Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs
阅读说明：本技术 嘧啶类小分子化合物及在制备抗分枝杆菌药物中的用途 (Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs ) 是由 罗有福 张天宇 于 2018-06-06 设计创作，主要内容包括：本发明提供了一种嘧啶类化合物,其化学结构如I式所示,式中X,Y,R<Sub>1</Sub>,R<Sub>2</Sub>,R<Sub>3</Sub>的定义如说明书和权利要求书中所述。同时,本发明还提供了上述化合物在抗分枝杆菌方面的应用。本发明提供的化合物具有较好的抗结核分枝杆菌活性,可用于制备抗结核药物。<Image he="368" wi="662" file="RE-DDA0001826287590000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a pyrimidine compound, the chemical structure of which is shown as formula I, wherein X, Y, R 1 ,R 2 ,R 3 Is as defined in the description and claims. Meanwhile, the invention also provides application of the compound in resisting mycobacteria. The compound provided by the invention has better anti-tuberculosis branchHas antibacterial activity, and can be used for preparing antituberculosis drugs.)
1. A pyrimidine compound or a pharmacologically acceptable salt thereof, wherein the chemical structure of the pyrimidine compound is represented by formula I:
Wherein R is1none or H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group;
R2is H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group;
R3Is a substituted OR unsubstituted 5-to 10-membered aromatic ring containing 0, 1, 2 OR 3 heteroatoms selected from N, O OR S, -OR5、-SR5、-NR4R5、-NHR5or-NH (C)1-C6Alkane) R5(ii) a Wherein R is4Is C1-C6An alkyl group; r5Is substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthalene, substituted or unsubstituted 5-to 10-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; or R4and R5and the attached N together form a substituted or unsubstituted 9-10 membered fused ring containing 1, 2 or 3 heteroatoms selected from N, O or S;
Wherein, the substituent can be positioned at each position of the ring and can be mono-substituted or multi-substituted, and the substituent is selected from the following groups: halogen, hydroxy, cyano, amino, carboxyl, amido, ester, isopropyl sulfone, C1-C6Alkyl, halogen-substituted lower alkyl, C1-C6An alkoxy group;
X and Y are each independently C, N or O.
2. A compound of formula I according to claim 1, wherein R is1None or H, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R2is H, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R3is-HNR5、-NH(C1-C6Alkane) R5OrWherein R is5Is substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl containing 1, 2 or 3 heteroatoms selected from N, O or SA 5-10 membered aromatic ring; the substituent can be positioned at each position of the ring, can be mono-substituted or multi-substituted, and is selected from the following group: halogen, hydroxy, cyano, amino, carboxyl, amido, ester, isopropyl sulfone, C1-C6Alkyl, halogen-substituted lower alkyl, C1-C6An alkoxy group;
X is C or N; y is N or O.
3. A compound of formula I according to claim 2, wherein R is1None or H, methyl; r2Is isopropyl;
R3is-HNR5、-NH(C1-C6Alkane) R5OrWherein R is5Is C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thienyl, substituted or unsubstituted quinolyl; the substituent can be positioned at each position of the ring, can be mono-substituted or multi-substituted, and is selected from the following group: halogen, hydroxy, cyano, carboxy, amido, isopropyl sulfone, trifluoromethyl, methoxy; x is C or N; y is N or O.
4. A compound of formula i, or a pharmacologically acceptable salt thereof, as claimed in claim 1, wherein said compound of formula i is:
5a 5-chloro-N2- (2-isopropoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5b 5-chloro-N2- (2-isopropoxy-5-methyl-4-morpholinylphenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5c 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5d 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol,
5e 4- (2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) ethyl) phenol,
5f N4- (3, 5-bis (trifluoromethyl) phenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5g of 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzamide,
5h (R) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (1-phenylethyl) pyrimidine-2, 4-diamine,
5i 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (naphthalen-1-yl) pyrimidine-2, 4-diamines,
5j N4-benzyl-5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5k 2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol,
5l 4-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4-phenethylpyrimidine-2, 4-diamine,
5m 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (4-methoxyphenylethyl) pyrimidine-2, 4-diamine,
5n N4- (4-bromophenylethyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5o 5-chloro-N4- (4-fluorophenethyl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5p 5-chloro-N4-cyclohexyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5q 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (naphthalen-2-yl) pyrimidine-2, 4-diamines、
5r N4- ((3s,5s,7s) -adamantan-1-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine
5s 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (thien-2-yl) ethyl) pyrimidine-2, 4-diamine,
5t N4- ([1,1' -Biphenyl)]-3-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5u N4- (3-bromo-4-methoxyphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5v N4- (4-bromo-2-isopropoxy-5-methylphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5w 5-chloro-N4-cyclopropyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5x 5-chloro-N4- (4', 6-dimethoxy- [1,1' -biphenyl)]-3-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5y 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-methyl-1- (naphthalen-2-yl) propyl-2-yl) pyrimidine-2, 4-diamine,
5z 5-chloro-N4- (3, 4-hydroquinin-1-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidin-2-amine
。
5. A process for the preparation of a compound of formula i and pharmacologically acceptable salts thereof as claimed in any one of claims 1 to 4, wherein a compound of formula ii or a salt thereof is used as a starting material, which is reacted with a compound of formula iii to give a compound of formula i:
Wherein R is1,R2,R3X, Y are as defined in claims 1-4.
