspect present invention provides formula I compound:
Or its pharmacologically acceptable salt,
Wherein,
R 1, R 2and R 3be independently of one another-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 ',
Or, R 1and R 2or R 2and R 3can form together-OCH 2o-;
R 4for-CN ,-CH=CH 2,-C ≡ CH, C 1-6alkyl, C 1-6alkoxyl group ,-CF 3, halogen ,-NH 2,-OH ,-COOH ,-SO 3h ,-C ≡ CR ' or-CH=CHR ';
R 5and R 6be halogen, C independently of one another 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-NH 2,-OH ,-COOH ,-SO 3h ,-COOR ' ,-NO 2,-CN ,-H or C 1-6alkyl;
R 7for-CN ,-HC=CH-CN, halogen, C 1-6alkyl, C 1-6alkoxyl group ,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, C 1-6alkyl, containing 1-3, be selected from heteroatomic five yuan or the six membered heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
Be selected from-NH-of X ,-O-,-S-,-CH 2-,-CO-,-CHOH-,-CHOR-,-NR-,-NCOR-; And
R is C 1-4alkyl.
The compound of either side above or below according to the present invention, wherein X is-O-.
The compound of either side above or below according to the present invention, its Chinese style I compound has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1and R 3be independently of one another-NO 2,-NH 2, halogen ,-OH ,-CN or-N (R) 2;
R 2for-H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-or-NCOR-; And
R is C 1-4alkyl.
The compound of either side above or below according to the present invention, its Chinese style I compound has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1for-NO 2,-NH 2, halogen ,-OH ,-CN or-N (R) 2;
R 2and R 3for-H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-CH=CHCOR ' ,-C ≡ CR ' ,-CH=CHR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-or-NCOR-; And
R is C 1-4alkyl.
The compound of either side above or below according to the present invention, its Chinese style I compound has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 2for-NO 2,-NH 2,-halogen ,-OH ,-CN or-N (R) 2;
R 1and R 3for H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-OH ,-CH 2-NHR ' ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-,-NCOR-; And
R is C 1-4alkyl.
The compound of either side above or below according to the present invention, its Chinese style I compound has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 3for-NO 2,-NH 2,-halogen ,-OH ,-CN or-N (R) 2;
R 1and R 2for H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-,-NCOR-; And
R is C 1-4alkyl.
The compound of either side above or below according to the present invention, its Chinese style I compound has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1, R 2and R 3be-H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-or-NCOR-; And
R is C 1-4alkyl.
The compound of either side above or below according to the present invention, its Chinese style I compound has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1for-NO 2, or-NH 2;
R 2and R 3be-H;
R 5and R 6be halogen, C independently of one another 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-NH 2,-OH ,-COOH ,-NO 2,-CN or-H; Preferably, R 5and R 6be halogen, C independently of one another 1-4alkyl ,-NH 2,-OH ,-NO 2, or-CN;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-6cycloalkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-or-NCOR-; And
R is C 1-4alkyl.
The compound of either side above or below according to the present invention, it is selected from:
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-bromine phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-cyano-benzene oxygen)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,4,6-trimethylammonium phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-formyl radical phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-propylene cyano-benzene oxygen)-3-nitropyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-cyano-benzene oxygen) pyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-hydroxy methyl phenyloxy) pyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-hydroxy methyl phenyloxy)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-allyl group phenoxy group)-3-nitropyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-propylene cyano-benzene oxygen) pyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-toluidine)-3-nitropyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-bromine phenoxy group) pyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-allyl group phenoxy group) pyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(1-hydroxyl-2-nitro-ethyl) phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(2-cyclopropyl amino methyl) phenoxy group)-3-nitro-pyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-iodine phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-nitrophenoxy)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(3-methyl-3-hydroxyl-ethyl acetylene base) phenoxy group)-3-nitropyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(3-methyl-3-hydroxyl-ethyl acetylene base) ethynyl phenoxy group) pyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(cyclopropyl acethlene base) phenoxy group)-3-nitropyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(cyclopropyl acethlene base) phenoxy group) pyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-ethynyl phenoxy group)-3-nitro-pyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-ethynyl phenoxy group) pyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-amino-benzene oxygen) pyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-iodine phenoxy group) pyridine;
2-(4-cyano-aniline base)-6-(2,4,6-tribromophenoxy)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(the bromo-4-formyl radical of 2,6-bis-phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(the bromo-4-hydroxy methyl phenyloxy of 2,6-bis-)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-difluoro phenoxy group)-3-nitropyridine; With
2-(4-cyano-aniline base)-6-(the bromo-4-propylene of 2,6-bis-cyano-benzene oxygen)-3-nitropyridine,
Or its pharmacologically acceptable salt.
Second aspect present invention provides the preparation method of the compound described in first aspect present invention any one, and its reaction scheme is as follows:
Z＝Cl，Br，I X＝NH 2，OH，NR′，SH X＝NH，O，NR′，S
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, and the definition of X with described in formula I compound above, described method comprise make formula II replacement 2,6-dihalo pyridine compounds and their reacts with para-orientation amino benzenes compounds under the effect of alkali, or carries out 2-(4-substituted anilinic) the polysubstituted pyridine compounds of solvent-free reaction accepted way of doing sth IV; Then make formula IV intermediate and polysubstituted phenol or amino benzenes compounds carry out linked reaction, or under palladium class catalyst action heating or under microwave condition coupling generate 2-(4-substituted anilinic) the polysubstituted pyridine compounds with formula I.
Third aspect present invention provides a kind of pharmaceutical composition, and it comprises compound or pharmaceutically acceptable salt thereof and one or more pharmaceutical carriers or vehicle described in first aspect present invention any one.
The purposes that fourth aspect present invention provides the compound or pharmaceutically acceptable salt thereof described in a kind of first aspect present invention any one to infect the medicine of relevant disease or illness for the preparation for the treatment of to HIV.
Fifth aspect present invention provides treatment to infect relevant disease or the method for illness to HIV, and it comprises to the compound or pharmaceutically acceptable salt thereof having described in the first aspect present invention any one of experimenter's administering therapeutic significant quantity of needs.
Detailed Description Of The Invention
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
The inventor has found that in the research of anti-HIV new medicament the compound of a class novel texture has great HIV (human immunodeficiency virus)-resistant activity.
The present invention is described in further detail below, and first aspect of the present invention relates to the formula I compound of 2-shown in formula I (4-substituted anilinic) polysubstituted pyridine class skeleton structure:
Or its pharmacologically acceptable salt,
Wherein,
R 1, R 2and R 3be independently of one another-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 ',
Or, R 1and R 2or R 2and R 3can form together-OCH 2o-;
R 4for-CN ,-CH=CH 2,-C ≡ CH, C 1-6alkyl, C 1-6alkoxyl group ,-CF 3, halogen ,-NH 2,-OH ,-COOH ,-SO 3h ,-C ≡ CR ' or-CH=CHR ';
R 5and R 6be halogen, C independently of one another 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-NH 2,-OH ,-COOH ,-SO 3h or-COOR ' ,-NO 2,-CN ,-H or C 1-6alkyl;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl or cyclic hydrocarbon radical; R " be NO 2, NH 2, or N 3;
Be selected from-NH-of X ,-O-,-S-,-CH 2-,-CO-,-CHOH-,-CHOR-,-NR-,-NCOR-; And
R is C 1-4alkyl.
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 one 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 infects the medicine of relevant disease or illness for the preparation for the treatment of to HIV.
In formula I compound of the present invention, A, B, C respectively encircle the particularly annular atoms numbering of A and C ring when name can be undertaken by following exemplary order:
Term term " halogen ", " halogen ", " Hal " or " halo " mentioned in the present invention refer to fluorine, chlorine, bromine and iodine.
The term adopting in the present invention " alkyl " comprises alkyl (for example straight chained alkyl, branched-chain alkyl), cycloalkyl, thiazolinyl and alkynyl.In one embodiment, " C of the present invention 1-6alkyl " comprise C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-6cycloalkyl, C 3-6cycloalkenyl group.In one embodiment, " C of the present invention 1-6alkyl " comprise " C 1-4alkyl ".In one embodiment, " C of the present invention 1-4alkyl " comprise C 1-4alkyl, C 2-4thiazolinyl, C 2-4alkynyl, C 3-4cycloalkyl, C 3-4cycloalkenyl group.In one embodiment, " C of the present invention 1-6alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, neo-pentyl, hexyl, vinyl, propenyl, allyl group, butenyl, ethynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutene base.
The term adopting in the present invention " five yuan of heterocyclic bases " refers to and in ring system, contains 1-3 heteroatomic 5-membered aromatic ring system that is selected from O, S or N, and it includes but not limited to furans, pyrroles, thiophene, pyrazoles etc.
" on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituent quinary heteroaryl of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group " of in the present invention, mentioning can schematically as follows, include but not limited to this:
Wherein,
R ' can be H, C 1-6alkyl;
R " can be H ,-CN, NO 2, N 3, C 1-4alkyl;
X, Y, Z represent to be independently of one another selected from the heteroatoms of N, O, S or are carbon atom.
