Medical application of pyrimidine sulfonamides derivatives

Abstract

The present disclosure provides application of a compound in conformity with a general formula I and an isomer or pharmaceutically acceptable salt thereof to preparation of a medicinal composition for treating or preventing a high altitude disease. The high altitude disease is selected from an acute high altitude disease and a chronic high altitude disease generated in a high altitude environment with an altitude of 2,000 m or above.

Claims

1. A method for treating or preventing a high altitude disease with a medicinal composition, comprising: administering a therapeutically effective amount of a compound in conformity with a general formula I and an isomer or pharmaceutically acceptable salt thereof, ##STR00036## wherein R.sub.1 is selected from H, F, Cl, Br, I, OH or NH.sub.2; R.sub.2 is selected from H or C.sub.1-3 alkyl, and the C.sub.1-3 alkyl is optionally substituted with 1, 2 or 3 X; R.sub.3 is selected from H, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, -C.sub.1-3 alkyl-C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkyl and —C.sub.1-3 alkyl-3- to 7-membered heterocycloalkyl, and the C.sub.1-6 alkyl, the C.sub.1-6 heteroalkyl, the -C.sub.1-3 alkyl-C.sub.3-6 cycloalkyl, the C.sub.3-6 cycloalkyl or the -C.sub.1-3 alkyl-3- to 7-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 X; or, R.sub.2 and R.sub.3 are connected to form a 3- to 8-membered ring optionally substituted with 1, 2 or 3 X; a ring B is selected from 3- to 7-membered heterocycloalkyl or 5-6-membered heteroaryl, and the 3- to 7-membered heterocycloalkyl or the 5-6-membered heteroaryl is optionally substituted with 1, 2 or 3 X; X is respectively and independently selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl, and the C.sub.1-6 alkyl or the C.sub.1-6 heteroalkyl is optionally substituted with 1, 2 or 3 X′; X′ is respectively and independently selected from F, Cl, Br, I, OH, NH.sub.2, CN, Me, CH.sub.2F, CHF.sub.2, CF.sub.3 and Et; and the C.sub.1-6 heteroalkyl, the 3- to 7-membered heterocycloalkyl and the 5-6-membered heteroaryl each comprise 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, —O—, —S—, —NH—, —S(═O).sub.2- or —S(═O)—.

2. The method of claim 1, wherein the X is selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, Me, CH.sub.2F, CHF.sub.2, CF.sub.3, Et, ##STR00037##

3. The method of claim 1, wherein the ring B is selected from tetrahydrofuryl, tetrahydrothienyl, 1,3-dioxolanyl, pyrrolidyl, thiazolyl, pyrazolyl or imidazolyl, and the tetrahydrofuryl, the tetrahydrothienyl, the 1,3-dioxolanyl, the pyrrolidyl, the thiazolyl, the pyrazolyl or the imidazolyl is optionally substituted with 1, 2 or 3 X.

4. The method of claim 1, wherein the R.sub.3 is selected from H or Me.

5. The method of claim 1, wherein the R.sub.3 is selected from H, Me, Et, ##STR00038##

6. The method of claim 1, wherein the R.sub.2 and the R.sub.3 are connected to form 6- to 8-membered heterocycloalkyl, and the obtained 6- to 8-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 X.

7. The method of claim 1, wherein the R.sub.1 is selected from H, F, Cl, Br, I, OH or NH.sub.2; the X is selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, Me, CH.sub.2F CHF.sub.2, CF.sub.3, Et, ##STR00039## the ring B is selected from tetrahydrofuryl, tetrahydrothienyl, 1,3-dioxolanyl, pyrrolidyl, thiazolyl, pyrazolyl or imidazolyl, and the tetrahydrofuryl, the tetrahydrothienyl, the 1,3-dioxolanyl, the pyrrolidyl, the thiazolyl, the pyrazolyl or the imidazolyl is optionally substituted with 1, 2 or 3 X; the R.sub.2 is selected from H or Me; and the R.sub.3 is selected from H, Me, Et, ##STR00040##

8. The method of claim 1, wherein the compound as shown in the general formula I is SC0062, and a structural formula of the SC0062 is as follows: ##STR00041##

9. The method of claim 1, wherein the high altitude disease is selected from an acute high altitude disease and a chronic high altitude disease generated in a high altitude environment.

