MEDICAL USE OF PROSTACYCLIN RECEPTOR AGONIST

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 and/or preventing a high altitude disease. The high altitude disease is selected from an acute high altitude disease or a chronic high altitude disease generated in a high altitude environment with an altitude of 2,000 m or above.

Claims

1. 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, ##STR00039## wherein n is selected from 1 or 2; R.sub.1 is selected from H or F; R.sub.2 is selected from H, OH, NH.sub.2, halogen, C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl, wherein the C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl is optionally substituted with 1, 2 or 3 Rb; and the Rb is respectively and independently selected from F, Cl, Br, I, OH and NH.sub.2; R.sub.3 is selected from H, OH, NH.sub.2, halogen, C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl, wherein the C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl is optionally substituted with 1, 2 or 3 Rc; and the Rc is respectively and independently selected from F, Cl, Br, I, OH and NH.sub.2; R.sub.4 is selected from OH, C.sub.1-6 alkoxy or C.sub.1-6 alkyl-S(═O).sub.2—NH—, wherein the C.sub.1-6 alkoxy or C.sub.1-6 alkyl-S(═O).sub.2—NH— is optionally substituted with 1, 2 or 3 Rd; and the Rd is respectively and independently selected from F, Cl, Br, I, OH and NH.sub.2; a ring A is selected from phenyl or 5-6-membered heteroaryl; a ring B is selected from phenyl, 5-6-membered heteroaryl, C.sub.3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; T.sub.1 is selected from N or CH; T.sub.2 is selected from N or CH; T.sub.3 is selected from N or CH; T.sub.4 is selected from N or C(R.sub.5); T.sub.5 is selected from N, CH or C; is selected from ##STR00040## R.sub.5 is selected from H, OH, NH.sub.2, halogen, C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl, wherein the C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl is optionally substituted with 1, 2 or 3 Re; and the Re is respectively and independently selected from F, Cl, Br, I, OH and NH.sub.2; and the C.sub.1-6 heteroalkyl, 3- to 6-membered heterocycloalkyl or 5-6-membered heteroaryl each comprise 1, 2 or 3 heteroatoms or heteroatom groups independently selected from —O—, —NH—, —S— or N.

2. The application of claim 1, characterized in that in the general formula I, the R.sub.2 is selected from H, F, Cl, Br, I, OH, NH.sub.2, Me, CF.sub.3, ##STR00041##

3. The application of claim 1, characterized in that in the general formula I, the R.sub.3 is selected from H, F, Cl, Br, I, OH, NH.sub.2, Me, CF.sub.3, ##STR00042##

4. The application of claim 1, characterized in that in the general formula I, the R.sub.4 is selected from OH, ##STR00043##

5. The application of claim 1, characterized in that in the general formula I, the R.sub.5 is selected from H, OH, NH.sub.2, F, Cl, Br, I, Me or ##STR00044##

6. The application of claim 1, characterized in that in the general formula I, the ring A is selected from phenyl or pyridyl.

7. The application of claim 1, characterized in that in the general formula I, the ring B is selected from phenyl, pyridyl, thiazolyl or cyclohexyl.

8. The application of claim 1, characterized in that the compound as shown in the general formula I is sc0253, and a structural formula of the sc0253 is as follows: ##STR00045##

9. Application of claim 1, characterized in that 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 application of claim 9, characterized in that 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 hypotension or a mixed disease with coexistence of the heart disease and the polycythemia.

11. The application of claim 1, characterized in that 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

[0086] The embodiments of the present disclosure will be illustrated in detail below in connection with the drawings, wherein:

[0087] FIG. 1 shows a structure of a compound in conformity with a general formula I.

[0088] FIG. 2 shows a change of a mean pulmonary arterial pressure (mPAP) of rats in each group (a blank control group, a model group, an experimental group A and an experimental group B).

[0089] FIG. 3 shows a change of a right ventricular ejection fraction (RVEF) of rats in each group (the blank control group, the model group, the experimental group A and the experimental group B).

[0090] FIG. 4 shows a change of right ventricular fractional shortening (RVFS) of rats in each group (the blank control group, the model group, the experimental group A and the experimental group B).

[0091] FIG. 5 shows a change of a right ventricular hypertrophy index (RV/(LV+OS)) of rats in each group (the blank control group, the model group, the experimental group A and the experimental group B).

DETAILED DESCRIPTION

[0092] The technical solutions in the embodiments of the present disclosure will be described in a clearly and fully understandable way in connection with the drawings in 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

[0093] ##STR00035##

S1: Synthesis of Compound A

[0094] A synthesis route of a compound A is as follows:

##STR00036##

[0095] 2-amino-5-fluoropyridine (2 g, 17.84 mmol), phenylboronic acid (4.35 g, 35.68 mmol), copper acetate (3.24 g, 17.84 mmol) and pyridine (2.82 g, 35.68 mmol) are added into dichloromethane (20 mL), and after reaction liquid is stirred for 14 hours at the temperature of 25° C. in an oxygen atmosphere (15 psi), concentration is carried out to obtain a crude product. The crude product is subjected to column separation (an eluent: petroleum ether/ethyl acetate=25:1) to obtain the compound A. MS m/z: 189.0[M+H]+.