According to an embodiment of the invention, the present invention relates to formula I compound as follows:
Or its pharmacologically acceptable salt,
Wherein,
R 1, R 2and R 3be independently of one another-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 ',
Or, R 1and R 2or R 2and R 3can form together-OCH 2o-;
R 4for-CN ,-CH=CH 2,-C ≡ CH, C 1-6alkyl, C 1-6alkoxyl group ,-CF 3, halogen ,-NH 2,-OH ,-COOH ,-SO 3h ,-C ≡ CR ' or-CH=CHR ';
R 5and R 6be halogen, C independently of one another 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-NH 2,-OH ,-COOH ,-SO 3h ,-COOR ' ,-NO 2,-CN ,-H or C 1-6alkyl;
R 7for-CN ,-HC=CH-CN, halogen, C 1-6alkyl, C 1-6alkoxyl group ,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, C 1-6alkyl, containing 1-3, be selected from heteroatomic five yuan or the six membered heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl is C for example 1-4chain hydrocarbon or C 3-6alkyl cyclic hydrocarbon radical; R " be NO 2, NH 2, or N 3;
Be selected from-NH-of X ,-O-,-S-,-CH 2-,-CO-,-CHOH-,-CHOR-,-NR-,-NCOR-; And
R is C 1-4alkyl.
According to a preferred embodiment of the present invention, X is-O-.
According to a preferred embodiment of the present invention, formula I compound of the present invention has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1and R 3be independently of one another-NO 2,-NH 2, halogen ,-OH ,-CN or-N (R) 2;
R 2for-H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-or-NCOR-; And
R is C 1-4alkyl.
According to another preferred embodiment of the present invention, formula I compound has above-mentioned formula Ia, wherein
R 1for-NO 2,-NH 2, halogen ,-OH ,-CN or-N (R) 2;
R 2and R 3for-H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-CH=CHCOR ' ,-C ≡ CR ' ,-CH=CHR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-or-NCOR-; And
R is C 1-4alkyl.
According to another preferred embodiment of the present invention, formula I compound has above-mentioned formula Ia, wherein
R 2for-NO 2,-NH 2,-halogen ,-OH ,-CN or-N (R) 2;
R 1and R 3for H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-OH ,-CH 2-NHR ' ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-,-NCOR-; And
R is C 1-4alkyl.
According to another preferred embodiment of the present invention, formula I compound has above-mentioned formula Ia, wherein
R 3for-NO 2,-NH 2-halogen ,-OH ,-CN or-N (R) 2;
R 1and R 2for H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-NH-,-NCOR-; And
R is C 1-4alkyl.
According to another preferred embodiment of the present invention, formula I compound has above-mentioned formula Ia, wherein
R 3for-NO 2,-NH 2,-halogen ,-OH ,-CN or-N (R) 2;
R 1and R 2for H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-or-NH-; And
R is C 1-4alkyl.
According to another preferred embodiment of the present invention, formula I compound has above-mentioned formula Ia, wherein
R 1and R 2or R 2and R 3be together-OCH 2o-, remaining R 3or R 1for-H, OH ,-NH 2,-NO 2or halogen;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' ,-CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, containing 1-3, be selected from the heteroatomic quinary heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group;
R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3;
X is-O-,-S-,-CH 2-,-NH-,-NCOR-; And
R is C 1-4alkyl.
Above or below the formula I compound of either side, wherein R according to the present invention 1, R 2and R 3be independently of one another-H, halogen ,-NO 2,-NH 2, or-NHR.In one embodiment, R 1, R 2and R 3be independently of one another-H, halogen ,-NO 2,-NH 2.In one embodiment, R 1for-H ,-NO 2, or-NH 2.In one embodiment, R 1for-NO 2, or-NH 2.Wherein, R is C 1-4alkyl; R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3.
Above or below the formula I compound of either side, wherein R according to the present invention 4for-CN ,-CH=CH 2,-C ≡ CH, C 1-6alkyl, C 1-6alkoxyl group ,-CF 3, halogen ,-NH 2,-OH ,-COOH ,-SO 3h ,-C ≡ CR ' or-CH=CHR '.In one embodiment, R 4for-CN, C 1-6alkyl, C 1-6alkoxyl group ,-CF 3, halogen ,-NH 2,-OH or-COOH.In one embodiment, R 4for-CN, C 1-6alkyl ,-CF 3, halogen ,-NH 2, or-OH.In one embodiment, R 4for-CN, C 1-6alkyl, halogen ,-NH 2.Wherein, R is C 1-4alkyl; R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3.
Above or below the formula I compound of either side, wherein R according to the present invention 5and R 6be halogen, C independently of one another 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-NH 2,-OH ,-COOH ,-SO 3h ,-COOR ' ,-NO 2,-CN ,-H or C 1-6alkyl.In one embodiment, R 5and R 6be halogen, C independently of one another 1-6alkyl ,-NH 2,-OH ,-COOH ,-NO 2,-CN or-H.In one embodiment, R 5and R 6be halogen, C independently of one another 1-6alkyl ,-NH 2,-NO 2,-CN or-H.In one embodiment, R 5and R 6be fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl independently of one another.Wherein, R is C 1-4alkyl; R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3.
Above or below the formula I compound of either side, wherein R according to the present invention 7be selected from-CN ,-HC=CH-CN, halogen, C 1-6alkyl, C 1-6alkoxyl group ,-NH 2,-CH 2-NHR '-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, C 1-6alkyl, containing 1-3, be selected from heteroatomic five yuan or the six membered heteroaryl of N, O, S, and optionally on its ring structure with aldehyde radical, ketone group, cyano group, α, the substituting group of the unsaturated cyanogen of β, alkene, alkynes, aldehyde radical or ketone group.In one embodiment, R 7be selected from-CN ,-HC=CH-CN, halogen, C 1-6alkyl, C 1-6alkoxyl group ,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, C 3-6cycloalkyl, C 2-6thiazolinyl, C 2-6alkynyl.In one embodiment, R 7be selected from-CN ,-HC=CH-CN, halogen, C 1-6alkyl, C 1-6alkoxyl group ,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-CH=CH 2,-C ≡ CH ,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ', CHO ,-C ≡ CR " ,-CH=CHR " ,-C ≡ C-CN, C 3-6cycloalkyl, C 2-6thiazolinyl, C 2-6alkynyl.Wherein, R is C 1-4alkyl; R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3.
Above or below the formula I compound of either side, be wherein selected from-NH-of X ,-O-,-S-,-CH according to the present invention 2-,-CO-,-CHOH-,-CHOR-,-NR-,-NCOR-.In one embodiment, be selected from-NH-of X ,-O-,-S-,-CH 2-,-CO-,-NR-,-NCOR-.In one embodiment, be selected from-NH-of X ,-O-,-S-,-CH 2-,-CO-,-NR-.In one embodiment, be selected from-NH-of X ,-O-,-CH 2-,-NR-.In one embodiment, be selected from-NH-of X ,-O-.Wherein, R is C 1-4alkyl; R ' is H or C 1-6alkyl; R " be NO 2, NH 2, or N 3.
The formula I compound of either side above or below according to the present invention, wherein R is C 1-4alkyl.In one embodiment, R is selected from C 1-4alkyl, C 2-4thiazolinyl, C 2-4alkynyl, C 3-4cycloalkyl.In one embodiment, R is selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, vinyl, propenyl, allyl group, ethynyl, propargyl, cycloalkyl, cyclobutyl.
The formula I compound of either side above or below according to the present invention, it is the compound that is selected from the embodiment of the present invention, or its pharmacologically acceptable salt.
In the test cell line (MT-2 and H9 lymphocyte) that the 2-of formula I of the present invention (4-substituted anilinic) polysubstituted pyridine compounds copies at inhibition HIV, demonstrate strong HIV (human immunodeficiency virus)-resistant activity and highly selective.Therefore, the compounds of this invention is furtherd investigate to the inverase making new advances being expected to exploitation.
The compounds of this invention can be prepared by reaction scheme below:
Z＝Cl，Br，I X＝NH 2，OH，NR′，SH X＝NH，O，NR′，S
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, and the definition of X with described in formula I compound above.
Make formula II replacement 2,6-dihalo substituted pyridines reacts with para-orientation amino benzenes compounds, generates 2-(4-substituted anilinic) polysubstituted pyridine, i.e. formula IV intermediate; Then make formula IV intermediate and polysubstituted phenol or amino benzenes compounds carry out linked reaction, or under palladium class catalyst action heating or under microwave condition coupling generate 2-(4-substituted anilinic) the polysubstituted pyridine class target compound with formula I.
In addition, the part target compound in formula I, under microwave reaction condition, also can two step coupled reactions carry out i.e. " one pot reaction " simultaneously.
