Benzoazaheterocycle compound and preparation method and pharmaceutical application thereof
阅读说明：本技术 苯并氮杂环类化合物及其制法和药物用途 (Benzoazaheterocycle compound and preparation method and pharmaceutical application thereof ) 是由 肖志艳 叶菲 杨亚军 杨颖� 田金英 李雪晨 张晓琳 王永成 邵蒙杰 张蕾 闫祯 于 2019-04-02 设计创作，主要内容包括：本发明公开了式I化合物所示新的苯并氮杂环类化合物及其生理上可接受的盐,溶剂化物以及结晶形式,所述化合物的制备方法,含有所述化合物的药物制剂,以及所述化合物在治疗与人尿酸盐转运蛋白1(hURAT1)相关疾病如高尿酸血症、痛风等临床中的应用。<Image he="439" wi="504" file="DDA0002016034350000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a novel benzo-nitrogen heterocyclic compound shown as a compound in a formula I, and a physiologically acceptable salt, a solvate and a crystal form thereofThe formula, the preparation method of the compound, the pharmaceutical preparation containing the compound and the clinical application of the compound in treating diseases related to human urate transporter 1(hURAT1), such as hyperuricemia, gout and the like.)
1. A benzoazacyclo-heterocyclic compound represented by the following general formula (I) and a physiologically acceptable salt thereof,
wherein the content of the first and second substances,
R1selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy, halogen, substituted or unsubstituted phenyl, the substituent being selected from halogen, C1-C3Alkyl radical, C1-C3An alkoxy group;
x is selected from oxygen or carbon atom;
n is 0 or 1;
a is a covalent bond or a carbonyl group;
R2selected from hydrogen or C1-C3An alkyl group;
y is selected from oxygen, sulfur or nitrogen atom;
R3is selected from COR4Or SO2R4，R4Is selected from C1-C3Alkyl, trifluoromethyl or pyridyl; or R3Selected from the group consisting of CR5R6COOH or CR5R6CH2COOH，R5And R6Independently selected from hydrogen, C1-C3An alkyl group.
2. The compound of claim 1, wherein the compound is a compound of formula (IA) and a physiologically acceptable salt thereof:
wherein the content of the first and second substances,
m is 0 or 1;
w is selected from oxygen or sulfur atom;
R1selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy, halogen, substituted or unsubstituted phenyl, the substituent being selected from halogen, C1-C3Alkyl radical, C1-C3Alkoxy radical；
R2Selected from hydrogen, C1-C3An alkyl group;
R5and R6Independently selected from hydrogen, C1-C3An alkyl group.
3. A compound according to claim 2, and the physiologically acceptable salts thereof, characterized in that said compound is of the general formula (IAa):
wherein the content of the first and second substances,
R1selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy, halogen, substituted or unsubstituted phenyl, the substituent being selected from halogen, C1-C3Alkyl radical, C1-C3An alkoxy group;
R5and R6Independently selected from hydrogen, C1-C3An alkyl group.
4. The compound of claim 1, wherein the compound is a compound of formula (IB) and physiologically acceptable salts thereof:
wherein R is5And R6Independently selected from hydrogen, C1-C3An alkyl group.
5. The compound of claim 1, wherein the compound is a compound of the general formula (IC):
wherein the content of the first and second substances,
x is selected from oxygen or carbon atom;
n is 0 or 1;
R4is selected from C1-C3Alkyl, trifluoromethyl or pyridyl.
6. The compound according to claim 5, wherein the compound is a compound of the general formula (ICa):
wherein R is4Is selected from C1-C3Alkyl, trifluoromethyl or pyridyl.
7. The compound according to claim 1, wherein the compound is a compound represented by the general formula (ID):
wherein the content of the first and second substances,
x is selected from oxygen or carbon atom;
n is 0 or 1;
R4is selected from C1-C3Alkyl, trifluoromethyl or pyridyl.
8. The compound of claim 7, wherein the compound is a compound of the formula (IDa):
wherein R is4Is selected from C1-C3Alkyl, trifluoromethyl or pyridyl.