S2: Synthesis of Compound B

[0096] ##STR00037##

[0097] A compound B-1 (2 g, 8.57 mmol) is uniformly mixed with ethyl acetate hydrochloride (10.00 mL), a mixed solution is stirred for 0.5 hour at the temperature of 20° C., and after the reaction is finished, reaction liquid is filtered to obtain a compound B-2.

[0098] The compound B-2 (3 g) and piperidyl methanol (2.44 g, 21.14 mmol) as well as triethylamine (2.24 g, 22.15 mmol, 3.08 mL) are added into dioxane (60.00 mL), uniform mixing is carried out, and reaction liquid is stirred for 2 hours at the temperature of 105° C. After the reaction is finished, a solvent is removed under reduced pressure, and the obtained residue is subjected to column chromatography separation (a developing agent: petroleum ether/ethyl acetate=10:1 to 3:1) to obtain a compound B-3.

[0099] The compound B-3 (3 g) and tetrabutylammonium hydrogen sulfate (4.47 g, 13.18 mmol) are dissolved into methylbenzene (60.00 mL), the temperature is reduced to 0° C., stirring is carried out for 10 minutes, after a 40% potassium hydroxide solution (60 mL) is added into reaction liquid and stirring is carried out for 20 minutes, tert-butyl bromoacetate (7.71 g, 39.53 mmol, 5.84 mL) is added into the reaction liquid, and the reaction liquid is stirred for 12 hours at the temperature of 30° C. The obtained product is poured into water (20 mL), extraction is carried out by ethyl acetate (30 mL), and a separated organic phase is washed with a saturated salt solution (20 mL) and dried by anhydrous sodium sulfate. After filtering is carried out to remove a desiccant, a solvent is removed under reduced pressure, and the obtained residue is subjected to column chromatography separation (a developing agent: ethyl acetate/petroleum ether=1:4) to obtain the target compound B. MS m/z: 360.0 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.16 (s, 1H), 7.74 (s, 1H), 4.24 (br d, J=13.6 Hz, 2H), 4.07 (s, 2H), 3.63 (d, J=19.2 Hz, 2H), 3.37 (d, J=3.0 Hz, 1H), 3.30 (d, J=3.0 Hz, 1H), 2.04-1.73 (m, 4H), 1.50 (s, 9H).

S3: Synthesis of Compound C

[0100] The compound B (0.1 g), cesium carbonate (285.95 mg, 877.62 μmol), xantphos (33.85 mg, 58.51 μmol) and Pd(dba)2 (16.82 mg, 29.25 μmol) are added into a dioxane solution (10 mL) of the compound A (54.77 mg), and a reaction system is stirred for 12 hours at the temperature of 100° C. under the protection of nitrogen gas. Water (20 mL) is added into the reaction system for dilution, and extraction is carried out by ethyl acetate (10 mL*3). A mixed organic phase is washed with a saturated salt solution (20 mL) and dried by anhydrous sodium sulfate. Filtering is carried out, and the obtained filtrate is concentrated to obtain a crude product. The crude product is subjected to preparative thin layer chromatography (a ratio of petroleum ether to tetrahydrofuran is 2:1) separation to obtain a compound C. MS m/z: 512.2 [M+H]+.

##STR00038##

S4: Synthesis of Compound X

[0101] 10% sodium hydroxide (8 mL) is added into a methanol (10 mL) solution of the compound C, and a reaction system is stirred for 0.5 hour at the temperature of 45° C. Reaction liquid is concentrated, diluted by water (20 mL) and stirred for 2 minutes, pH of the reaction system is regulated into 5 by diluted hydrochloric acid (2N), and extraction is carried out by ethyl acetate (30 mL*2). A mixed organic phase is washed with a saturated salt solution (20 mL), dried by anhydrous sodium sulfate and filtered, and the obtained product is concentrated under the vacuum condition to obtain a crude product. The crude product is subjected to high performance liquid chromatography (HPLC) (neutral) separation to obtain the compound X. MS m/z: 456.0 [M+H]+. 1H NMR (CHLOROFORM-d, 400 MHz) δ ppm 8.21 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.43-7.35 (m, 4H), 7.28-7.24 (m, 1H), 7.19 (d, J=7.2 Hz, 2H), 7.10 (dd, J=3.6, 8.8 Hz, 1H), 4.14 (s, 2H), 3.90 (d, J=13.6 Hz, 2H), 3.58 (br d, J=19.2 Hz, 2H), 3.19 (t, J=12.0 Hz, 2H), 1.92-1.86 (m, 2H), 1.76-1.59 (m, 2H).