For example, formula Ia compound of the present invention can be prepared according to following synthetic route:
Wherein, Z=halogen, R 1, R 2, R 3, R 4, R 5, R 6, R 7definition with described in formula I compound above, can select as required to have suitable R 1, R 2, R 3substituent formula II is raw material.
synthesizing of intermediate compound IV
Specifically, at potassium tert.-butoxide, sodium hydride, triethylamine, pyridine, N, under the cuprous existence of N dimethylamine yl pyridines, sodium bicarbonate, salt of wormwood or salt of wormwood/halo, make 2,6-dihalo substituted pyridines (II) and para-orientation aniline or phenol solvent such as but not limited to ethanol, the trimethyl carbinol, DMF, acetonitrile, THF or DMSO in, below room temperature to 130 ℃, react 5 minutes-24 hours, generate 2-(4-substituted anilinic) polysubstituted pyridine or 2-(4-substituent phenoxy) polysubstituted pyridine (IVa).The molar ratio of reactant II/III can be 1: 1-1: 2.
This reaction also can be take DMF or DMSO as solvent under microwave condition, and temperature can be within the scope of 110-180 ℃, reaction 5-30 minute, obtains intermediate compound IV a.Alkali and reactant ingredient proportion can be same as above.
This reaction also can make II and III under protection of inert gas, directly carries out solvent-free reaction under temperature 50-180 ℃ of condition, and the feed ratio of II and III is same as above.
target compound I's is synthetic
For example, the X in general formula is-during O-, its synthetic method can be:
Method 1: making 2-(4-substituted anilinic)-6-halo polysubstituted pyridine (formula IVa) and polysubstituted phenol (formula V) take DMSO, DMF etc. is solvent, with K 2cO 3for example, for alkali, under Cu or cuproine (CuI, CuBr) exist for catalyzer, be for example heated to 100-150 ℃ under nitrogen protection and react for example 2-8 hour.Or under catalyst-free existence condition, for example, under 130-150 ℃ of condition, reacting for example 2-24h.
Method 2: in dry ether, make the trisubstituted benzene phenol of formula V react and become sodium salt or sylvite with NaH or potassium tert.-butoxide, its salt and the IVa 0.5-8 hour that refluxes in DMF;
Method 3: make intermediate compound IV a react for example 5-30 minute with sodium phenolate or sylvite under microwave condition in DMF;
Method 4: take DMSO as solvent, make intermediate compound IV a react for example 5-30 minute together with fortified phenol (formula V) and salt of wormwood under microwave.
And for example, the X in target compound general formula is-during NH-, its synthetic method can be:
Wherein each substituent definition, with described in above formula I, can select to have suitable R as required 1, R 2, R 3substituent formula IV is raw material.
Method 5: make intermediate substituted pyridines (formula IV) and substituted aniline (formula V) at aprotic polar solvent (as DMSO or DMF etc.), take α-benzoinoxime such as Cu, CuI or CuBr etc. is catalyzer, at K 2cO 3under existence, under nitrogen protection, temperature for example 140-160 ℃ react for example 2-24 hour.
Method 6: take palladium reagent as catalytic reagent, toluene is solvent, under cesium carbonate exists, under nitrogen protection, make intermediate substituted pyridines (formula IV) react for example 1-24 hour with substituted aniline (formula V) in for example 100 ℃ of left and right;
Method 7: if arylamine (formula VI) is liquid, can directly VI be mixed with intermediate compound IV without using other solvent, reaction is approximately for example about 15-20 minute under arylamine boiling temperature, microwave;
Method 8: take DMSO or NMP etc. is solvent, make arylamine (formula V) with intermediate substituted pyridines (formula IV) with 4: 1 mol ratios, under potassium tert.-butoxide exists, react for example 15-30 minute under for example 200-250 ℃ of temperature, microwave.
Similarly, can also prepare the compound of Formula I that X is other definition.For example, those skilled in the art can be according to its existing knowledge and method well known in the art, with reference to X in above-mentioned formula I, be-method of the compound of NH-, obtains X in formula I to be-compound of NR-and-NCOR-, and wherein R is C 1-4alkyl such as methyl, ethyl, propyl group etc.
In the method for synthetic compound of formula i of the present invention, the various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make by the known method of document, or can buy by business.In above reaction scheme, intermediate used, starting material, reagent, reaction conditions etc. all can be made appropriate change according to those skilled in the art existing knowledge.Or, other formula I compound that those skilled in the art also can specifically not enumerate according to the synthetic the present invention of second aspect present invention method.
The compounds of this invention both can itself also can its pharmacologically acceptable salt form 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, acetic acid, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, flutters 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-METHYL-ALPHA-L-GLUCOSAMINE and PROCAINE HCL, PHARMA GRADE etc. form.While relating to the compounds of this invention herein, comprise formula I compound and pharmacologically acceptable salt thereof.
Formula I compound or pharmaceutically acceptable salt thereof of the present invention also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I compound of the present invention and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges in vivo described activeconstituents after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non-solvent compound form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.
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.
Term used herein " composition " means to comprise the product of respectively specifying composition that comprises specified amount, and any product of the direct or indirect combination results of respectively specifying composition from specified amount.
Use the familiar pharmaceutical carrier of those skilled in the art can be prepared into the pharmaceutical composition containing the compounds of this invention of effective dose.Therefore the present invention also provides the pharmaceutical composition that comprises the compounds of this invention formulated together with one or more nontoxic drug acceptable carriers.That described pharmaceutical composition can be mixed with especially is specially for oral administration with solid or liquid form, for parenteral injection or for rectal administration.
Pharmaceutical composition of the present invention can by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, part (as by powder, ointment or drops), a mouthful cheek give the mankind and other Mammalss, or give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenously, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
The composition that is suitable for parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise that water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester are as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee to prevent the effect of microorganism.Also expectation comprises isotonic agent, such as carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin, can reach the prolongation absorption of injectable drug form.
In suspensoid, also can contain suspension agent except active ingredient beyond the region of objective existence, such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials partially.
In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or intramuscularly medicine.This can realize by the liquid suspension of the crystal with poorly water-soluble or amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.
Injectable depot formulations form can be prepared by form the microcapsule matrix of medicine in as polylactide-PGA (polylactide-polyglycolide) at biodegradable polymer.Can, according to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopting, drug releasing rate be controlled.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can be for example by filtering or carry out sterilizing by mixing the disinfectant of aseptic solid composite form with bacterial filter, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention or its composition can be by oral methods or parenteral administration modes.Oral administration can be tablet, capsule, Drug coating, and enteron aisle external application preparation has injection and suppository etc.These preparations are prepared according to method appreciated by those skilled in the art.In order to manufacture tablet, capsule, Drug coating auxiliary material used, it is the auxiliary material of conventional use, for example starch, gelatin, gum arabic, silica, polyoxyethylene glycol, liquid dosage form solvent used is as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).In the preparation that contains the compounds of this invention, also has other auxiliary material, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives and pigment etc.The dosage that contains formula I compound of the present invention in tablet, capsule, Drug coating, injection and suppository is that the compound amount existing in unit dosage form is calculated.In unit dosage form, the general content of formula I compound of the present invention is 1-5000mg, and preferred unit dosage form contains 10-500mg, and preferred unit dosage form contains 20-300mg.Specifically, the solid dosage for oral administration that the present invention can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier with the medicine of at least one inertia and mix as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material: a) weighting agent or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks is as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agent is as paraffin; F) absorb accelerator as quaternary ammonium compound; G) wetting agent is as hexadecanol and Zerol; H) sorbent material is as kaolin and wilkinite and i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.The in the situation that of capsule, tablet and pill, in described formulation, also can comprise buffer reagent.
The solids composition of similar type is used such as lactose and high molecular weight polyethylene glycol etc. of vehicle, also can be used as the weighting material in soft capsule and hard capsule.
The solid dosage of tablet, dragee (dragees), capsule, pill and granule can be prepared together with dressing and shell material other clothing materials as known in enteric coating material and field of medicine preparations.These solid dosages can optionally contain opalizer, and its form also can make it just or preferentially at certain position of enteron aisle optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, active compound also can be made into micro-capsule form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain the conventional inert diluent in this area except containing active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture for example.Oral compositions also can comprise auxiliary material except comprising inert diluent, for example wetting agent, emulsification and suspension agent, sweeting agent, correctives and flavouring agent.
The composition of confession rectum or vagina administration is suppository preferably.Suppository can be by by the compounds of this invention and suitable non-irritating excipient or carrier, for example theobroma oil, polyoxyethylene glycol or suppository wax mix to prepare, they are at room temperature solid, therefore but next at body temperature is liquid, can in rectal cavity or vaginal canal, melts and discharge active compound.
Compound of the present invention and composition thereof are also considered for topical.For the local dosage form that gives the compounds of this invention, comprise powder, sprays, ointment and inhalation.Under aseptic condition by active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution are also considered within the scope of the present invention.
The compounds of this invention also can liposome form administration.As known in the art, liposome makes with phosphatide or other lipid materials conventionally.Liposome is formed by the single or multiple lift aquation liquid crystal being scattered in water-bearing media.On any nontoxic, physiology that can form liposome, can accept and metabolizable lipid all can be used.The present composition of liposome form, except containing the compounds of this invention, also can contain stablizer, sanitas, vehicle etc.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method that forms liposome is well known in the art.Referring to for example Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.
