The sulfur-bearing of anti HIV-1 virus is polycyclic-Hydroxypyridinone formamide analog and its application

文档序号：1766404 发布日期：2019-12-03 浏览：25次中文

阅读说明：本技术 抗hiv病毒的含硫多环-羟基吡啶酮甲酰胺类似物及其应用 (The sulfur-bearing of anti HIV-1 virus is polycyclic-Hydroxypyridinone formamide analog and its application ) 是由莫云芬林翠梧赵安然于 2018-05-23 设计创作，主要内容包括：本发明公开了一种抗HIV病毒的含硫多环-羟基吡啶酮甲酰胺类似物及其应用。所述含硫多环-羟基吡啶酮甲酰胺类似物,具有下式(I)化合物或其立体异构体或可药用盐：<Image he="393" wi="700" file="DDA0001670881530000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明提供的含硫多环-羟基吡啶酮甲酰胺类似物均具有良好的抗HIV活性,尤其化合物2、化合物18和化合物34和化合物66体外对HIV-1复制的抑制作用非常强,其对HIV病毒的治疗指数达到现有药物TDF和Dolutegravir药物的上百倍,该类化合物的开发对艾滋病药物的研制具有十分重要的意义,将为艾滋病患者带来福音。(The invention discloses a kind of sulfur-bearing of anti HIV-1 virus it is polycyclic-Hydroxypyridinone formamide analog and its application.The sulfur-bearing is polycyclic-Hydroxypyridinone formamide analog, there is lower formula (I) compound or its stereoisomer or officinal salt: Sulfur-bearing provided by the invention is polycyclic-and Hydroxypyridinone formamide analog all has good HIV-resistant activity, especially compound 2, compound 18 and compound 34 and compound 66 are very strong to the inhibiting effect of HIV-1 duplication in vitro, its hundreds of times for reaching existing drug TDF and Dolutegravir drug to the therapeutic index of inhibition of HIV, the exploitation of such compound has a very important significance the development of AIDS-treating medicine, will bring glad tidings for AIDS patient.)

1. a kind of active sulfur-bearing of anti HIV-1 virus is polycyclic-Hydroxypyridinone formamide analog, have lower formula (I) compound or Its stereoisomer or its pharmaceutically acceptable salt:

Wherein, Z is selected from S, SO, SO₂；

R⁰For hydrogen, halogen, hydroxyl, optionally the low alkyl group that replaces or optionally replace low-grade alkenyl, respectively can be by selected from following Heteroatom group insertion: OR⁶、SR⁶、SOR⁶、SO₂R⁶、NR⁶；R⁶For hydrogen, optionally the low alkyl group replaced, the ring optionally replaced Alkyl, the cycloalkyl low-grade alkyl optionally replaced, the low-grade alkenyl optionally replaced, the lower alkoxy optionally replaced, optionally Substituted aryl, the aryloxy group optionally replaced, the heterocycle optionally replaced, optionally replaces the aromatic yl elementary alkyl optionally replaced Heterocyclo lower alkyl, the heterocyclic oxy group, hydroxyl, the optional amino, the phosphate optionally replaced that optionally replace；

Each R^aIt is low to stand alone as hydrogen, halogen, the low alkyl group optionally replaced, the naphthenic base optionally replaced, the naphthenic base optionally replaced Grade alkyl, the low-grade alkenyl optionally replaced, the lower alkoxy optionally replaced, the aryl optionally replaced, the virtue optionally replaced Base low alkyl group, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, optionally replaces the aryloxy group optionally replaced Heterocyclic oxy group；

The integer that n is 0 to 8；Ring where indicating when n is 0 is five-membered ring；

R¹For hydrogen, optionally the low alkyl group that replaces, the cycloalkyl low-grade alkyl optionally replaced, optionally takes the naphthenic base optionally replaced The low-grade alkenyl in generation, the aryl optionally replaced, the aromatic yl elementary alkyl optionally replaced, is appointed at the lower alkoxy optionally replaced The aryloxy group for choosing generation, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, the heterocyclic oxy group optionally replaced；