9. A compound according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of:
10. a process for the preparation of a compound according to any one of claims 1 to 9, comprising the steps of:
1) carrying out nucleophilic reaction on the compound A and the compound B to generate an intermediate C, carrying out C-N coupling reaction on the intermediate C and the compound D to generate an intermediate E, and hydrolyzing the intermediate E to obtain a target compound shown in the formula IA;
wherein m, W and R1、R2、R5And R6Is as defined in claim 2;
2) carrying out nucleophilic reaction on mercaptobenzoic acid and ethyl bromoacetate to generate an intermediate F, acylating the intermediate F and benzomorpholine to generate an intermediate G, and hydrolyzing the intermediate G to obtain a target object IB;
wherein R is5And R6Is as defined in claim 4;
3) carrying out acylation reaction on the compound H and nitrobenzoic acid to generate an intermediate J, reducing the intermediate J to generate an intermediate K, and sulfonylating the intermediate K to generate a target object IC;
wherein n, X, R4Is as defined in claim 5;
4) carrying out acylation reaction on the compound H and nitrobenzoic acid to generate an intermediate J, reducing the intermediate J to generate an intermediate K, and acylating the intermediate K to generate a target object ID;
wherein n, X, R4Is as defined in claim 7.
11. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections, sustained release formulations, controlled release formulations, and various microparticle delivery systems.
13. Use of a compound according to any one of claims 1 to 9 for the preparation of an inhibitor of hiurat 1.
14. Use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for the prevention or treatment of hyperuricemia or gout.
Technical Field
The invention relates to novel benzoazaheterocycles of the general formula I and their physiologically acceptable salts. The use of these compounds in the treatment of hyperuricemia and gout, as well as to methods for their use in therapy, and to pharmaceutical compositions containing them.
Background
Uric acid is the final metabolite of purine compounds in human body, and is also related to the pathogenesis of various diseases. Hyperuricemia is a disease caused by accumulation of uric acid due to purine metabolic disorder, and the clinical treatment mainly comprises two ways of inhibiting uric acid generation and promoting uric acid excretion. About 90% of hyperuricemia is related to the decrease of uric acid clearance of renal tubules in vivo, and along with the marketing of the urate transporter 1(URAT 1) inhibitor rasinurad (Lesinurad) at the end of 2015, URAT1 becomes an important target for developing novel anti-hyperuricemia drugs.
Statistics show that hyperuricemia and gout caused by the hyperuricemia become the second metabolic disease next to diabetes in the world. In recent years, with the improvement of the living standard of people in China, the incidence rate of hyperuricemia and gout also tends to rise year by year, and heavy burden is brought to the society and families.
Because the main cause of hyperuricemia is the increase of uric acid in vivo, the effective reduction of uric acid level in vivo is the key for treating hyperuricemia. The main routes for reducing uric acid levels in vivo include inhibiting uric acid production and promoting uric acid excretion, and therefore, clinically used uric acid-lowering drugs are mainly classified into two categories, namely Xanthine Oxidase (XO) inhibitors (allopurinol, febuxostat, topirostat, etc.) for inhibiting uric acid production and human urate transporter 1 (haurat 1) inhibitors (probenecid, benzbromarone, rasidone, etc.) for promoting uric acid excretion, which reduce uric acid levels by inhibiting reabsorption of uric acid in renal tubules to increase uric acid excretion. The commercial hURAT1 inhibitor Lesinurad (Ravinard) in 2015 proves that URAT1 can become an important target for developing novel anti-hyperuricemia drugs. The existing URAT1 inhibitors have limited types and have the problems of low activity, combined use or large toxic and side effects, and the like, so that the development of a novel URAT1 inhibitor with high efficiency and low toxicity is urgently needed.
The invention aims to provide a novel benzo-nitrogen heterocyclic compound which has high URAT1 inhibitory activity and can be used for treating hyperuricemia and gout and other related diseases caused by the hyperuricemia.
Disclosure of Invention
The invention aims to provide a novel benzo-nitrogen heterocyclic compound shown in a formula I.
The invention also aims to provide a method for preparing the benzo-nitrogen heterocyclic compound shown in the formula I and analogues thereof.
The invention also aims to provide application of the compound shown in the formula I in preparing an hURAT1 inhibitor and in preparing a medicament for preventing or treating hyperuricemia or gout.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
wherein R is1Selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy, halogen, substituted or unsubstituted phenyl, the substituent being selected from halogen, C1-C3Alkyl radical, C1-C3An alkoxy group; x is selected from oxygen or carbon atom; n is 0 or 1; a is a covalent bond or a carbonyl group; r2Selected from hydrogen or C1-C3An alkyl group; y is selected from oxygen, carbon or nitrogen atom; r3Is selected from COR4Or SO2R4，R4Is selected from C1-C3Alkyl, trifluoromethyl or pyridyl; or R3Selected from the group consisting of CR5R6COOH or CR5R6CH2COOH，R5And R6Independently selected from hydrogen, C1-C3An alkyl group.