When treating and/or preventing or other treatment and/or when prevention for above-mentioned, a kind of the compounds of this invention that treats and/or prevents significant quantity can be applied with pure form, or with the acceptable ester of pharmacy or prodrug forms (in the situation that there are these forms) application.Or described compound can be accepted the pharmaceutical composition administration of vehicle to contain this object compound and one or more medicines.The compounds of this invention that word " treats and/or prevents significant quantity " refers to be applicable to the reasonable effect/risk of any therapeutic treatment and/or prevention than the compound of the q.s for the treatment of obstacle.But the total daily dosage portion that it should be understood that the compounds of this invention and composition must maked decision within the scope of medical judgment reliably by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises the severity of treated obstacle He this obstacle; The activity of the particular compound adopting; The concrete composition adopting; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound adopting, route of administration and excretion rate; The treatment time length; The medicine that is used in combination or uses simultaneously with adopted particular compound; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.In general, particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example, between 0.01～100mg/kg body weight/day, for example, between 0.01～10mg/kg body weight/day for Mammals for formula I compound of the present invention.
Embodiment
The following examples are used for further illustrating the present invention, but it does not mean that the present invention only limits to this.
preparation Example 1: the preparation of the chloro-2-of 6-(4-cyano-aniline base)-3-nitropyridine (IV-1)
2,6-dichloro-3-nitropyridine (II-1,193mg, 1mmol) and cyano-aniline (III-1,236mg, 2mmol) is dissolved in to DMF (DMF, 3mL).Ice-water bath is cooling, and add potassium tert.-butoxide (then 224mg, 2mmoD at room temperature react 2h in batches.Reaction solution is poured in frozen water, with rare HCl adjust pH, to 5-6, stirred 30 minutes, separate out solid.Solid is leached, be washed to neutrality, dry, silicagel column separated (methylene dichloride is eluent), obtains compound IV-11 (186mg, 68%), faint yellow solid, mp 175-178 ℃. 1H NMR(CDCl 3)δ10.47(1H，br s，NH)，8.53(1H，d，J＝8.4Hz，ArH-4)，7.86(2H，d，J＝8.8Hz，ArH-2’，6’)，7.70(2H，d，J＝8.8Hz，ArH-3’，5’)，6.96(1H，d，J＝8.4Hz，ArH-5)；MS(m/z)：275(M +)。
preparation Example 2: the preparation of the chloro-3-nitropyridine of 2-anilino-6-(IV-2)
2,6-dichloro-3-nitropyridine (II-1,193mg, 1mmol), aniline (III-2,93mg, 1mmol) and sodium bicarbonate (84mg, 1mmol) are joined in 10mL dehydrated alcohol, under room temperature, react 24h.Reaction solution is poured in frozen water, with rare HCl adjust pH, to 5-6, stirred 30 minutes, separate out solid.Solid is leached, be washed to neutrality, dry.Obtain compound IV-2 (219mg, 88), red solid, mp 95-98 ℃. 1H NMR(CDCl 3)δ10.28(1H，b s，NH)，8.47(1H，d，J＝8.4Hz，ArH-4)，7.66(2H，d，J＝8.0Hz，ArH-2’，6’)，7.42(2H，t，J＝8.0Hz，ArH-3’，5’)，7.21(1H，t，J＝7.2Hz，ArH-4’)，6.81(1H，d，J＝8.4Hz，ArH-5)；MS(m/z)：250(M +)。
preparation Example 3: the preparation of the chloro-2-of 6-(4-toluidine)-3-nitropyridine (IV-3)
The same IV-2 of preparation method, yield: 49%. 1H NMR(CDCl 3)δ10.22(1H，br s，NH)，8.45(1H，d，J＝8.8Hz，ArH-4)，7.30(2H，d，J＝8.4Hz，ArH-2’，6’)，7.21(2H，d，J＝8.8Hz，ArH-3’，5’)，6.77(1H，d，J＝8.8Hz，ArH-5)，2.37(3H，s，CH 3)。
preparation Example 4: the preparation of the chloro-2-of 6-(4-anisole amido)-3-nitropyridine (IV-4)
The same IV-2 of preparation method, yield: 76%. 1H NMR(CDCl 3)δ10.17(1H，br s，NH)，8.45(1H，d，J＝8.8Hz，ArH-4)，7.53(2H，d，J＝8.8Hz，ArH-2’，6’)，6.95(2H，d，J＝8.8Hz，ArH-3’，5’)，6.75(1H，d，J＝8.8Hz，ArH-5)，3.84(3H，s，CH 3)；MS(m/z)：280(M +)。
preparation Example 5: the preparation of the chloro-2-of 6-(4-phenetole amido)-3-nitropyridine (IV-5)
The same IV-2 of preparation method, yield: 86%. 1H NMR(CDCl 3)δ10.16(1H，br s，NH)，8.44(1H，d，J＝8.4Hz，ArH-4)，7.52(2H，d，J＝8.8Hz，ArH-2’，6’)，6.93(＝2H，d，J＝8.8Hz，ArH-3’，5’)，6.75(1H，d，J＝8.4Hz，ArH-5)，4.06(2H，q，J＝7.0Hz，CH 2)，1.44(3H，t，J＝7.0Hz，CH 3)。
embodiment 1: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-bromine phenoxy group)-3-nitropyridine (I-1)
Compound IV-1 (274.5mg, 1mmol) and the bromo-2，6-xylenol of 4-(241.2mg, 1.2mmol) are dissolved in 1mL DMF, add salt of wormwood (345mg, 2.5mmol).Under nitrogen protection, under 130 ℃ of conditions, react 6h.Reactant is poured in frozen water, and dilute hydrochloric acid is adjusted pH to 5-6, stirs 30min.Leach solid, washing, dry, the separated yellow compound I-1 (280mg, 64%) that obtains of silicagel column. 1H NMR(CDCl 3)δ10.65(1H，br s，NH)，8.63(1H，d，J＝9.0Hz，ArH-4)，7.37(4H，m，ArH-3’，5’，3”，5”)，7.21(2H，d，J＝8.6Hz，ArH-2’，6’)，6.65(1H，d，J＝9.0Hz，ArH-5)，2.08(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)：439(M +)。
embodiment 2: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-cyano-benzene oxygen)-3-nitropyridine (I-2)
The same I-1 of preparation method, makes intermediate compound IV-1 (274.5mg, 1mmol) and 2,6-dimethyl-4-cyanophenol (147.6mg, 1.2mmol) react to obtain product I-b (225mg, 58%). 1H NMR(CDCl 3)δ10.68(1H，br s，NH)，8.66(1H，d，J＝8.8Hz，ArH-4)，7.53(2H，s，ArH-3’，5’)，7.32(2H，d，J＝8.3Hz，ArH-3”，5”)，7.19(2H，d，J＝8.3Hz，ArH-2”，6”)，6.67(1H，d，J＝9.2Hz，ArH-5)，2.16(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)386(M +)。
embodiment 3: the preparation of 2-(4-cyano-aniline base)-6-(2,4,6-trimethylammonium phenoxy group)-3-nitropyridine (I-3)
The same I-1 of preparation method, intermediate compound IV-1 (274.5mg, 1mmol) and 2，4，6-trimethyl phenol (163.2mg, 1.2mmol) react to obtain product I-3 (268.1mg, 72%). 1H NMR(DMSO-d 6)δ10.38(1H，br s，NH)，8.65(1H，d，J＝8.8Hz，ArH-4)，7.39(4H，m，ArH-2’，3’，5’，6’)，7.04(2H，s，ArH-3”，5”)，6.78(1H，d，J＝8.8Hz，ArH-5)，2.36(3H，CH 3-4”)，2.00(s，CH 3-2”，CH 3-6”)；MS(m/z)375(M +)。
embodiment 4: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-formyl radical phenoxy group)-3-nitropyridine (I-4)
The same I-1 of preparation method, makes intermediate compound IV-1 (274.5mg, 1mmol) and 3,5-dimethyl-4-hydroxy benzaldehyde (180mg, 1.2mmol) react to obtain product I-4 (257mg, 66%). 1H NMR(CDCl 3)δ10.68(1H，br s，NH)，10.08(1H，s，CHO)，8.66(1H，d，J＝8.8Hz，ArH-4)，7.75(2H，s，ArH-3’，5’)，7.20(4H，s，ArH-2”，3”，5”，6”)，6.69(1H，d，J＝9.2Hz，ArH-5)，2.21(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)389(M +)。
embodiment 5: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-propylene cyano-benzene oxygen)-3-nitropyridine (I-5)
By (EtO) 2p (O) CH 2cN (265.7mg, 1.5mmol) is dissolved in 15mL THF, and ice-water bath is cooling, adds potassium tert.-butoxide (168mg, 1.5mmol), stirs 30min.At room temperature react again 30min.Add the 15mL THF solution that is dissolved with Compound I-4 (388.4mg, 1mmol), reaction 24h.Add 100mL water, standing 12h.Filter, washing, obtains yellow solid I-5 (346mg, 84%). 1H NMR(DMSO-d 6)δ10.37(1H，br s，NH)，8.68(1H，d，J＝8.8Hz，ArH-4)，7.72(1H，d，J＝16.8Hz，Ar-CH＝C)，7.56(2H，s，ArH-3”，5”)，7.34(4H，s，ArH-2’，3’，5’，6’)，6.84(1H，d，J＝8.8Hz，ArH-5)，6.53(1H，J＝16.8Hz，-C＝CHCN)，2.06(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)412(M +)。