R²For hydrogen, optionally the low alkyl group that replaces, the cycloalkyl low-grade alkyl optionally replaced, optionally takes the naphthenic base optionally replaced The low-grade alkenyl in generation, the aryl optionally replaced, the aromatic yl elementary alkyl optionally replaced, is appointed at the lower alkoxy optionally replaced The aryloxy group for choosing generation, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, the heterocyclic oxy group optionally replaced；

R³,R^3’Respectively stand alone as hydrogen, the low alkyl group that optionally replaces, the naphthenic base optionally replaced, the naphthenic base optionally replaced it is low Grade alkyl, the low-grade alkenyl optionally replaced, the lower alkoxy optionally replaced, the aryl optionally replaced, the virtue optionally replaced Base low alkyl group, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, optionally replaces the aryloxy group optionally replaced Heterocyclic oxy group, hydroxyl, optional amino, the phosphate optionally replaced；

R⁴,R⁵The respective low alkyl group for standing alone as hydrogen or optionally replacing, the naphthenic base optionally replaced, the naphthenic base optionally replaced are low Grade alkyl, the low-grade alkenyl optionally replaced, the lower alkoxy optionally replaced, the aryl optionally replaced, the virtue optionally replaced Base low alkyl group, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, optionally replaces the aryloxy group optionally replaced Heterocycle；

Or in which R⁴And R⁵It is combined together to form-W-, wherein W is [C (R^b)₂]_L(integer that L is 1 to 4)；

Each R^bIt is low to stand alone as hydrogen, halogen, the low alkyl group optionally replaced, the naphthenic base optionally replaced, the naphthenic base optionally replaced Grade alkyl, the low-grade alkenyl optionally replaced, the lower alkoxy optionally replaced, the aryl optionally replaced, the virtue optionally replaced Base low alkyl group, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, optionally replaces the aryloxy group optionally replaced Heterocyclic oxy group.

2. a kind of active sulfur-bearing of anti HIV-1 virus as described in claim 1 is polycyclic-Hydroxypyridinone formamide analog, tool There are following formula (I-A) compound or its stereoisomer or its pharmaceutically acceptable salt:

Wherein, Z is selected from S, SO, SO₂；

Wherein R⁰、R^a、n、R³、R^3’、R⁴、R⁵The selection of respective group is as described in the appended claim 1；

X respectively stands alone as hydrogen, halogen, hydroxyl, the low alkyl group optionally replaced, the naphthenic base optionally replaced, the ring optionally replaced Alkyl lower alkyl, the lower alkoxy optionally replaced, the aryl optionally replaced, optionally takes the low-grade alkenyl optionally replaced The aromatic yl elementary alkyl in generation, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, is appointed at the aryloxy group optionally replaced Choose heterocyclic oxy group, hydroxyl, the optional amino, the phosphate optionally replaced in generation；

M is the integer of 0-3, preferably 1-3；

When m is 1, X is preferably halogen；It is more preferably located at the fluorine or 4- fluorine of the position 2- of the phenyl ring；

When m is 2, X is preferably halogen；It is more preferably located at the fluorine and 4- fluorine, 2- fluorine and 3- of the position 2- of the phenyl ring Fluorine, 2- fluorine and 6- fluorine, the 3- fluorine and 4- fluorine, 3- fluorine of position and 4- chlorine, 2- fluorine and 4- The chlorine or 2- chlorine of position and 4- fluorine；Most preferably positioned at the fluorine and 4- fluorine of the position 2- of the phenyl ring；

When m is 3, X is preferably halogen；It is more preferably located at the fluorine of the position 2- of the phenyl ring, the fluorine or 2- of 4- fluorine and 6- The fluorine of position, the fluorine of 3- fluorine and 4- are most preferably located at the fluorine of the position 2- of the phenyl ring, the fluorine of 4- fluorine and 6-.