Embodiment 2

I Material and Method

1. Experimental Animals and Feeding

[0102] 40 SD rats (about 200 g, male, clean) are purchased from Beijing Vital River Laboratory Animal Technology Co. Ltd and have the license number of SCXK(Jing).sub.2016-0006. The SD rats are fed in a low-pressure oxygen cabin, and regularly fed with a complete nutritional feed under the conditions of the room temperature of 22 to 25° C. and the humidity of 30% to 50%.

2. Reagents and Sample Groups

[0103] A compound sc0253 is the compound X prepared in Embodiment 1 of the present disclosure;

[0104] HP-β-CD is purchased from solaxbio;

[0105] Solvent configuration: 20% of HP-β-CD and 80% of double distilled water, and pH=8.

Groups:

[0106] A blank control group: normal-pressure normal-oxygen feeding

[0107] A model group: a low-pressure low-oxygen cabin, and intragastric administration of a solvent

[0108] An experimental group A: a low-pressure low-oxygen cabin, and intragastric administration of sc0253 (5 mg/kg) as well as a solvent

[0109] An experimental group B: a low-pressure low-oxygen cabin, and intragastric administration of sc0253 (10 mg/kg) as well as a solvent

3. Instruments

[0110] 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);

[0111] A small animal breathing machine (kent scientific, the United States);

[0112] A multifunctional physiograph (Millar, the United States);

[0113] A small animal ultrasonic instrument (Visual Sonics Inc, Canada).

4. Experiment Design and Process

[0114] 40 rats are randomly divided into four groups, and each group includes 10 rats. 3 groups are placed into an experiment module, the pressure inside the module is regulated to 380 mmHg, a high altitude environment with an altitude of 5,500 meters is simulated, the experiment module is opened for 1 hour every day so as to add feed and water for animals and carry out corresponding medicine treatment, meanwhile, the environment where the rats are positioned are kept alternate day and night according to a ratio of 12h:12h, and after 14 days, intragastric administration is respectively carried out in which the solvent (the model group), the sc0253 (5 mg/kg) and the solvent (the experimental group A) or the sc0253 (10 mg/kg) and the solvent (the experimental group B) are respectively applied, and the operation is carried out twice every day and continued for 14 days. Rats in the fourth group are placed in the same room to be fed in the normal-pressure normal-oxygen environment (the blank control group).

5. Index Detection Method

[0115] 3% pentobarbital sodium (0.2 mL/100 g) is intraperitoneally injected to anesthetize the rats, and ultrasonic detection is carried out. The following ultrasonic data is recorded: right ventricular ejection fraction (RVEF); and right ventricular fractional shortening (RVFS). Then the anesthetized rats are fixed on an operating table in a supine position mode, tracheotomy is carried out, a breathing machine is connected, thoracotomy is carried out to expose the hearts, a catheter is inserted into each right ventricle, right heart catheterization is carried out, and the right ventricular systolic pressure is recorded. Then each catheter is slowly pushed forwards, and 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. The rats are executed, the hearts are taken out, the atrial tissue and attached fat are removed, left and right ventricles are separated, moisture is sucked up by filter paper, the weights of the right ventricles and the left ventricles are respectively weighed, and (RV/(LV+IS)) is calculated.

6. Statistical Method

[0116] 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 SPSS19.0 software package.

II Experimental Result

[0117] 1. Influence on Rat mPAP

[0118] After the rats are fed for 14 days in a low-pressure low-oxygen environment, compared with the blank control group, the mPAP of the rats in the model group is obviously increased and the difference has significance (P<0.001). In the low-pressure low-oxygen environment, compared with the model group, the mPAP of the rats in the experimental group A (the compound sc0253-5 mg/kg) and the experimental group B (sc0253-10 mg/kg) is obviously reduced and the difference has statistical significance (P<0.05).

2. Influence on Rat RVEF and RVFS

[0119] After the rats are fed for 14 days in the low-pressure low-oxygen environment, compared with the blank control group, the RVEF and the RVFS of the rats in the model group are obvious reduced and the differences have significance (P<0.05). In the low-pressure low-oxygen environment, compared with the model group, the RVEF and the RVFS of the rats in the experimental group B (the compound sc0253-10 mg/kg) are obviously increased and the differences have statistical significance (P<0.01).

3. Influence on Rat RV/(LV+OS)

[0120] After the rats are fed for 14 days in the low-pressure low-oxygen environment, compared with the blank control group, the RV/(LV+OS) of the rats in the model group is obvious increased and the difference has significance (P<0.01). In the low-pressure low-oxygen environment, compared with the model group, the RV/(LV+OS) of the rats in the experimental group B (the compound sc0253-10 mg/kg) is obviously reduced and the difference has statistical significance (P<0.01).

[0121] 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 and particularly a prevention and treatment medicament with resistance to high altitude cardiopulmonary and blood vessel injuries.

[0122] 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.

[0123] In addition, it should be noted that each specific technical characteristic described in the specific embodiments, without conflict, may 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.