embodiment 6: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-cyano-benzene oxygen) pyridine (I-6)
The mixture of Compound I-2 (385.4mg, 1mmol), 5mL tetrahydrobenzene, 100mL Virahol and 100mg10%Pd/C is reacted to 3-5h at reflux conditions, and TLC shows that reaction finishes.Filtered while hot, column chromatography for separation (ethyl acetate and sherwood oil are eluent) after filtrate is concentrated, obtains gray solid Compound I-6 (235mg, 66%). 1H NMR(DMSO-d 6)δ8.36(1H，br s，NH)，7.73(2H，s，ArH-3’，5’)，7.32(2H，d，J＝9.2Hz，ArH-3’，5’)，7.26(2H，s，ArH-2’，6’)，7.14(1H，d，J＝8.0Hz，ArH-4)，6.49(1H，d，J＝8.0Hz，H-5)，4.88(2H，br s，NH 2)，2.08(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)：356(M +)。
embodiment 7: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-hydroxy methyl phenyloxy) pyridine (I-7)
By Compound I-4 (388.4mg, 1mmol), NiCl 26H 2o (71mg, 0.3mmol) is dissolved in the mixed solution of 25mL methyl alcohol and 25mL THF, stirs, and ice-water bath is cooling.When temperature is down to below 5 ℃, add NaBH in batches 4(228mg, 6mmol).After reaction 30min, in reaction solution, add 50mL water.With the HCl of 1N, regulate pH to 5-6.Remove ice-water bath, reaction solution is heated to 50-60 ℃.After 10min, stop heating, question response liquid cooling is but afterwards respectively with 50mL EtOAc extraction three times.Merge organic phase, dry, concentrated.The separated product I-7 (254mg, 70%) that obtains of post. 1H NMR(DMSO-d 6)δ8.27(1H，br s，NH)，7.34(4H，s，ArH-2’，3’，5’，6’)，7.11(1H，d，J＝8.0Hz，ArH-4)，7.10(2H，s，ArH-3”，5”)，6.38(1H，d，J＝8.0Hz，ArH-5)，5.22(1H，t，J＝6.4Hz，OH)，4.76(2H，br s，NH 2)，4.49(2H，d，J＝6.4Hz，CH 2)，2.03(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)361(M +)。
embodiment 8: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-hydroxy methyl phenyloxy)-3-nitropyridine (I-8)
Compound I-4 (388.4mg, 1mmol) is dissolved in the mixed solution of 25mL methyl alcohol and 25mL THF, stirs, ice-water bath is cooling.When temperature is down to below 5 ℃, add NaBH in batches 4(114mg, 4mmol).After reaction 30min, in reaction solution, add 50mL water.With the HCl of 1N, regulate pH to 5-6.Remove ice-water bath, reaction solution is heated to 50-60 ℃.After 10min, stop heating, question response liquid cooling is but afterwards respectively with 50mL EtOAc extraction three times.Merge organic phase, dry, concentrated.The separated product I-8 (286mg, 73%) that obtains of post. 1H NMR(DMSO-d 6)δ10.41(1H，br s，NH)，8.67(1H，d，J＝8.8Hz，ArH-4)，7.45(2H，d，J＝8.8Hz，ArH-3’，5’)，7.37(2H，d，J＝8.8Hz，ArH-2’，6’)，7.19(2H，s，ArH-3”，5”)，6.81(1H，d，J＝8.8Hz，ArH-5)，5.39(1H，t，J＝6.4Hz，OH)，4.55(2H，d，J＝6.4Hz，CH 2)，2.04(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)：391(M +)。
embodiment 9: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-allyl group phenoxy group)-3-nitropyridine (I-9)
The same I-1 of preparation method, makes intermediate compound IV-1 (274.5mg, 1mmol) and 2,6-dimethyl-4-chavicol (194.4mg, 1.2mmol) react to obtain product I-9 (225mg, 56%). 1H NMR(CDCl 3)δ10.67(1H，br s，NH)，8.61(1H，d，J＝8.8Hz，ArH-4)，7.27(4H，m，ArH-2’，3’，5’，6’)，7.01(2H，s，ArH-3”，5”)，6.63(1H，d，J＝8.8Hz，ArH-5)，6.05(1H，m，-CH＝)，5.24(2H，m，-CH 2-)，3.44(1H，d，J＝3.2Hz，CH 2＝)，2.08(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)：401(M +)。
embodiment 10: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-propylene cyano-benzene oxygen) pyridine (I-10)
Compound I-5 (411.4mg, 1mmol) joined to Isosorbide-5-Nitrae-dioxane of 30mL and the H of 30mL 2in the mixing solutions of O, then add 1mL ammoniacal liquor, Na 2s 2o 4(1741mg, 10mmol), at room temperature stirs 2h.Respectively with 50mL EtOAc extraction three times.Merge organic phase, dry, concentrated.Separated Compound I-10 (192mg, 50%) that obtain of post. 1H NMR(DMSO-d 6)δ8.35(1H，br s，NH)，7.68(1H，J＝16.8Hz，Ar-CH＝C)，7.50(2H，s，ArH-3”，5”)，7.37(2H，d，J＝8.8Hz，ArH-3’，5’)，7.25(2H，d，J＝8.8Hz，ArH-2’，6’)，7.13(1H，d，J＝8.0Hz，ArH-4)，6.45(1H，d，J＝8.0Hz，ArH-5)，6.45(1H，J＝16.8Hz， ＝CHCN)，2.06(6H，s，CH 3-2”，CH 3-6”).MS(m/z)：382(M +)。
embodiment 11: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-toluidine)-3-nitropyridine (I-11)
Compound IV-1 (274.5mg, 1mmol) and 2，4，6-trimethyl aniline (810mg, 6mmol) are added in microwave tube, then add the t-BuOH of Anhydrous potassium carbonate (483mg, 3.5mmol) and 3mL.Microwave heating, reacts 30min under 180 ℃ of conditions.After reaction finishes, reaction solution is poured in frozen water, with the HCl of 1N, regulated pH to 2-3, stir.Filter, dry.Post separation obtains yellow solid 267mg, yield: 72%. 1H NMR(DMSO-d 6)δ10.80(1H，br s，NH)，9.73(1H，br s，NH)，8.29(1H，d，J＝9.2Hz，ArH-4)，7.50(2H，d，J＝8.8Hz，ArH-2’，6’)，7.31(2H，d，J＝8.8Hz，ArH-3’，5’)，7.05(2H，s，ArH-3”，5”)，6.47(1H，d，J＝9.2Hz，ArH-5)，2.37(3H，s，CH3-4”)，2.08(6H，s，CH3-2”，CH3-6”)；MS(m/z)374(M +)。
Those skilled in the art can be according to its existing knowledge and method well known in the art, with reference to X in above-mentioned formula I, be-method of Compound I-11 of NH-or be initial substance from above Compound I-11, further in acquisition formula I, X be-compound of NR-and-NCOR-, and wherein R is C 1-4alkyl such as methyl, ethyl, propyl group etc.
embodiment 12: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-bromine phenoxy group) pyridine (I-12)
The same I-7 of preparation method, reaction raw materials is Compound I-1 (439mg, 1mmol), obtains gray solid 336mg, yield 82%, mp 190-193 ℃. 1H-NMR(DMSO-d 6)δ8.35(1H，br s，NH)，7.42(2H，s，ArH-3”，5”)，7.32(4H，s，ArH-3’，4’，5’，6’)，7.12(1H，d，J＝8.0Hz，ArH-4)，6.44(1H，d， J＝8.0Hz，ArH-5)，4.84(2H，br s，NH 2)，2.03(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)：409(M +)。
embodiment 13: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-allyl group phenoxy group) pyridine (I-13)
The same I-10 of preparation method, reaction raw materials is Compound I (400mg, 1mmol), obtains gray solid 160mg, yield 43%, mp 150-152 ℃. 1H-NMR(DMSO-d 6)δ8.30(1H，br s，NH)，7.36(2H，d，J＝8.8Hz，ArH-3’，5’)，7.29(2H，d J＝8.8Hz，ArH-2’，6’)，7.11(1H，d，J＝8.0Hz，ArH-4)，6.98(2H，s，ArH-3”，5”)，6.39(1H，d，J＝8.0 Hz，ArH-5)，6.03(1H，m，-CH＝)，5.14(2H，m，-CH 2-)，4.76(2H，br s，NH 2)，3.36(2H，d，J＝3.6Hz，CH 2＝)，2.01(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)371(M +)。
embodiment 14: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(1-hydroxyl-2-nitro-ethyl) phenoxy group)-3-nitropyridine (I-14)
388mg (1mmol) Compound I-4 are dissolved in 20mL THF, add 2mL CH 3nO 2, stirring, ice-water bath is cooling, dropwise adds the NaOH solution of 1mL 33%, finishes rear continuation and stirs 1h, then moves to continuation reaction 12h under room temperature.Stopped reaction, pours reaction solution in 50mL frozen water into, with dichloromethane extraction (25mL * 3).Anhydrous sodium sulfate drying organic phase, concentrated, gained solid column chromatographic separation (eluent: methylene chloride/methanol=60/1,200-300 order silica gel), obtains yellow solid 306mg, yield 68%, mp 230-234 ℃. 1h-NMR (DMSO-d 6) δ ppm 12.43 (1H, br s, NH), 8.68 (1H, d, J=8.0Hz, ArH-4), 7.49 (2H, d, J=8.8Hz, ArH-3 ', 5 '), 7.40 (2H, d, J=8.4Hz, ArH-2 ', 6 '), 7.33 (2H, s, ArH-3 ", 5 "), 6.81 (2H, d, J=8.8Hz, ArH-5), 6.32 (1H, d, J=6.4Hz, AOH), 5.33 (1H, m, CH 2nO 2 cHoH), 4.94 (1H, m, CH 2nO 2), 4.66 (1H, m, cHoH), 2.06 (6H, s, CH 3-2 ", CH 3-6 "); MS (m/z) 450 (M +).