3. a kind of active sulfur-bearing of anti HIV-1 virus as described in claim 1 is polycyclic-Hydroxypyridinone formamide analog, tool There are following formula (I-B) compound or its stereoisomer or its pharmaceutically acceptable salt:

Wherein, Z is selected from S, SO, SO₂；

Wherein R⁰、R^a、n、R³、R^3’The selection of respective group is as described in the appended claim 1；

W is [C (R^b)₂]_L(integer that L is 1 to 4)；Wherein, each R^bIt stands alone as hydrogen, halogen, the low alkyl group optionally replaced, appoint The naphthenic base for choosing generation, the cycloalkyl low-grade alkyl optionally replaced, the low-grade alkenyl optionally replaced, the lower alkyl optionally replaced Oxygroup, the aryl optionally replaced, the aromatic yl elementary alkyl optionally replaced, the aryloxy group optionally replaced, the heterocycle optionally replaced, The heterocyclo lower alkyl optionally replaced, the heterocyclic oxy group optionally replaced；

M is the integer of 0-3, preferably 1-3；

When m is 1, X is preferably halogen；It is more preferably located at the fluorine or 4- fluorine of the position 2- of the phenyl ring；

4. a kind of active sulfur-bearing of anti HIV-1 virus as described in claim 1 is polycyclic-Hydroxypyridinone formamide analog, tool There are following formula (I-C) compound or its stereoisomer or its pharmaceutically acceptable salt:

Wherein, Z is selected from S, SO, SO₂；

Wherein R⁰、R¹、R²、R³、R^3’、R⁴、R⁵The selection of respective group is as described in the appended claim 1.

5. a kind of active sulfur-bearing of anti HIV-1 virus as described in claim 1 is polycyclic-Hydroxypyridinone formamide analog, tool There are following formula (I-D) compound or its stereoisomer or its pharmaceutically acceptable salt:

Wherein, Z is selected from S, SO, SO₂；

Wherein R⁰、R³、R^3’、R^a、R⁴、R⁵The selection of respective group is as described in the appended claim 1；

M is the integer of 0-3, preferably 1-3；

When m is 1, X is preferably halogen；It is more preferably located at the fluorine or 4- fluorine of the position 2- of the phenyl ring；

6. a kind of active sulfur-bearing of anti HIV-1 virus as described in claim 1 is polycyclic-Hydroxypyridinone formamide analog, tool There are the structure of compound A-13 or compound A6 or compound A7 or the stereoisomer of the compound or its is pharmaceutically acceptable Salt:

7. a kind of active sulfur-bearing of anti HIV-1 virus as described in claim 1 is polycyclic-Hydroxypyridinone formamide analog, Structure is the compound or its enantiomter of following 1-93 serial number；Or its diastereoisomer；Or its enantiomter is mixed Close object；Or the mixture of its diastereoisomer；Or the mixture of its enantiomter and diastereoisomer；Or it is pharmaceutically Acceptable salt；

8. as a kind of described in any item active sulfur-bearings of anti HIV-1 virus of claim 1-7 it is polycyclic-Hydroxypyridinone benzamide type Like object, it is characterised in that: the pharmaceutically acceptable salt is sodium salt or sylvite.

9. a kind of pharmaceutical composition, comprising the described in any item compounds of claim 1-7 or its pharmaceutically acceptable salt or Its solvate is active component.

10. pharmaceutical composition according to claim 9, it is characterised in that: described pharmaceutical composition further contains one kind Or a variety of other anti-hiv therapy agent.

11. the described in any item compounds of claim 1-7 or its pharmaceutically acceptable salt or its solvate are anti-in preparation Application in inhibition of HIV drug.

12. the preparation method of compound A-13 described in claim 6, this method are as follows:

Compound A1 and amineothiot class compound carry out heat condensation under acid catalysis, are converted to compound A2, compound A2 Protecting group P is sloughed, compound A-13 is generated.

13. the preparation method of compound A-13 described in claim 6, this method are as follows:

Compound A4 and amineothiot class compound heat condensation under acid catalysis generate compound A-45；Pass through amine and coupling examination Compound A-45 is converted to amide by agent, is then sloughed protecting group P, is obtained compound A-13.

14. the preparation method of compound A6, this method described in claim 6 are as follows:

Compound A-13 is converted into compound A6 by the way that oxidant is added.

15. the preparation method of compound A7, this method described in claim 6 are as follows:

Compound A-13 is converted into compound A7 by the way that oxidant is added.

Technical field

The present invention relates to antiviral drugs technical fields, and in particular to and a kind of active sulfur-bearing of anti HIV-1 virus is polycyclic-hydroxyl Pyridone-carboxylamide analog and its application.

Background technique

Since 1981 U.S. find first case AIDS patient, this communicable disease starts to annoying human civilization.Disease It is malicious and the mankind to coexist for being fought for existence because effractor kill people but also eliminate them certainly each other Oneself host.Body protects itself from bacterium using its immune system, virus and other cause disease, and when failing Immune deficiency disorder.This kind of disease is referred to as acquired immunodeficiency syndrome AIDS (AIDS), is by human immune deficiency The most common result after viral (HIV) infection.Once HIV, HIV-1 and the HIV-2 of two kinds of closely related types were identified.And HIV-2 Sent out in India and West Africa, HIV-1 it is more fatal and in the world the first AIDS the reason of.Although patient has Different Results a bit, HIV infection person continues to develop into AIDS AIDS and ultimately succumbs to opportunistic infection or cancer in most of cases.

Human immunodeficiency virus (HIV) is a kind of retrovirus, causes acquired immunodeficiency syndrome AIDS Sick (AIDS).Therapeutic agent for AIDS is mainly selected from one group of reverse transcriptase inhibitor (e.g., AZT, 3TC and Abacavir) and egg White enzyme inhibitor (e.g., Indinavir, Amprenavir), but they are proved with side effect such as nephrosis and drug resistance occur Virus.Therefore thirst for the anti-HIV drug that exploitation has other mechanism of action.

In addition frequently occurring due to drug resistant mutants is had been reported that, combination therapy can effectively treat AIDS.Reverse transcriptase suppression Preparation and protease inhibitors are clinically used as anti-HIV drug, however the drug with identical mechanism of action usually shows friendship Pitch drug resistance.Therefore need to have other mechanism of action makees anti-HIV drug.

In the above case, the exploitation of hiv integrase inhibitor concentrates on the anti-HIV drug for the mechanism of action for having new. Integration is vital to gene expression and virus replication to retroviral gene group.Viral genome is by viral reverse transcription Enzyme is inversely transcribed into the DNA of infected cell, is integrated into host cell dyeing followed by viral integrase enzyme dna Body.Rna transcription is generated from the viral DNA being integrated and mRNAs such as is used to instruct the synthesis of virus protein and afterwards as new virus Grain rna gene group.Coating [membrane envelope] is respectively enclosed in from cell evasion from plasma membrane by plasmavirus particle It is interior.HIV-1 integrase is important and therefore designs very promising target spot to anti-AIDS drug in this process.

Have been found that integrase inhibitor mutation causes the drug resistant variation more than 60 in vivo and in vitro.Due to these mutation With drug resistant generation inhibitor be to it is viral effectively it is lower [Drug resistance updates 2010,13 (4-5), 139- 150].The drug resistance of integrase inhibitor is equivalent to other antiretroviral drugs.Integrase drug resistance first passes through Primary mutations Lower integrase inhibitor sensibility and secondary mutation further lowers viral susceptibility and/or lowers viral appropriateness reparation In conjunction with caused.Second pair of integrase inhibitor drug resistance has hereditary barrier, is defined as living to clinical integrase inhibitor is lost Property need mutation count.Third has not exclusively intersection-drug resistance [The Joournal of among extensive but integrase inhibitor infectious diseases 2011,203(9),1201-1214].One ring is located at catalysis containing 40-149 residue of amino acid 1 Nuclear structure area and integrase function is important as described above.Although this ring is flexible and even it is acted on not very Know that it is considered being important with its function to DNA in conjunction with most important.Drug resistance seems in this integrase-code area It is mutated [Drug resistance updates 2010,13 (4-5), 139-150].Replace La Wei's and elvitegravir to drawing Each of drug resistance mainly due to identical two mutational pathways but to drug is also related to other Primary mutations [Clinical therapeutics 2008,30(10),1747-1765].Since having resistance problems to drawing for La Wei and elvitegravir, newly The exploitation of generation integrase inhibitor is still an important research direction.Wherein polycyclic-Hydroxypyridinone formamide is derivative Object is a kind of novel compound with antiviral activity, such as Dolutegravir (patent document WO2006/116764) and Bictegravir (patent document WO2014/100323).The Dolutegravir listed at present still has asking for drug resistance Topic, therefore develop novel anti HIV-1 virus drug and have a very important significance.

