阅读说明：本技术 三唑己酮联芳（杂）环衍生物及其制备方法和用途 (Triazole hexanone biaryl (hetero) ring derivative and preparation method and application thereof ) 是由 赵瀛兰 罗有福 陈强 于 2019-01-11 设计创作，主要内容包括：本发明属于化学医药领域,具体涉及抗恶性肿瘤、血液系统恶性疾病、关节炎、多发性硬化症和免疫排斥反应小分子及其制备方法和用途。本发明要解决的技术问题是目前临床上缺乏活性高、安全性好的二氢乳酸脱氢酶小分子抑制剂上市用于临床肿瘤治疗,且目前处于临床研究二氢乳酸脱氢酶小分子抑制剂毒副作用大的缺点。本发明解决上述技术问题的方案是提供了一种三唑己酮联芳(杂)环衍生物,该衍生物主要是与三唑连接不同芳(杂)环以及己酮上的不同取代,发明提供的化合物具有全新结构,抗恶性肿瘤活性高,显著抑制二氢乳酸脱氢酶活性,在治疗恶性肿瘤药物开发上具有很大的价值。(The invention belongs to the field of chemical medicine, and particularly relates to small molecules for resisting malignant tumors, hematological malignant diseases, arthritis, multiple sclerosis and immune rejection, a preparation method and application thereof. The invention aims to solve the technical problems that the prior dihydrolactate dehydrogenase small-molecular inhibitor with high activity and good safety is lack clinically and is used for clinical tumor treatment on the market, and the prior clinical research on the defect of large toxic and side effects of the dihydrolactate dehydrogenase small-molecular inhibitor is carried out. The invention provides a triazole hexanone biaryl (hetero) ring derivative for solving the technical problems, the derivative is mainly different aryl (hetero) rings connected with triazole and different substitutions on hexanone, and the compound provided by the invention has a brand new structure, high malignant tumor resistance activity, obvious inhibition on the activity of dihydrolactate dehydrogenase and great value in the development of medicaments for treating malignant tumors.)

1. The structure of the triazol hexanone biaryl (hetero) ring derivative is shown as the formula I

R₁～R₄When is-H, halogen, -OH, -NH₂、-NO₂C1-C8 alkyl, C1-C8 alkoxy, -CF₃C1-C8 alkenyl or C1-C8 ester group;

R₅～R₉independently is-H, halogen, -OH, -NH₂、-NO₂C1-C8 alkyl, C1-C8 alkoxy, -CF₃、-OCF₃C1-C8 alkenyl or C1-C8 ester group;

R₁₀～R₁₂independently C1-C8 alkyl, substituted phenyl substituted C1-C8 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C8 alkyl, C1-C8 alkoxy, phenyl,-CF₃、-OCF₃Or C1-C8 alkenyl and carboxyl.

2. The triazolohexanone biaryl (hetero) cyclic derivative according to claim 1

R₁～R₄When is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃C1-C4 alkenyl or C1-C4 ester group;

R₅～R₉independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃C1-C4 alkenyl or C1-C4 ester group;

R₁₀～R₁₂independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl,-CF₃、-OCF₃Or C1-C4 alkenyl and carboxyl

Preferably, the first and second liquid crystal materials are,

R₁～R₄when is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃

R₅～R₉Independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃Or C1-C4 ester group;

R₁₀～R₁₂independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl,-CF₃、-OCF₃Or C1-C4 alkenyl and carboxyl

It is further preferred that the first and second liquid crystal compositions,

R₁～R₄when is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃

R₅～R₉Independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃

R₁₀～R₁₂Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl,-CF₃、-OCF₃Or C1-C4 alkenyl, carboxyl

Preferably, the first and second liquid crystal materials are,

R₁～R₄when is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy

R₅～R₉Independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃

R₁₀～R₁₂Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-4; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1EC4 alkyl, C1-C4 alkoxy, phenyl,-CF₃、-OCF₃Or C1-C4 alkenyl and carboxyl.