embodiment 15: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(2-cyclopropyl amino methyl) phenoxy group)-3-nitropyridine (I-15)
388mg (1mmol) Compound I-4 are dissolved in the mixing solutions of 40mL THF and 30mL methyl alcohol, add 228mg (4mmol) cyclopropylamine, add 1mL triethylamine, stir backflow 4d.Stopped reaction, ice-water bath is cooling, adds 151mg (4mmol) NaBH in batches 4, stir 30min.Stopped reaction, pours reaction in 100mL frozen water into, regulates pH to 4-5, and be heated to 40-50 ℃ with HCl (1N), stirs 10min.Ethyl acetate extraction (20mL * 3), anhydrous sodium sulfate drying organic phase, concentrated, gained solid, with combiflash companion separated (eluent: ethyl acetate/petroleum ether, 0-50% gradient elution), obtains yellow solid 92mg, yield 21%, mp 175-177 ℃. 1H-NMR δppm10.68(1H，br s，NH)，8.61(1H，d，J＝9.2Hz，ArH-4)，7.31(2H，d，J＝8.8Hz，ArH-3’，ArH-5’)，7.26(2H，d，J＝8.8Hz，ArH-2’，ArH-6’)，7.14(2H，s，ArH-3”，ArH-5”)，6.63(1H，d，J＝9.2Hz，ArH-5)，3.90(2H，s，CH 2)，2.10(6H，s，CH 3-2”，CH 3-6”)，0.52(4H，m，CH 2，CH 2)；MS(m/z)430(M +)。
embodiment 16: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-iodine phenoxy group)-3-nitropyridine (I-16)
The same I-1 of preparation method, makes intermediate compound IV-1 (274.5mg, 1mmol) and 2,6-dimethyl-4-iodophenol (297mg, 1.2mmol) react to obtain product I-16 (399mg, 82%), mp 162-165 ℃. 1H-NMR(CDCl 3)δ10.65(1H，br s，NH)，8.63(1H，d，J＝8.8Hz，ArH-4)，7.54(2H，s，ArH-3”，5”)，7.38(2H，d，J＝8.8Hz，ArH-3’，5’)，7.21(2H，d，J＝8.8Hz，ArH-2’，6’)，6.65(1H，d，J＝8.8Hz，ArH-5)，2.06(6H，s，CH 3-2”，CH 3-6”)；MS(m/z：487(M +)。
embodiment 17: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-nitrophenoxy)-3-nitropyridine (I-17)
The same I-1 of preparation method, makes intermediate compound IV-1 (274.5mg, 1mmol) and 2,6-dimethyl-4-nitrophenols (200mg, 1.2mmol) react to obtain product I-16 (271mg, 63%), mp 250-252 ℃. 1H-NMR(CDCl 3)δ10.98(1H，br s，NH)，8.68(1H，d，J＝9.2Hz，ArH-4)，8.10(2H，s，ArH-3”，5”)，7.26(2H，d，J＝8.8Hz，ArH-3’，5’)，7.20(2H，d，J＝8.8Hz，ArH-2’，6’)，6.70(1H，d，J＝9.2Hz，ArH-5)，2.23(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)406(M +)。
embodiment 18: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(3-methyl-3-hydroxyl-ethyl acetylene base) phenoxy group)-3-nitropyridine (I-18)
486mg (1mmol) Compound I-16 are dissolved in 5mL DMF, add 69mg (0.1mmol) Pd (PPh 3) 2cl 2, 19mg CuI (0.1mmol), 0.6mL triethylamine, N 2protection, stirs.Under room temperature, add 420mg (5mmol) 2-methyl-2-hydroxyl-3-butine, stir 7h.Stopped reaction adds 30mL water in reaction solution, dichloromethane extraction (25mL * 3).Anhydrous sodium sulfate drying organic phase, concentrated, crude product, with combiflash companion separated (eluent: ethyl acetate/petroleum ether, 0-40% gradient elution), obtains yellow solid 362mg, yield 78%, mp 114-116 ℃. 1H-NMR(DMSO-d 6)δ10.37(1H，br s，NH)，8.67(1H，d，J＝8.8Hz，ArH-4)，7.40(2H，d，J＝8.8Hz，ArH-2’，6’)，7.34(2H，d，J＝8.8Hz，ArH-3’，5’)，7.31(2H，s，ArH-3”，5”)，6.83(1H，d，J＝8.8Hz，ArH-5)，5.47(1H，s，OH)，2.00(6H，s，CH 3-2”，CH 3-6”)，1.53(6H，s，C≡C-C( CH 3 ) 2OH)；MS(m/z)：465(M+Na +)。
embodiment 19: the preparation of 6-(2,6-dimethyl-4-(3-methyl-3-hydroxyl-ethyl acetylene base) ethynyl phenoxy group)-2-(4-cyano-aniline base)-3-aminopyridine (I-19)
442mg (1mmol) Compound I-18 are joined in 20mL THF, add 20mL water, 0.5mL ammoniacal liquor, stirs under room temperature, adds 1.93g (content 90%, 10mmol) Na 2s 2o 4, stir 2h, TLC (methylene chloride/methanol=15/1) demonstration reacts completely.Reaction solution is poured in 100mL water.By ethyl acetate (50mL * 3) extraction, anhydrous sodium sulfate drying organic phase, concentrated, carry out column chromatography for separation (eluent: methylene chloride/methanol=30/1,200-300 order silica gel), obtain gray solid 198mg, yield 48%, mp 155-157 ℃. 1H-NMR(DMSO-d 6)δ8.33(1H，br s，NH)，8.01(1H，br s，OH)，7.41(1H，d，J＝8.8Hz，ArH-4)，7.29(4H，m，ArH-2’，3’，5’，6’)，7.23(2H，s，ArH-3”，5”)，6.55(1H，d，J＝8.8Hz，ArH-5)，4.83(2H，br s，NH 2)，2.08(6H，s，CH 3-2”，CH 3-6”)，1.51(6H，s，C≡C-C( CH 3 ) 2OH)；MS(m/z)413(M +)。
embodiment 20: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(cyclopropyl acethlene base) phenoxy group)-3-nitropyridine (I-20)
Compound I-16486mg (1mmol) is dissolved in 5mL DMF, adds 69mg (0.1mmol) Pd (PPh 3) 2cl 2, 19mg CuI (0.1mmol), 0.6mL triethylamine, N 2protection, stirs.Under room temperature, add 330mg (5mmol) cyclopropyne, stir 7h.Stopped reaction adds 30mL water in reaction solution, dichloromethane extraction (25mL * 3).Anhydrous sodium sulfate drying organic phase, concentrated, crude product, with combiflash companion separated (eluent: ethyl acetate/petroleum ether, 0-40% gradient elution), obtains yellow solid 290mg, yield 68%, mp 188-192 ℃. 1H-NMR(CDCl 3)δ10.65(1H，br s，NH)，8.61(1H，d，J＝9.2Hz，ArH-4)，7.36(2H，d，J＝8.8Hz，ArH-3’，5’)，7.22(2H，s，ArH-3”，5”)，7.19(2H，d，J＝8.8Hz，ArH-2’，6’)，6.64(1H，d，J＝9.2Hz，ArH-5)，2.05(6H，s，CH 3-2”，CH 3-6”)，1.52(1H，m，CH)，0.89(4H，m，2×CH 2)；MS(m/z)425(M +)。
embodiment 21: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-(cyclopropyl acethlene base) phenoxy group) pyridine (I-21)
424mg (1mmol) Compound I-20 are joined in 20mL THF, add 20mL water, 0.5mL ammoniacal liquor, stirs under room temperature, adds 1.93g (content 90%, 10mmol) Na 2s 2o 4, stir 2h, TLC (methylene chloride/methanol=15/1) demonstration reacts completely.Reaction solution is poured in 100mL water.By ethyl acetate (50mL * 3) extraction, anhydrous sodium sulfate drying organic phase, concentrated, carry out column chromatography for separation (eluent: methylene chloride/methanol=30/1,200-300 order silica gel), obtain gray solid 193mg, yield 49%, mp 82-85 ℃. 1H-NMR(CDCl 3)δ7.33(2H，d，J＝8.4Hz，ArH-3’，5’)7.22(2H，s，ArH-3”，5”)，7.18(3H，m，ArH-2’，6’，4)，6.36(1H，d，J＝8.0Hz，ArH-5)，2.06(6H，s，CH 3-2”，CH 3-6”)，1.51(1H，m，CH)，0.89(4H，m，2×CH 2)；MS(m/z)395(M +)。