10. The method of claim 9, wherein the acute high altitude disease is selected from high altitude coma, high altitude cerebral edema, high altitude pulmonary edema or a mixed disease with coexistence of cerebral and pulmonary abnormality symptoms; and/or the chronic high altitude disease is selected from a high altitude heart disease, high altitude polycythemia, high altitude hypertension, high altitude hypotention or a mixed disease with coexistence of the heart disease and the polycythemia.

11. The method of claim 1, wherein the medicinal composition comprises the compound which is used as an active ingredient and has the general formula I, the isomer or the pharmaceutically acceptable salt of the compound, and a medicinal auxiliary material.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The embodiments of the present disclosure will be illustrated in detail below in connection with the drawings, wherein:

(2) FIG. 1 shows a structure of a compound in conformity with a general formula I.

DETAILED DESCRIPTION

(3) Clear and full description will be carried out below in connection with the technical solution of the embodiments of the present disclosure. It is obvious that the described embodiments are just a part but not all of the embodiments of the present disclosure. Based on the embodiments of the present disclosure, those of ordinary skill in the art can obtain other embodiment(s), without any inventive work, which should be within the scope of protection of the present disclosure.

Embodiment 1

(4) Preparation steps of a target compound

(5) ##STR00029##
X are as follows:

(6) S1, Synthesis of Compound F

(7) ##STR00030##

(8) 1) At the room temperature, a compound A (30.00 g, 211.97 mmol, 18.40 mL) is dissolved in dichloromethane (200 mL), then cooling is carried out to the temperature of 0° C., a dichloromethane (100 mL) solution of tert-butyl alcohol (15.71 g, 211.97 mmol, 20.40 mL) is slowly added (the dropwise adding time is about 1 hour), and a reaction mixture is heated to the room temperature and stirred for 1 hour. A target compound B (a crude product) is reserved in the reaction solvent dichloromethane and directly used for the subsequent reaction.

(9) ##STR00031##

(10) 2) At the room temperature, compounds 2-methoxyethylamine (2.00 g, 26.63 mmol, 2.33 mL) and triethylamine (5.39 g, 53.26 mmol, 7.38 mL) are dissolved into dichloromethane (100.00 mL), then a reaction mixture is cooled to the temperature of 0° C., a dichloromethane solution of the compound B (26.63 mmol, the crude product) is slowly added into the above reaction liquid (the dropwise adding time is about 0.5 hour), and the reaction mixture is heated to the room temperature and stirred for 15 hours. After the reaction is finished, the solvent is removed under reduced pressure, water (100 mL) is added into the obtained residue, pH is regulated to 5 by 1M hydrochloric acid, and extraction is carried out by ethyl acetate (100 mL×3). Organic phases are mixed, washing is carried out by a saturated salt solution (100 mL), drying is carried out by anhydrous sodium sulfate, filtering is carried out, and the solvent is removed from the obtained filtrate under reduced pressure so as to obtain a target compound C (white solid, 6.00 g, the yield of 88.59%). 1H NMR (400 MHz, CDCl.sub.3) δ: 7.37 (s, 1H) 5.50 (br s, 1H) 3.53 (t, J=5.0 Hz, 2H), 3.40 (s, 3H), 3.26 (d, J=4.8 Hz, 2H) 1.51 (s, 9H).

(11) ##STR00032##

(12) 3) At the room temperature, the compound C (6.00 g, 23.59 mmol) is added into water (100.00 mL), and a reaction mixture is heated to the temperature of 100° C. and stirred for 1 hour. After the reaction is finished, cooling is carried out to the room temperature, and extraction is carried out by ethyl acetate (100 mL×3). Organic phases are mixed, washing is carried out by a saturated salt solution (100 mL), drying is carried out by anhydrous sodium sulfate, filtering is carried out, and the solvent is removed from the obtained filtrate under reduced pressure so as to obtain a target compound D (yellow solid, 2.00 g, the yield of 54.99%). 1H NMR (400 MHz, CDCl3) δ: 5.52 (br s, 2H), 3.58-3.48 (m, 2H), 3.41-3.19 (m, 5H).

(13) ##STR00033##

(14) 4) At the room temperature, the compound D (1.12 g, 7.24 mmol) and potassium tert-butoxide (2.22 g, 19.75 mmol) are added into dimethyl sulfoxide (20.00 mL), a reaction mixture is stirred for 0.5 hour at the room temperature, then 5-bromo-4,6-dichloropyrimidine (1.50 g, 6.58 mmol) is added into the above reaction liquid, and the reaction mixture is continuously stirred for 6 hours at the room temperature. After the reaction is finished, water (100 mL) is added, pH is regulated to 6 by 1M diluted hydrochloric acid, and extraction is carried out by ethyl acetate (100 mL×3). Organic phases are mixed, washing is carried out by a saturated salt solution (100 mL), drying is carried out by anhydrous sodium sulfate, filtering is carried out, the solvent is removed from the obtained filtrate under reduced pressure, and the obtained residue is subjected to column chromatography (an eluent: a volume ratio of dichloromethane to methyl alcohol is 30:1) separation so as to obtain a target compound E (yellow solid, 1.40 g, the yield of 61.56%). 1H NMR (400 MHz, CDCl3) δ: 8.57 (s, 1H), 7.89 (br s, 1H), 5.99 (br s, 1H), 3.36 (br d, J=2.3 Hz, 2H), 3.32-3.20 (m, 5H).

(15) ##STR00034##

(16) 5) At the room temperature, potassium tert-butoxide (1.36 g, 12.15 mmol) is added into ethylene glycol (22.20 g, 357.66 mmol, 20.00 mL), a reaction mixture is heated to the temperature of 40° C. and stirred for 0.5 hour, then an ethylene glycol dimethyl ether (10.00 mL) solution of the compound E (1.40 g, 4.05 mmol) is added into the above solution, and the reaction mixture is heated to the temperature of 110° C. and continuously stirred for 12 hours. After the reaction is finished, cooling is carried out to the room temperature, water (50 mL) is added, pH is regulated to 3 by 1M diluted hydrochloric acid, and extraction is carried out by ethyl acetate (50 mL×3). Organic phases are mixed, washing is carried out by a saturated salt solution (50 mL), drying is carried out by anhydrous sodium sulfate, filtering is carried out, the solvent is removed from the obtained filtrate under reduced pressure, and the obtained residue is subjected to column chromatography (an eluent: a volume ratio of dichloromethane to methyl alcohol is 20:1) separation so as to obtain the target compound F (yellow solid, 1.20 g, the yield of 76.63%). MS-ESI m/z: 370.8 [M+H]+, 372.8 [M+H]+. 1H NMR (400 MHz, CDCl3) δ: 8.39 (s, 1H), 7.64 (br s, 1H), 6.03-5.94 (m, 1H), 4.65-4.54 (m, 2H), 3.99 (d, J=3.0 Hz, 2H), 3.49 (t, 0.7=5.0 Hz, 2H), 3.33-3.19 (m, 5H), 2.39 (t, J=5.3 Hz, 1H).

(17) S2: Synthesis of Compound H

(18) ##STR00035##

(19) At the room temperature, a compound G (3.00 g, 14.92 mmol), bis(pinacolato)diboron (7.58 g, 29.84 mmol) and potassium acetate (4.39 g, 44.76 mmol) are added into 1,4-dioxane (30.00 mL), then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (3.28 g, 4.48 mmol) is added, and under the protection of nitrogen gas, a reaction mixture is heated to the temperature of 80° C. and stirred for 16 hours. After the reaction is finished, cooling is carried out to the room temperature, filtering is carried out, the solvent is removed from the obtained filtrate under reduced pressure, water (30 mL) is added into the obtained residue, and extraction is carried out by ethyl acetate (20 mL×3). Organic phases are mixed, and drying is carried out by anhydrous sodium sulfate. Filtering is carried out, the solvent is removed from the obtained filtrate under reduced pressure, and the obtained residue is subjected to column chromatography (an eluent: a volume ratio of petroleum ether to ethyl acetate is 1:0 to 100:1) separation so as to obtain the target compound H. 1H NMR (400 MHz, CDCl3) δ: 7.38 (dd, 0.7=7.8, 0.8 Hz, 1H), 7.26 (s, 1H), 6.85 (d, J=7.8 Hz, 1H), 5.97 (s, 2H), 1.35 (s, 12H).

(20) S3: Synthesis of Compound I

(21) At the room temperature, the compound F (300.00 mg), the compound H (419.04 mg) and potassium phosphate (537.83 mg, 2.53 mmol) are added into N,N-dimethylformamide (20.00 mL), then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (185.39 g, 253.37 μmol) is added, and under the protection of nitrogen gas, a reaction mixture is heated to the temperature of 80° C. and stirred for 16 hours. After the reaction is finished, cooling is carried out to the room temperature, water (100 mL) is added, extraction is carried out by ethyl acetate (20 mL×1), and an organic phase is discarded. pH of a water phase is regulated to 5 to 6 by 3M diluted hydrochloric acid, and extraction is carried out by ethyl acetate (20 mL×3). The organic phases are mixed, drying is carried out by anhydrous sodium sulfate, filtering is carried out, the solvent is removed from the obtained filtrate under reduced pressure, and the obtained residue is subjected to preparative chromatography plate (an eluent: a volume ratio of petroleum ether to ethyl acetate is 1:2) separation so as to obtain the compound I.

(22) S4: Synthesis of Compound X

(23) At the room temperature, sodium hydride (145.30 mg, 3.63 mmol, the purity of 60%) is added into anhydrous tetrahydrofuran (20 mL), then an anhydrous N,N-dimethylformamide (1 mL) solution of the compound I (180.00 mg, 454.06 μmol) and an anhydrous tetrahydrofuran (1 mL) solution of 5-bromo-2-chloropyrimidine (175.66 mg, 908.13 μmol) are respectively added, and under the protection of nitrogen gas, a reaction mixture is heated to the temperature of 70° C. and stirred for 2 hours.

(24) After the reaction is finished, cooling is carried out to the room temperature, a saturated ammonium chloride solution (30 mL) is added, pH is regulated to 4 to 5 by 1M diluted hydrochloric acid, and extraction is carried out by ethyl acetate (20 mL×3). Organic phases are mixed, washing is carried out by a saturated salt solution (50 mL), drying is carried out by anhydrous sodium sulfate, filtering is carried out, the solvent is removed from the obtained filtrate under reduced pressure, and the obtained residue is subjected to preparative high performance liquid chromatography (HPLC) separation so as to obtain the target compound X. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 8.49 (s, 2H), 8.46 (s, 1H), 6.97 (s, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.68-6.43 (m, 2H), 6.02-5.91 (m, 3H), 4.71-4.61 (m, 2H), 4.60-4.52 (m, 2H), 3.42 (t, J=5.0 Hz, 2H), 3.22 (s, 3H), 3.13-3.01 (M, 2H). Liquid chromatography mass spectrometry (LCMS) data is that MS-ESI m/z: 569.0 [M+H]+, 571.0 [M+H+2]+.

Embodiment 2

(25) I Material and Method

(26) 1. Experimental Animals and Feeding

(27) 40 healthy SD rats (180-220 g, male) are purchased from Beijing Vital River Laboratory Animal Technology Co. Ltd, belong to the SPF grade and have the license number of SCXK(Jing)2016-0006. The healthy SD rats are fed in a low-pressure oxygen cabin, and regularly fed with a complete nutritional feed under the conditions of the temperature of 22 to 25° C. and the humidity of 30% to 50%.

(28) 2. Reagents and Sample Groups

(29) SC0062 is the compound X prepared in Embodiment 1 of the present disclosure; Solutol is purchased from Beijing Taize Jiaye Technology Development Co., Ltd.; HP-β-CD is purchased from solaxbio, with the specification of 25 mg per pack and CAS of 128446-35-5;

(30) Solvent configuration: 5% of DMSO and 95% of normal saline with 10% of HP-β-CD, and pH=9.

(31) Groups:

(32) A blank control group: normal-pressure normal-oxygen feeding

(33) A model group: a low-pressure low-oxygen cabin, and intragastric administration of a solvent

(34) An experimental group A: a low-pressure low-oxygen cabin, and intragastric administration of sc0062 (15 mg/kg) as well as a solvent

(35) An experimental group B: a low-pressure low-oxygen cabin, and intragastric administration of sc0062 (30 mg/kg) as well as a solvent

(36) 3. Instruments

(37) A multi-factor composite environment simulated medical science experiment module (the type of DYC-3285, the Instrument Center of the Beijing Military Medical Science Academy);

(38) A small animal breathing machine (kent scientific, the United States);

(39) A multifunctional physiograph (Millar, the United States);

(40) A full-automatic animal blood cell analysis meter (Mindray Co., Ltd); and

(41) A small animal ultrasonic instrument (Visual Sonics Inc, Canada).

(42) 4. Experiment Design and Process

(43) 40 rats are randomly divided into four groups, each group includes 10 rats, 3 groups are placed into a low-pressure low-oxygen cabin, the pressure of the oxygen cabin is regulated to 380 mmHg, a high altitude environment with an altitude of 5,500 meters is simulated, the low-pressure low-oxygen cabin is opened for 1 hour every day so as to add foods and water for animals and carry out corresponding medicine treatment, and meanwhile, the environment where the rats are positioned are kept alternate day and night according to a ratio of 12 h:12 h. After 3 groups of rats are in the oxygen-poor environment for 14 days, intragastric administration is respectively carried out on the 3 groups of rats, the solvent (the model group), the sc0062 (15 mg/kg) and the solvent (the experimental group A) and the sc0062 (30 mg/kg) and the solvent (the experimental group B) are respectively applied to the 3 groups of rats, and the operation is continued for 14 days. Rats in the fourth group (the blank control group) are placed in the same room to be fed in the normal-pressure normal-oxygen environment.

(44) 5. Index Detection Method

(45) 3% pentobarbital sodium (0.2 mL/100 g) is intraperitoneally injected to anesthetize the rats, ultrasonic detection is carried out, and the following ultrasonic data is recorded: PAT/PET (pulmonary arterial blood flow acceleration time/right ventricular pre-ejection period); right ventricular ejection fraction EF; a right ventricular fractional shortening FS; and tricuspid annular plane systolic excursion TAPSE. The anesthetize rats are fixed on an operating table in a supine position mode, tracheotomy is carried out, a breathing machine is connected, and thoracotomy is carried out to expose the hearts. A catheter is inserted into each right ventricle, and the right ventricular systolic pressure is recorded. Then each catheter is slowly pushed forwards, can reach a corresponding pulmonary artery through a corresponding right ventricular outflow tract, the pressure waveform of a monitor is observed, and the mean pulmonary arterial pressure mPAP is recorded. Blood is collected and the rats are executed. The hearts and the lung tissue are taken out, the atrial tissue and the root of the main artery are removed, left and right ventricles are separated, bloodstain is washed out in PBS, moisture is sucked up by filter paper, and the weight of the right ventricles (RV) and the weight of the left ventricles and the atrioventricular septum (LV+IS) are respectively weighed. Calculation is carried out according to the following formula: right ventricular hypertrophy index=RV/(LV+IS).

(46) 6. Statistical Method

(47) All the data is represented by x±s, comparison among the groups is single factor analysis of variance, when P<0.05, it represents that the difference has a statistical significance, and statistical treatment is carried out by adopting an SPSS 22.0 software package.

(48) II Experimental Result

(49) 1. Influence on Rat Echocardiography

(50) The right ventricular function of the model group (the solvent group) in the low-pressure low-oxygen cabin is obviously reduced, and has the obvious difference from that of the blank control group. The EF value, the FS value and the TAPSE value are significantly reduced (p<0.01), the PAT/PET value is reduced, and both of them have the statistic differences (p<0.05). Compared with the model group, the experimental group A and the experimental group B are remarkably improved in EF value and FS value and are obviously increased in TAPSE value and PAT/PET value, and the specific data are as shown in Table 1.

(51) TABLE-US-00001 TABLE 1 Changes of parameters EF, FS, TAPSE and PAT/PET after echocardiography on each group of rats Right Right Groups ventricular EF ventricular FS PAT/PET TAPSE Blank control 80.61 ± 6.65  48.3 ± 6.96 0.39 ± 0.08 3.05 ± 0.71 group Model group 50.51 ± 13.51 25.13 ± 8.28  0.35 ± 0.05 1.66 ± 0.31 A: sc0062 67.25 ± 13.01 37.02 ± 10.63 0.39 ± 0.07 2.05 ± 0.29 (15 mg/kg) B: sc0062 71.32 ± 9.35  39.76 ± 7.24  0.40 ± 0.07 1.93 ± 0.44 (30 mg/kg)

(52) 2. Influence on Rat Haemodynamics

(53) The mean pulmonary arterial pressure of the model group (the solvent group) in the low-pressure low-oxygen cabin is obviously raised, and has the significant difference (p<0.01) from that of the blank control group. Compared with the mean pulmonary arterial pressure of the model group, the mean pulmonary arterial pressures of the SC0062 treatment groups (the experimental groups A and B) are significantly raised (p<0.01), and the specific data is as shown in Table 2.

(54) TABLE-US-00002 TABLE 2 Influence of compounds prepared in Embodiment 1 of the present disclosure on pulmonary arterial hypertension of model rats Groups mPVP Blank control group 14.35 ± 3.41 Model group 36.63 ± 3.03 Experimental group A: sc0062 31.39 ± 3.90 (15 mg/kg) Experimental group B: sc0062 26.91 ± 4.35 (30 mg/kg)

(55) 3. Influence on Rat Right Ventricular Hypertrophy

(56) The right ventricular hypertrophy index of the model group (the solvent group) in the low-pressure low-oxygen cabin is obviously increased, and has the significant difference (p<0.01) from that of the blank control group. Compared with the right ventricular hypertrophy index of the model group, the right ventricular hypertrophy indexes of the SC0062 groups (the experimental groups A and B) are reduced, there is a statistic difference (p<0.05), and the specific data is as shown in Table 3.

(57) TABLE-US-00003 TABLE 3 Change situations of right ventricular hypertrophy indexes of each group of rats Groups RV Full heart RV/(LV + IS) Blank control group 0.27 ± 0.02 1.22 ± 0.08 0.28 ± 0.04 Model group 0.57 ± 0.81 1.38 ± 0.20 0.71 ± 0.15 Experimental group A: 0.56 ± 0.09 1.47 ± 0.24 0.38 ± 0.02 sc0062 (15 mg/kg) Experimental group B: 0.48 ± 0.11 1.30 ± 0.21 0.36 ± 0.02 sc0062 (30 mg/kg)

(58) From the above, the compound provided by the present disclosure has treatment and/or prevention effects on the high altitude disease generated in the high altitude low-pressure low-oxygen environment, particularly has the very strong protection effect on the heart and the lung in the high altitude low-pressure low-oxygen environment, and can be developed into a medicament for preventing and treating the high altitude disease.

(59) The preferred embodiments of the present disclosure are described in detail above, but the present disclosure is not limited to the specific details in the above-mentioned embodiments. Various simple modifications can be made to the technical solution of the present disclosure within the scope of the technical concept of the present disclosure, and those simple modifications all shall fall within the scope of protection of the present disclosure.

(60) In addition, it should be noted that each specific technical characteristic described in the specific embodiments, without conflict, can be combined in any proper mode, and in order to avoid unnecessary repetition, various possible combination modes will not be additionally illustrated in the present disclosure.