6. Use of a compound of formula i or a pharmacologically acceptable salt thereof as claimed in claims 1 to 4, for the manufacture of a medicament, which is a pharmaceutical composition comprising a compound of formula i or a pharmacologically acceptable salt thereof as an active ingredient in combination with conventional pharmaceutical carriers.
7. Use of a compound of formula i, or a pharmacologically acceptable salt thereof, as claimed in claim 6, in the manufacture of a medicament for the treatment of mycobacterium, wherein the pharmacologically acceptable salt of the compound is an inorganic or organic salt selected from the group consisting essentially of: hydrochloride, sulfate, phosphate, nitrate, hydrobromide, p-toluenesulfonate, acetate, tartrate, oxalate or fumarate.
8. Use of a compound of formula i or a pharmacologically acceptable salt thereof in the manufacture of a medicament for the treatment of mycobacterium as claimed in claim 6, wherein the pharmaceutical composition is in the form of a tablet, a dispersible tablet, a sustained release formulation, a capsule, a granule.
9. The use of a compound of formula i, or a pharmacologically acceptable salt thereof, as claimed in claim 6, in the manufacture of a medicament for the treatment of tuberculosis caused by infection with mycobacterium tuberculosis.
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a 2, 4-pyrimidinediamine antitubercular compound as well as a preparation method and application thereof.
Background
Tuberculosis is a serious infectious disease caused by Mycobacterium tuberculosis (m.tb). According to the evaluation of WHO, about 1040 million new tuberculosis patients and 167 million tuberculosis deaths worldwide have become one of the main diseases died due to infectious diseases in 2016.
At present, the drugs for treating pulmonary tuberculosis mainly comprise isoniazid, rifampicin, streptomycin, ethambutol and the like, but the drugs have toxic and side effects of liver injury and the like, and the treatment period is as long as more than six months, which brings great difficulty to the prevention and treatment of tuberculosis. In recent years, the emergence of drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has brought about greater difficulties in the treatment of tuberculosis. Therefore, the search for antituberculosis drugs with definite curative effect, little side effect and no drug resistance through various ways becomes an important target of vast pharmaceutical workers.
In a word, the research and development of antituberculosis drugs with new structures and new action mechanisms makes the development of safer, more efficient and less toxic tuberculosis treatment schemes urgent.
Disclosure of Invention
The invention aims to provide a pyrimidine compound with a novel structure and application thereof in preparing anti-mycobacteria medicaments.
In a first aspect of the invention, there is provided a compound of formula I, a pharmacologically acceptable salt or a stereoisomer thereof,
Wherein R is1None or H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6A cycloalkyl group; r2Is H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C6a cycloalkyl group;
X, Y are each independently C, N or O;
R3Is a substituted OR unsubstituted 5-to 10-membered aromatic ring containing 0, 1, 2 OR 3 heteroatoms selected from N, O OR S, -OR5、-SR5、-NR4R5、-NHR5or-NH (C)1-C6Alkane) R5(ii) a Wherein R is4Is C1-C6An alkyl group; r5Is substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthalene, substituted or unsubstituted 5-to 10-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; or R4And R5And the attached N together form a substituted or unsubstituted 9-10 membered fused ring containing 1, 2 or 3 heteroatoms selected from N, O or S;
wherein the substituent can be positioned at each position of the ring and can be mono-substituted or multi-substituted, and the substituent is selected from the following groups: halogen, hydroxy, cyano, amino, carboxyl, amido, ester, isopropyl sulfone, C1-C6Alkyl, halogen-substituted lower alkyl, C1-C6An alkoxy group.
When the pyrimidine compounds are applied as antimycobacterial drugs, the more preferable compounds are: in the general formula I, R1None or H, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R2Is H, C1-C6Alkyl radical, C3-C6A cycloalkyl group;
R3is-HNR5、-NH(C1-C6Alkane) R5OrWherein R is5Is substituted or unsubstituted C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-to 10-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from N, O or S; the substituent can be positioned at each position of the ring, can be mono-substituted or multi-substituted, and is selected from the following group: halogen, hydroxy, cyano, amino, carboxyl, amido, ester, isopropyl sulfone, C1-C6Alkyl, halogen-substituted lower alkyl, C1-C6An alkoxy group;
X is C or N; y is N or O.