embodiment 22: the preparation of 2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-ethynyl phenoxy group)-3-nitropyridine (I-22)
442mg (1mmol) Compound I-18 are dissolved in to 20mL toluene, add 16mg (0.4mmol) NaOH (fully grinding), N 2protection, backflow 24h.Stopped reaction, adds 2 acetic acid wherein after question response liquid cooling but, remove solvent under reduced pressure, gained solid, with combiflash companion separated (eluent: ethyl acetate/petroleum ether, 0-40% gradient elution), obtains yellow solid 265mg, yield 69%, mp186-188 ℃. 1H-NMR(CDCl 3)δ10.66(1H，br s，NH)，8.63(1H，d，J＝8.8Hz，ArH-4)，7.35(2H，d，J＝8.8Hz，ArH-3’，5’)，7.34(2H，s，ArH-3”，5”)，7.19(2H，d，J＝8.8Hz，ArH-2’，6’)，6.66(1H，d，J＝8.8Hz，ArH-5)，3.17(1H，s，C≡CH)，2.09(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)385(M +)。
embodiment 23: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-ethynyl phenoxy group) pyridine (I-23)
384mg (1mmol) Compound I-22 are joined in 20mL THF, add 20mL water, 0.5mL ammoniacal liquor, stirs under room temperature, adds 1.93g (content 90%, 10mmol) Na 2s 2o 4, stir 2h, TLC (methylene chloride/methanol=15/1) demonstration reacts completely.Reaction solution is poured in 100mL water.By ethyl acetate (50mL * 3) extraction, anhydrous sodium sulfate drying organic phase, concentrated, gained solid, with combiflash companion separated (eluent: ethyl acetate/petroleum ether, 0-60% gradient elution), obtains gray solid 217mg, yield 61%, mp 79-82 ℃. 1H-NMR(DMSO-d 6)δ8.34(1H，br s，NH)，7.37(2H，s，ArH-3”，5”)，7.03(4H，m，ArH-2’，3’，5’，6’)，6.56(1H，d，J＝8.4Hz，ArH-4)，6.44(1H，d，J＝8.4Hz，ArH-5)，4.84(2H，br s，NH 2)，3.36(1H，s，CH)，2.02(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)355(M +)。
embodiment 24: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-amino-benzene oxygen) pyridine (I-24)
The same I-4 of preparation method, reaction raw materials is Compound I-17 (405mg, 1mmol), obtains gray solid 210mg, yield 61%, mp 195-198 ℃. 1H-NMR(CDCl 3)δ8.29(1H，br s，NH)， 7.47(2H，d，J＝8.8Hz，ArH-3’，5’)，7.39(2H，d，J＝8.8Hz，ArH-2’，6’)，7.07(1H，d，J＝8.0Hz，ArH-4)，6.35(2H，s，ArH-3”，5”)，6.30(1H，d，J＝8.0Hz，ArH-5)，4.88(2H，br s，NH 2)，4.73(2H，br s，NH 2)，1.89(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)346(M +)。
embodiment 25: the preparation of 3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-iodine phenoxy group) pyridine (I-25)
The same I-10 of preparation method, reaction raw materials is Compound I-16 (486mg, 1mmol), obtains gray solid 225mg, yield 49%, mp 186-188 ℃. 1H-NMR(CDCl 3)δ7.50(2H，s，NH 2)，7.33(2H，d，J＝8.8Hz，ArH-3’，5’)，7.22(2H，d，J＝8.8Hz，ArH-2’，6’)，6.98(1H，d，J＝8.4Hz，ArH-4)，6.44(1H，d，J＝8.4Hz，ArH-5)，2.09(6H，s，CH 3-2”，CH 3-6”)；MS(m/z)357(M +)。
embodiment 26: the preparation of 2-(4-cyano-aniline base)-6-(2,4,6-tribromophenoxy)-3-nitropyridine (I-26)
The same I-1 of preparation method, makes intermediate compound IV-1 (274.5mg, 1mmol) and 2,4,6-tribromophenol (397mg, 1.2mmol) reaction, obtains yellow solid 380mg, yield 67%, mp 188-191 ℃. 1H-NMR(CDCl 3)δ10.57(1H，br s，NH)，8.68(1H，d，J＝8.8Hz，ArH-4)，7.83(2H，s，ArH-3”，5”)，7.38(2H，d，J＝8.8Hz，ArH-3’，5’)，7.24(2H，d，J＝8.8Hz，ArH-2’，6’)，6.72(1H，d，J＝8.8Hz，ArH-5)；MS(m/z)569(M +)。
embodiment 27: the preparation of 2-(4-cyano-aniline base)-6-(the bromo-4-formyl radical of 2,6-bis-phenoxy group)-3-nitropyridine (I-27)
The same I-1 of preparation method, makes intermediate compound IV-1 (275mg, 1mmol) and 3,5-dibromine-4-hydroxy benzaldehyde (336mg, 1.2mmol) reaction, obtains yellow solid 251mg, yield 48%, mp 218-220 ℃. 1H-NMR(CDCl 3)δ10.58(1H，br s，NH)，10.03(1H，s，CHO)，8.71(1H，d，J＝9.2Hz，ArH-4)，8.18(2H，s，ArH-3”，5”)，7.25(4H，m，ArH-2’，3’，5’，6’)，6.76(1H，d，J＝9.2Hz，ArH-5)；MS(m/z)519(M +)。
embodiment 28: the preparation of 2-(4-cyano-aniline base)-6-(the bromo-4-hydroxy methyl phenyloxy of 2,6-bis-)-3-nitropyridine (I-28)
The same I-1 of preparation method, makes intermediate compound IV-1 (274.5mg, 1mmol) and the bromo-4-methylolphenol of 2,6-bis-(338mg, 1.2mmol) reaction, obtains yellow solid 271mg, yield 52%, mp 209-213 ℃. 1H-NMR(CDCl 3)δ10.57(1H，br s，NH)，8.67(1H，d，J＝9.2Hz，ArH-4)，7.69(2H，s，ArH-3”，5”)，7.36(2H，d，J＝8.8Hz，ArH-3’，5’)，7.26(2H，d，J＝8.8Hz，ArH-2’，6’)，6.73(1H，d，J＝9.2Hz，ArH-5)，4.81(2H，s，CH 2)；MS(m/z)521(M +)。
embodiment 29: the preparation of 2-(4-cyano-aniline base)-6-(2,6-difluoro phenoxy group)-3-nitropyridine (I-29)
The same I-1 of preparation method, makes intermediate compound IV-1 (274.5mg, 1mmol) and 2,6-difluorophenol (156mg, 1.2mmol) reaction, obtains yellow solid 162mg, yield 44%, mp 234-236 ℃. 1H-NMR(CDCl 3)δ10.64(1H，br s，NH)，8.66(1H，d，J＝8.8Hz，ArH-4)，7.33(5H，m，ArH-2’，3’，5’，6’，4”)，7.11(2H，m，ArH-3”，4”，5”)，6.73(1H，d，J＝8.8Hz，ArH-5)；MS(m/z)369(M +)。
embodiment 30: the preparation of 2-(4-cyano-aniline base)-6-(the bromo-4-propylene of 2,6-bis-cyano-benzene oxygen)-3-nitropyridine (I-30)
The same I-5 of preparation method, reaction raw materials is Compound I-27 (518mg, 1mmol), obtains yellow solid 363mg, yield 67%, mp 223-226 ℃. 1H-NMR(DMSO-d 6)δ10.31(1H，br s，NH)，8.72(1H，d，J＝8.8Hz，ArH-4)，8.17(2H，s，ArH-3”，5”)，7.71(1H，d，J＝16.4Hz，Ar-CH＝C)，7.44(2H，d，J＝8.4Hz，ArH-3’，5’)，7.36(2H，d，J＝8.4Hz，ArH-2’，6’)，6.94(1H，d，J＝8.8Hz，ArH-5)，6.76(1H，d，J＝16.4Hz，-C＝CHCN)；MS(m/z)540(M +)。
Compound I-30 (539mg, 1mmol) are dissolved in acetone, slowly splash into HCl diethyl ether solution, separate out yellow crystal, filter, obtain the hydrochloride of Compound I-30.