Summary of the invention

The object of the present invention is to provide a kind of active sulfur-bearing of anti HIV-1 virus it is polycyclic-Hydroxypyridinone benzamide type seemingly Object and its application.

Present invention technical solution used for the above purpose is as follows:

A kind of active sulfur-bearing of anti HIV-1 virus is polycyclic-Hydroxypyridinone formamide analog, there is lower formula (I) compound Or its stereoisomer or officinal salt:

Wherein, Z is selected from S, SO, SO₂；

R⁰For hydrogen, halogen, hydroxyl, optionally the low alkyl group that replaces or optionally replace low-grade alkenyl, can respectively be chosen It is inserted into from heteroatom group below: OR⁶、SR⁶、SOR⁶、SO₂R⁶、NR⁶；R⁶For hydrogen, optionally the low alkyl group that replaces optionally takes The naphthenic base in generation, the cycloalkyl low-grade alkyl optionally replaced, the low-grade alkenyl optionally replaced, the rudimentary alcoxyl optionally replaced Base, the aromatic yl elementary alkyl optionally replaced, the aryloxy group optionally replaced, the heterocycle optionally replaced, is appointed at the aryl optionally replaced Choose the heterocyclo lower alkyl in generation, the heterocyclic oxy group optionally replaced, hydroxyl, optional amino, the phosphate optionally replaced；

Each R^aStand alone as hydrogen, halogen, the low alkyl group optionally replaced, the naphthenic base optionally replaced, the ring optionally replaced Alkyl lower alkyl, the lower alkoxy optionally replaced, the aryl optionally replaced, optionally takes the low-grade alkenyl optionally replaced The aromatic yl elementary alkyl in generation, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, is appointed at the aryloxy group optionally replaced Choose the heterocyclic oxy group in generation；

The integer that n is 0 to 8；Ring where indicating when n is 0 is five-membered ring；

R¹For hydrogen, optionally the low alkyl group that replaces, the naphthenic base optionally replaced, the cycloalkyl low-grade alkyl optionally replaced, The low-grade alkenyl that optionally replaces, the lower alkoxy optionally replaced, the aryl optionally replaced, the aryl lower alkane optionally replaced Base, the aryloxy group optionally replaced, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, the heterocycle oxygen optionally replaced Base；

R²For hydrogen, optionally the low alkyl group that replaces, the naphthenic base optionally replaced, the cycloalkyl low-grade alkyl optionally replaced, The low-grade alkenyl that optionally replaces, the lower alkoxy optionally replaced, the aryl optionally replaced, the aryl lower alkane optionally replaced Base, the aryloxy group optionally replaced, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, the heterocycle oxygen optionally replaced Base；

R³,R^3’Stand alone as hydrogen, the low alkyl group that optionally replaces, the naphthenic base optionally replaced, the naphthenic base optionally replaced it is low Grade alkyl, the low-grade alkenyl optionally replaced, the lower alkoxy optionally replaced, the aryl optionally replaced, the virtue optionally replaced Base low alkyl group, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, optionally replaces the aryloxy group optionally replaced Heterocyclic oxy group, hydroxyl, optional amino, the phosphate optionally replaced；

R⁴,R⁵The respective low alkyl group for standing alone as hydrogen or optionally replacing, the naphthenic base optionally replaced, the cycloalkanes optionally replaced Base low alkyl group, the lower alkoxy optionally replaced, the aryl optionally replaced, optionally replaces the low-grade alkenyl optionally replaced Aromatic yl elementary alkyl, optionally replace aryloxy group, optionally replace heterocycle, optionally replace heterocyclo lower alkyl, optionally Substituted heterocycle；

Or in which R⁴And R⁵It is combined together to form-W-, wherein W is [C (R^b)₂]_L(integer that L is 1 to 4)；

Each R^bStand alone as hydrogen, halogen, the low alkyl group optionally replaced, the naphthenic base optionally replaced, the ring optionally replaced Alkyl lower alkyl, the lower alkoxy optionally replaced, the aryl optionally replaced, optionally takes the low-grade alkenyl optionally replaced The aromatic yl elementary alkyl in generation, the heterocycle optionally replaced, the heterocyclo lower alkyl optionally replaced, is appointed at the aryloxy group optionally replaced Choose the heterocyclic oxy group in generation.

Preferably, a kind of active sulfur-bearing of anti HIV-1 virus it is polycyclic-Hydroxypyridinone formamide analog, have following formula (I- A) compound or its stereoisomer or officinal salt:

Wherein, Z is selected from S, SO, SO₂；

Wherein R⁰、R^a、n、R³、R^3’、R⁴、R⁵The selection of respective group is as previously described；

X respectively stands alone as hydrogen, halogen, hydroxyl, the low alkyl group optionally replaced, the naphthenic base optionally replaced, optionally replaces Cycloalkyl low-grade alkyl, optionally replace low-grade alkenyl, optionally replace lower alkoxy, optionally replace aryl, appoint The aromatic yl elementary alkyl for choosing generation, the aryloxy group optionally replaced, the heterocycle optionally replaced, the heterocyclo lower alkane optionally replaced Base, the heterocyclic oxy group optionally replaced, hydroxyl, optional amino, the phosphate optionally replaced；

M is the integer of 0-3, preferably 1-3；

When m is 1, X is preferably halogen；It is more preferably located at the fluorine or 4- fluorine of the position 2- of the phenyl ring；

When m is 2, X is preferably halogen；It is more preferably located at the fluorine and 4- fluorine, 2- fluorine of the position 2- of the phenyl ring With 3- fluorine, 2- fluorine and 6- fluorine, 3- fluorine and 4- fluorine, 3- fluorine and 4- chlorine, 2- fluorine With the chlorine and 4- fluorine of 4- chlorine or 2-；Most preferably positioned at the fluorine and 4- fluorine of the position 2- of the phenyl ring；

When m is 3, X is preferably halogen；It is more preferably located at the fluorine of the position 2- of the phenyl ring, the fluorine of 4- fluorine and 6- Or 2- fluorine, the fluorine of 3- fluorine and 4-, it is most preferably located at the fluorine of the position 2- of the phenyl ring, 4- fluorine and 6- Fluorine.

Preferably, a kind of active sulfur-bearing of anti HIV-1 virus it is polycyclic-Hydroxypyridinone formamide analog, have following formula (I- B) compound or its stereoisomer or officinal salt:

Wherein, Z is selected from S, SO, SO₂；

Wherein R⁰、R^a、n、R³、R^3’The selection of respective group is as previously described；

Wherein W is [C (R^b)₂]_L(integer that L is 1 to 4)；

M is the integer of 0-3, preferably 1-3；

When m is 1, X is preferably halogen；It is more preferably located at the fluorine or 4- fluorine of the position 2- of the phenyl ring；

Preferably, a kind of active sulfur-bearing of anti HIV-1 virus it is polycyclic-Hydroxypyridinone formamide analog, have following formula (I- C) compound or its stereoisomer or its pharmaceutically acceptable salt:

Wherein, Z is selected from S, SO, SO₂；

Wherein R⁰、R¹、R²、R³、R^3’、R⁴、R⁵The selection of respective group is as previously described.

Preferably, a kind of active sulfur-bearing of anti HIV-1 virus it is polycyclic-Hydroxypyridinone formamide analog, have following formula (I- D) compound or its stereoisomer or its pharmaceutically acceptable salt:

Wherein, Z is selected from S, SO, SO₂；

Wherein R⁰、R³、R^3’、R^a、R⁴、R⁵The selection of respective group is as previously described；

M is the integer of 0-3, preferably 1-3；

When m is 1, X is preferably halogen；It is more preferably located at the fluorine or 4- fluorine of the position 2- of the phenyl ring；

Preferably, a kind of active sulfur-bearing of anti HIV-1 virus it is polycyclic-Hydroxypyridinone formamide analog, have compound The structure of A3 or compound A6 or compound A7 or the stereoisomer of the compound or its pharmaceutically acceptable salt:

Preferably, a kind of active sulfur-bearing of anti HIV-1 virus it is polycyclic-Hydroxypyridinone formamide analog, under structure is Arrange the compound or its enantiomter of 1-93 serial number；Its diastereoisomer；The mixture of its enantiomter；Its is diastereomeric The mixture of isomers；The mixture of its enantiomter and diastereoisomer；And its pharmaceutically acceptable salt；

Preferably, the pharmaceutically acceptable salt is sodium salt or sylvite.

The present invention also provides a kind of pharmaceutical compositions, include the described in any item compounds of claim 1-5 or its pharmacy Upper acceptable salt or solvate are active component.

Preferably, described pharmaceutical composition further contains one or more other anti-hiv therapy agent.

Preferably, described pharmaceutical composition further contains pharmaceutically acceptable carrier.

The present invention also provides the compounds or its pharmaceutically acceptable salt or solvate to prepare AntiHIV1 RT activity disease Application in cytotoxic drug.The anti HIV-1 virus drug is anti-AIDS drug.

The present invention also provides the preparation method of the compound A-13, this method are as follows:

Compound A1 and amineothiot class compound are in acid (such as formic acid or acetic acid or propionic acid or methanesulfonic acid p-methyl benzenesulfonic acid Or magnesium triflate) the lower progress heat condensation of catalysis, it is converted to compound A2, compound A2 sloughs protecting group P, generates chemical combination Object A3.

The present invention also provides another preparation method of the compound A-13, this method are as follows:

Compound A4 and amineothiot class compound heat condensation under acid catalysis generate compound A-45；Pass through amine and idol Compound A-45 is converted to amide by joint-trial agent, is then sloughed protecting group P, is obtained compound A-13.

The present invention also provides the preparation method of the compound A6, this method are as follows:

By being added oxidant, for example, peroxide organic acid class sour (m-CPBA or Peracetic acid or peroxy trifluoroacetic acid etc.) or Hydrogen peroxide (phosphomolybdic acid catalysis) or tert-Butanol peroxide, are converted into compound A6 for compound A-13.

The present invention also provides the preparation method of the compound A7, this method are as follows:

Compared with prior art, beneficial effects of the present invention are as follows:

Sulfur-bearing provided by the invention is polycyclic-and Hydroxypyridinone formamide analog all has good HIV-resistant activity, especially Compound 2, compound 18 and compound 34 and compound 66 are very strong to the inhibiting effect of HIV-1 duplication in vitro, to HIV disease The therapeutic index of poison reaches the hundreds of times of existing drug TDF and Dolutegravir drug, and the exploitation of such compound is to AIDS The development of medicine has a very important significance, and will bring glad tidings for AIDS patient.

Specific embodiment

Illustrate technical solution of the present invention below by way of specific embodiment.The equal city of raw materials and reagents used in the present invention Selling can obtain.

Sulfur-bearing of the present invention is polycyclic-the general synthetic schemes of Hydroxypyridinone formamide analog:

1-3 is as a further embodiment of the present invention for offer scheme, and illustrates and be used to prepare the change with formula (I) It closes object and can be used for preparing the conventional method of the other compound with formula (I).

Scheme 1

By A1 and suitable amineothiot in suitable acid catalysis and heat condensation, A1 can be converted to A2, A2 connects Deprotection P, formed A3.

Scheme 2

By A4 and suitable amineothiot in suitable acid catalysis and heat condensation, A4 can be converted to A5.Pass through A5 can be converted to amide with suitable amine and coupling reagent such as HATU or CDI or HOBt, then Deprotection P, be formed A3。

Scheme 3

By the way that A3 can be converted to sulfoxide A6 or sulfone A7 with suitable oxidant.

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The sulfur-bearing of anti HIV-1 virus is polycyclic-Hydroxypyridinone formamide analog and its application

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