In a further aspect of the present invention there is provided a compound of formula (IA) and physiologically acceptable salts thereof:
wherein m is 0 or 1; w is selected from oxygen or sulfur atom; r1Selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy, halogen, substituted or unsubstituted phenyl, the substituent being selected from halogen, C1-C3Alkyl radical, C1-C3An alkoxy group; r2Selected from hydrogen, C1-C3An alkyl group; r5And R6Independently selected from hydrogen, C1-C3An alkyl group.
A further embodiment of the present invention provides compounds of the general formula (IAa) and physiologically acceptable salts thereof:
wherein R is1Selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy, halogen, substituted or unsubstituted phenyl, the substituent being selected from halogen, C1-C3Alkyl radical, C1-C3An alkoxy group; r5And R6Independently selected from hydrogen, C1-C3An alkyl group.
Another embodiment of the present invention provides a compound represented by the general formula (IB):
wherein R is5And R6Independently selected from hydrogen, C1-C3An alkyl group.
Still another embodiment of the present invention is to provide a compound represented by the general formula (IC):
wherein X is selected from oxygen or carbon atom; n is 0 or 1; r4Is selected from C1-C3Alkyl, trifluoromethyl or pyridyl.
In a further aspect of the present invention there is provided a compound of formula (ICa):
wherein R is4Is selected from C1-C3Alkyl, trifluoromethyl or pyridyl.
Still another embodiment of the present invention is to provide a compound represented by the general formula (ID):
wherein X is selected from oxygen or carbon atom; n is 0 or 1; r4Is selected from C1-C3Alkyl, trifluoromethyl or pyridyl.
Still another embodiment of the present invention is to provide a compound represented by the general formula (IDa):
wherein R is4Is selected from C1-C3Alkyl, trifluoromethyl or pyridyl.
In another aspect, the present invention provides the compound and physiologically acceptable salts thereof, wherein the compound is selected from the group consisting of:
the invention also provides a synthesis method of the compound shown in the formula I, which comprises the following steps:
1) and (3) carrying out nucleophilic reaction on the compound A and the compound B to generate an intermediate C, carrying out C-N coupling reaction on the intermediate C and the compound D to generate an intermediate E, and hydrolyzing the intermediate E to obtain the target compound of the formula IA.
Wherein m, W and R1、R2、R5And R6Is as defined for formula IA.
2) Nucleophilic reaction is carried out on mercaptobenzoic acid and ethyl bromoacetate to generate an intermediate F, acylation is carried out on the intermediate F and benzomorpholine to generate an intermediate G, and the intermediate G is hydrolyzed to obtain a target object IB.
Wherein R is5And R6Is as defined for formula IB.
3) Acylation reaction of compound H and nitrobenzoic acid to obtain intermediate J, reduction of intermediate J to obtain intermediate K, sulfonylation of intermediate K to obtain target IC
Wherein n, X, R4Is as defined for formula IC.
4) Acylation reaction is carried out on the compound H and nitrobenzoic acid to generate an intermediate J, the intermediate J is reduced to generate an intermediate K, and the intermediate K is acylated to generate a target object ID
Wherein n, X, R4Is as defined for general formula ID.
For the preparation of medicaments, the compounds of the formula I are mixed in a known manner with suitable pharmaceutical carrier substances, fragrances, flavors and colors in a known manner and are tableted or coated, or are suspended or dissolved in water or oil with other additional substances.
The invention also relates to a pharmaceutical composition containing a pharmaceutically effective dose of the compound shown in the general formula I and a pharmaceutically acceptable carrier.
Pharmacological research shows that the compound of the general formula I has the activity of inhibiting URAT1, and can effectively reduce the blood uric acid level in vivo, thereby achieving the purpose of treatment.
The compounds of the invention may be administered orally or parenterally. The oral preparation can be tablet, capsule, and coating agent, and the parenteral preparation can be injection and suppository. These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, coatings are the customary auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, etc. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.
The invention also provides application of the compound in preparing an hURAT1 inhibitor and in preparing a medicament for preventing or treating hyperuricemia or gout.
Drawings
FIG. 1: 1A and 1B are compounds TM-1 and TM-2 for pharmacodynamic evaluation of anti-acute hyperuricemia
FIG. 2: pharmacodynamic evaluation of compounds TM-1 and TM-2 against chronic hyperuricemia
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS) or High Resolution Mass Spectrometry (HRMS). NMR shifts () are given in parts per million (ppm). m.p. is the melting point given in ° c, the temperature is uncorrected. The column chromatography generally uses 200-300 mesh silica gel as a carrier. NMR was measured using INOVA-300 and CDCl as the solvent3、DMSO-D6The internal standard is TMS and the chemical shifts are given in ppm. MS was measured using an Agilent LC/MSD TOF LC/MS spectrometer.