embodiment 31: HIV (human immunodeficiency virus)-resistant activity test (H9 cell model)
Reference literature (J.Med.Chem.2004,47,756-760).Lymphocyte H9 is at nutrient solution 1640,5%CO 2, under the condition of 37 ℃, cultivate.Tested compound is dissolved in DMSO at first, is diluted to conventional screening concentration subsequently with nutrient solution: 100,20,4,0.8 μ g/mL.Cultured H9 cell is divided into two portions, and wherein a part infects with HIV virus (IIIB) (m.i.o.0.1～0.01infectious Units/cell), active used for surveying.Another part cell does not add virus, only adds nutrient solution, used for surveying toxicity.Two-part cell under identical condition (37 ℃, 5%CO 2) cultivate 4 hours after, with fresh nutrient solution, wash 3 times, two portions cell is joined respectively in the test sample of the different concns preparing or (the positive infection contrast of the latter or the contrast of negative medicine) in nutrient solution completely, with AZT, do positive drug contrast simultaneously.All these cells are at 5%CO 2, cultivate 4 days under 37 ℃ of conditions.At the 4th day, the cell being infected by the virus is first removed to cytolemma, the activity of P24 antigen ELISA method working sample for cytosol, uses EC 50represent.EC 50effective concentration during for inhibition virus replication 50%.The cell that does not add virus part is determined the toxicity of test sample by the method for several cells, use CC 50represent.CC 50concentration when killing grown cell 50%.
embodiment 32:hIV (human immunodeficiency virus)-resistant activity test (MT-2 cell model)
Reference literature (Jiang, S., et al.Antimicrob.Agents Chemother.2004,48,4349-4359).In 96 porocyte culture plates, by the compound solution of 50 μ l different concns and isopyknic HIV-1 iIIBvirus strain (100 TCID 50) mix, in 37 ℃ of incubations 30 minutes, then add the MT-2 cell (1 * 10 of 100 μ l 5/ mL, containing the RPIM RPMI-1640 of 10% serum), mix, 37 ℃ are incubated overnight.Within the 2nd day, suck 150 μ l supernatant liquors, fill into equal-volume fresh medium, 37 ℃ are continued incubation 3 days, record cytopathy (CPE) effect in the 4th day.Then draw the culture supernatant of 100 μ l, the Triton X-100 lytic virus particle with 5%, adopts ELISA method to detect wherein p24 antigen.In brief, with HIVIG (2 μ g/mL) coated elisa plate, then seal with 1% nonfat milk, successively add employing virus cracking liquid, 37 ℃ of incubations 60 minutes.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.Then with TMB colour developing, at 450nm place, detect optical density(OD).Half virus inhibition concentration (EC with CalcuSyn computed in software compound 50).
embodiment 33:the cell toxicity test of compound
Reference literature (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, then add 100 μ l MT-2 (or H9) cells (1 * 10 5/ mL, containing the RPIM RPMI-1640 of 10% serum), mix, 37 ℃ are incubated overnight.Within the 2nd day, suck 150 μ l supernatant liquors, fill into equal-volume fresh medium, 37 ℃ were continued incubation after 3 days, added the freshly prepared XTT solution (1mg/mL) containing PMS of 50 μ l in the 4th day, detected the optical density(OD) at 450nm place after 4h.Half cytotoxicity concentration (CC with CalcuSyn computed in software compound 50).
The biological assessment of part of compounds the results are shown in table 1:
Table 1 HIV (human immunodeficiency virus)-resistant activity testing data (H9 and MT-2 cell)
SI: the selectivity index of compound is toxicity CC 50value and active EC 50the ratio of value.In upper table not other embodiment compound of the present invention of row also have with upper table in the close CC of most compounds 50, EC 50, and SI value.
Result of study of the present invention shows: formula I compound of the present invention is the HIV (human immunodeficiency virus)-resistant activity compound that a class has Novel framework structure.Because the molecular flexibility of this compounds is relatively good, therefore, the compounds of this invention has strong inhibition active to HIV resistance virus strain, likely develops into the anti-HIV new medicament that a class has novel texture.

Claims (12)

1. formula I compound:
Or its pharmacologically acceptable salt,
Wherein,
R 1, R 2and R 3be independently of one another-H, halogen ,-NO 2,-NH 2,-NHR ,-N (R) 2,-CN ,-OH, C 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-SO 3h ,-CONHR' or-COOR',
Or, R 1and R 2or R 2and R 3can form together-OCH 2o-;
R 4for-CN ,-CF 3, halogen or-COOH;
R 5and R 6be halogen, C independently of one another 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-NH 2,-OH ,-SO 3h or-COOR';
R 7for-CN ,-HC=CH-CN, halogen, C 1-6alkyl, C 1-6alkoxyl group ,-NH 2,-CH 2-NHR' ,-OH ,-NO 2,-CF 3,-C ≡ CR' ,-CH=CHR ' ,-CH=CHCOR' or CHO;
R ' is H or C 1-6alkyl;
Be selected from-NH-of X ,-O-,-S-,-NR-; And
R is C 1-4alkyl.
2. the compound of claim 1, it has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1and R 3be independently of one another-NO 2,-NH 2, halogen ,-OH ,-CN or-N (R) 2;
R 2for-H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR' ,-OH ,-NO 2,-CF 3,-C ≡ CR' ,-CH=CHR' ,-CH=CHCOR' or-CHO;
R ' is H or C 1-6alkyl;
X is-O-or-NH-; And
R is C 1-4alkyl.
3. the compound of claim 1, it has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1for-NO 2,-NH 2, halogen ,-OH ,-CN or-N (R) 2;
R 2and R 3for-H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR' ,-OH ,-NO 2,-CF 3,-CH=CHCOR' ,-C ≡ CR' ,-CH=CHR' or-CHO;
R ' is H or C 1-6alkyl;
X is-O-or-NH-; And
R is C 1-4alkyl.
4. the compound of claim 1, it has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 2for-NO 2,-NH 2,-halogen ,-OH ,-CN or-N (R) 2;
R 1and R 3for H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-OH ,-CH 2-NHR ' ,-NO 2,-CF 3,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' or-CHO;
R ' is H or C 1-6alkyl;
X is-O-or-NH-; And
R is C 1-4alkyl.
5. the compound of claim 1, it has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 3for-NO 2,-NH 2,-halogen ,-OH ,-CN or-N (R) 2;
R 1and R 2for H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' or-CHO;
R ' is H or C 1-6alkyl;
X is-O-or-NH-; And
R is C 1-4alkyl.
6. the compound of claim 1, it has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1, R 2and R 3be-H;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' or-CHO;
R ' is H or C 1-6alkyl;
X is-O-or-NH-; And
R is C 1-4alkyl.
7. the compound of claim 1, it has following formula Ia:
Or its pharmacologically acceptable salt,
Wherein,
R 1for-NO 2, or-NH 2;
R 2and R 3be-H;
R 5and R 6be halogen, C independently of one another 1-6alkyl, C 1-6alkoxyl group ,-CF 3,-NH 2,-OH or-COOH;
R 7for-CN ,-HC=CH-CN, halogen ,-CH 3,-OCH 3,-NH 2,-CH 2-NHR ' ,-OH ,-NO 2,-CF 3,-C ≡ CR ' ,-CH=CHR ' ,-CH=CHCOR ' or-CHO;
R ' is H, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-6cycloalkyl;
X is-O-or-NH-; And
R is C 1-4alkyl.
8. the compound of claim 7, wherein R 5and R 6be halogen, C independently of one another 1-4alkyl ,-NH 2, or-OH.
9. compound, it is selected from:
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-bromine phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-cyano-benzene oxygen)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,4,6-trimethylammonium phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-formyl radical phenoxy group)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-propylene cyano-benzene oxygen)-3-nitropyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-cyano-benzene oxygen) pyridine;
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-hydroxy methyl phenyloxy) pyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-hydroxy methyl phenyloxy)-3-nitropyridine;
2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-allyl group phenoxy group)-3-nitropyridine; With
3-amino-2-(4-cyano-aniline base)-6-(2,6-dimethyl-4-propylene cyano-benzene oxygen) pyridine,
Or its pharmacologically acceptable salt.
10. the preparation method of the compound of claim 1, its reaction scheme is as follows:
r wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, and the definition of X with described in claim 1 formula I compound, described method comprise make formula II replacement 2,6-dihalo pyridine compounds and their reacts with para-orientation amino benzenes compounds under the effect of alkali, or carries out 2-(4-substituted anilinic) the polysubstituted pyridine compounds of solvent-free reaction accepted way of doing sth IV; Then make formula IV intermediate and polysubstituted phenol or amino benzenes compounds carry out linked reaction, or under palladium class catalyst action heating or under microwave condition coupling generate 2-(4-substituted anilinic) the polysubstituted pyridine compounds with formula I.
11. 1 kinds of pharmaceutical compositions, the compound or pharmaceutically acceptable salt thereof that it comprises claim 1 to 9 any one and one or more pharmaceutical carriers or vehicle.
The compound or pharmaceutically acceptable salt thereof of 12. claim 1 to 9 any one is for the preparation of the purposes of the medicine for the treatment of acquired immune deficiency syndrome (AIDS).
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