Preferably, the first and second liquid crystal materials are,

R₁～R₄when is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy

R₅～R₉Independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃

R₁₀～R₁₂Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-2; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl

Preferably, the first and second liquid crystal materials are,

R₁～R₄when is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy

R₅～R₉Independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃

R₁₀～R₁₂Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-2; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl

Preferably, the first and second liquid crystal materials are,

R₁～R₄when is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkaneOxy radical

R₅～R₉Independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃

R₁₀～R₁₂Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-2; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl

Preferably, the first and second liquid crystal materials are,

R₁～R₄when is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkoxy

R₅～R₉Independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃

R₁₀～R₁₂Independently C1-C4 alkyl, substituted phenyl substituted C1-C4 alkyl, substituted 6-12-membered aryl and substituted 5-10-membered saturated or unsaturated heterocyclic ring, wherein hetero atom of the heterocyclic ring is N, O or S, and the number of the hetero atoms is 1-2; the substituent of the substituted phenyl, the substituted aryl and the substituted heterocycle is-H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl

Most preferably, the first and second substrates are,

R₁～R₄when is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkoxy

R₅～R₉Independently is-H, halogen, -OH, -NH₂、-NO₂C1-C4 alkyl, C1-C4 alkoxy, -CF₃、-OCF₃

R₁₀～R₁₂Independently H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, phenyl and carboxyl.

3. A triazolohexanone biaryl (hetero) cyclic derivative having the structural formula:

4. a pharmaceutically acceptable salt or hydrate of a triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2.

5. A prodrug of a triazolohexanone biaryl (hetero) ring derivative according to any one of claims 1 to 2.

6. A composition comprising the triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2, the salt or hydrate according to claim 4 or the prodrug according to claim 5, and pharmaceutically acceptable auxiliary components.

7. Use of a triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2, a salt or hydrate according to claim 12, a prodrug according to claim 5 or a composition according to claim 6 in the preparation of a diltiazem lactate dehydrogenase inhibitor; preferably, the use of the above-mentioned triazolohexanone biaryl (hetero) cyclic derivative, its salt or hydrate for the preparation of a diispropyl lactate dehydrogenase inhibitor.

8. Use of a triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2, a salt or hydrate according to claim 12, a prodrug according to claim 5 or a composition according to claim 6 for the preparation of a medicament for the treatment of malignant tumors.

9. Use of a pyrimido morpholine derivative according to any one of claims 1 to 2, a salt or hydrate according to claim 12, a prodrug according to claim 5 or a composition according to claim 6 for the manufacture of a medicament for the treatment of acute leukemia.

10. Use of a triazolohexanone biaryl (hetero) cyclic derivative according to any one of claims 1 to 2, a salt or hydrate according to claim 12, a prodrug according to claim 5 or a composition according to claim 6 for the preparation of a medicament for the treatment of rheumatoid arthritis, multiple sclerosis and immune rejection.

Technical Field

The invention belongs to the field of chemical medicine, and particularly relates to a triazolone biaryl (hetero) ring derivative, and a preparation method and application thereof.

Background

The micromolecule targeted anti-tumor medicine has definite curative effect and high safety, and can realize accurate treatment for tumor patients, so the micromolecule targeted anti-tumor medicine becomes a hotspot and trend of research and development of tumor medicines in recent years.

Dihydroorotate dehydrogenase (DHODH) is present in the inner membrane of human mitochondria and is an iron-containing flavin-dependent enzyme. It catalyzes the step 4 reaction in the de novo synthesis pathway of pyrimidine nucleotides in nucleic acids in organisms and is the rate-limiting enzyme of pyrimidine nucleotide synthesis. Pyrimidine nucleotides are essential for the synthesis of DNA, RNA, glycoproteins, and phospholipids in organisms, the synthesis of which is critical for cellular proliferation and metabolism. In tumor cells, pyrimidine nucleotides are required in amounts far greater than normal cells, and their synthesis relies primarily on de novo synthetic pathways. The inhibition of DHODH can block the synthesis of new pyrimidine nucleotide, which causes the biosynthesis of DNA (containing adenine and cytosine), RNA (containing uracil and cytosine), glycoprotein and phospholipid to generate obstacle, thereby causing cell cycle block and inhibiting the abnormal proliferation of tumor cells. The research shows that the DHODH is highly expressed in various tumors, and is positively correlated with poor prognosis of clinical tumor patients, and the inhibition of the DHODH expression can inhibit the tumor proliferation. Therefore, DHODH has become a potential anti-tumor therapeutic target, and the development and research of specific inhibitors aiming at the DHODH have important significance.

Currently, small molecule inhibitors against DHODH include Brequinar (Brequinar), which has a certain antitumor activity, and phase I clinical trials for treating tumors were performed in 1986, 1988, and 1990, respectively, but the antitumor activity was limited, and side effects such as myelosuppression were large, and thus, the DHODH small molecule inhibitors have not been clinically approved for treating malignant tumors. Therefore, the development of a high-efficiency and low-toxicity DHODH inhibitor for treating the tumor is of particular significance.

Disclosure of Invention

The invention provides a triazol hexanone biaryl (hetero) ring derivative with a structure shown as a formula I

Wherein X, Y, Z is C or N

R₁～R₄is-H, halogen, -OH, methoxy,

R₅～R₉is-H, halogen, -OH, methoxy, amino, nitro, methoxycarbonyl, trifluoromethoxy, trifluoromethyl, alkyl

R₁₀～R₁₂is-H, halogen, -OH, methoxyl, alkane, alkene, alkyne.

The triazolohexanone biaryl (hetero) cyclic derivative according to claim 1, characterized in that: the structural formula is as follows:

the preparation method of the triazol hexanone biaryl (hetero) ring derivative comprises the following synthetic route

Route one:

R₁～R₄is-H, halogen, -OH, methoxy,

R₅～R₉is-H, halogen, -OH, methoxy, amino, nitro, methoxycarbonyl, trifluoromethoxy, trifluoromethyl or alkyl.

R₁₀～R₁₂is-H, halogen, -OH, methoxyl, alkane, alkene, alkyne.

The preparation operation steps of the triazol hexanone biaryl (hetero) ring derivative shown in the formula II comprise:

a. the intermediate 1 is obtained by taking the raw material 1 and catalyzing with different substituted aryl boric acids, wherein the catalyst is [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the alkali is any one of cesium carbonate, potassium carbonate and the like; the reaction temperature is 90-100 ℃; the molar ratio of the raw material 1, the boric acid, the alkali and the ligand is 1:1.3: 6: 0.1; the reaction time is 12-24 h;

b. and in the operation, under the reaction condition of minus fifteen ℃, dripping a tetrahydrofuran solution of the intermediate 1 into an ether solution of boron trifluoride, reacting for 10-30min, dripping tert-butyl isobutyl ester into the mixture to react for 1-2h, adding tert-butyl isobutyl ester into the mixture to react for 2h, observing the occurrence of precipitates (deep oily liquid drops), heating the reaction to minus 5, adding 10ml of n-pentane, heating to 25 alkane, and adding 10ml of n-pentane to obtain a solid or deep oily liquid drop product. Putting the product into a new reaction bottle, adding sodium azide and 30ml of acetonitrile solution (acetonitrile: water is 3:1), and reacting for 1-4h at 80: of reaction time;

d. diazotizing the intermediate 3 in the raw material 1, and then obtaining azide, wherein in the operation, under the condition of reaction at minus fifteen ℃, a tetrahydrofuran solution of the raw material 1 is dripped into an ether solution of boron trifluoride, after the reaction is carried out for 10-50min, isobutyl tert-butoxide is dripped, after the reaction is carried out for 1-4h, isobutyl tert-butoxide is added for reaction for 2h, a precipitate (a deep-color oily liquid drop) is observed, the reaction is heated to minus 5, 10ml of n-pentane is added, then the reaction is heated to 25 alkane, 10ml of n-pentane is added, solid or deep-color oily liquid drops and a new reaction bottle are taken, then sodium azide is added, 30ml of acetonitrile (water: 3:1) is added, and the reaction is carried out for 1-8h at 80;

e. the intermediate 4 is obtained under the catalysis of aryl boric acid which is differently substituted in the intermediate 3, and the catalyst is [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the alkali is any one of cesium carbonate, potassium carbonate and the like; the reaction temperature is 90% palladium; the method comprises the following steps of (1); the molar ratio of the raw material 1, the boric acid, the alkali and the ligand is 1:1.3: 6: 0.1; the reaction time is 12-24 h;

c. the compounds of the formulae 2.1, 2.2 and 2.3 are obtained by basification of intermediate 2 and starting material 2 (intermediate 4 starting material 2), the reaction temperature being 85 deg.c; the base is 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU); the raw material 2: intermediate 2 DBU molar ratio: 1:1.3:0.2, the raw material 4: intermediate 2 DBU molar ratio: 1:1.3:0.2. The reaction time is 12-24 h;

Detailed Description