When the above pyrimidine compound is used as an antimycobacterial agent, more preferable compounds are: in the general formula I
R1None or H, methyl; r2Is isopropyl;
R3is-HNR5、-NH(C1-C6Alkane) R5OrWherein R is5Is C3-C10Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted thienyl, substituted or unsubstituted quinolyl; the substituent can be positioned at each position of the ring, can be mono-substituted or multi-substituted, and is selected from the following group: halogen, hydroxy, cyano, carboxy, amido, isopropyl sulfone, trifluoromethyl, methoxy;
X is C or N; y is N or O.
Some preferred compounds of the invention are described in Table 1:
5a 5-chloro-N2- (2-isopropoxy-5-methyl-4- (4-methylpiperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5b 5-chloro-N2- (2-isopropoxy-5-methyl-4-morpholinylphenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5c 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperazin-1-yl) phenyl) -N4- (2- (sulfonylisopropyl) phenyl) pyrimidine-2, 4-diamine,
5d 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (naphthalen-1-yl) pyrimidine-2, 4-diamines,
5e 4- (2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) ethyl) phenol,
5f N4- (3, 5-bis (trifluoromethyl) phenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5g of 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzamide,
5h (R) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (1-phenylethyl) pyrimidine-2, 4-diamine,
5i 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol,
5j N4-benzyl-5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5k 4- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenol,
5l 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4-phenethylpyrimidine-2, 4-diamine,
5m 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (4-methoxyphenylethyl) pyrimidine-2, 4-diamine,
5n N4- (4-bromophenylethyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5o 5-chloro-N4- (4-fluorophenethyl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5p 5-chloro-N4-cyclohexyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5q 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (naphthalen-2-yl) pyrimidine-2, 4-diamines,
5r N4- ((3s,5s,7s) -adamantan-1-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine
5s 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (thien-2-yl) ethyl) pyrimidine-2, 4-diamine,
5t N4- ([1,1' -Biphenyl)]-3-yl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamines,
5u N4- (3-bromo-4-methoxyphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5v N4- (4-bromo-2-isopropoxy-5-methylphenyl) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5w 5-chloro-N4-cyclopropyl-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine,
5x 5-chloro-N4- (4', 6-dimethoxy- [1,1' -biphenyl)]-3-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine
5Y 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-methyl-1- (naphthalen-2-yl) propyl-2-yl) pyrimidine-2, 4-diamines
5z 5-chloro-N4- (3, 4-hydroquinin-1-yl) -N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) pyrimidin-2-amine.
Preferred compound structures in Table 1
。
Further, the present invention provides the compound of the above formula i or a pharmacologically acceptable salt thereof, wherein the pharmacologically acceptable salt (pharmaceutically acceptable salt) is an inorganic acid salt or an organic acid salt.
The inorganic acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or nitric acid and the like;
The organic acid is p-toluenesulfonic acid, acetic acid, tartaric acid, p-toluenesulfonic acid, oxalic acid, fumaric acid, etc.
The preferred pharmaceutically acceptable salts of the present invention are the hydrochloride or the p-toluenesulfonate salt.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I as hereinbefore defined, by reacting a compound of formula II or a salt thereof with a compound of formula III to give a compound of formula I;
Wherein R is1,R2,R3,R4X, Y and n are as defined above.
In a third aspect of the invention, the application of the aminopyrimidine compound or the pharmacologically acceptable salt thereof in preparing anti-tuberculosis drugs is provided.
The invention selects mycobacterium tuberculosis H37Ra as a screening strain to carry out in vivo and in vitro experiments, and the results show that: the compound of the invention has better activity of resisting mycobacterium tuberculosis in vivo and in vitro, has the characteristic of low toxicity, and can be used for preparing anti-tuberculosis drugs.
The invention relates to application of a compound shown in formula I or a pharmacologically acceptable salt thereof in preparing antituberculosis drugs, wherein the antituberculosis drugs are pharmaceutical compositions prepared from the compound shown in formula I or the pharmacologically acceptable salt thereof as an active ingredient and conventional pharmaceutical carriers.
The pharmaceutical composition can be tablets, dispersible tablets, sustained-release agents, capsules and granules.
the compound or the pharmacologically acceptable salt thereof of the present invention provides a novel drug for anti-tuberculosis treatment.
Detailed Description
The present invention will now be described in detail with reference to examples, but the practice of the present invention is not limited thereto.
The reagents and starting materials used in the present invention are commercially available or can be prepared according to literature procedures. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers.