1,4-dihydropyridine-3,5-dicarboxylate derivatives and preparation and use thereof
The present invention relates to a 1,4-dihydropyridine-3,5-dicarboxylate compound of general compound (I), a process for preparing the same, a use thereof for the manufacture of a medicament for treating and/or preventing kidney injury, cardiovascular diseases and/or endocrine diseases, as well as a pharmaceutical composition and a pharmaceutical formulation containing said compounds, wherein the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, n 1 , n 2 , p and q are the same as those defined in the description.
1. A compound of general formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof:
wherein:
R 1 and R 4 are each independently selected from methyl, ethyl and ethoxymethyl that are unsubstituted or substituted by 1-3 Q 1 substituents, and the carbon atom(s) therein can be optionally replaced with 1-3 groups from O, N(H) x or C(O), wherein x is selected from 1 or 2; Q 1 is selected from halogen, hydroxy, amino, methoxy and ethoxy;
R 2 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, pyrrolidinylmethyl and morpholinylmethyl that are unsubstituted or substituted by 1-3 Q 2 substituents, Q 2 is selected from fluoro, chloro, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkyl and C 1-4 alkoxy that are substituted by 1-3 fluoro and/or chloro atoms;
R 3 is selected from hydrogen, fluoro, chloro and nitro;
R 5 and R 6 are each independently selected from methyl or ethyl that is unsubstituted or substituted by 1-3 Q 3 substituents, Q 3 is selected from fluoro, chloro, hydroxy, amino, methoxy and ethoxy;
R 7 and R 8 are each independently selected from hydrogen, methyl, ethyl, and phenylC 0-2 alkyl, pyridylC 0-2 alkyl, furylC 0-2 alkyl, thienylC 0-2 alkyl, pyrrolylC 0-2 alkyl, thiazolylC 0-2 alkyl and thiadiazolylC 0-2 alkyl that are unsubstituted or substituted by 1-3 Q 4 substituents, and R 7 and R 8 are not both hydrogen at the same time, Q 4 is selected from fluoro, chloro, hydroxy, amino, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy;
m is selected from 1, 2 or 3, when m is 2 or 3, R 3 can be identical or different;
n 1 is 2, n 2 is 1;
p and q are each independently selected from 0, 1, 2 or 3, wherein when q is 0, neither R 7 nor R 8 is phenylC 0-2 alkyl.
2. The compound of claim 1 , a pharmaceutically acceptable salt or a stereoisomer thereof:
wherein, R 1 and R 4 are each independently selected from methyl, ethyl or ethoxymethyl that are unsubstituted or substituted by 1-3 Q 1 substituents, wherein Q 1 is selected from fluoro, chloro, amino, methoxy or ethoxy;
R 2 is selected from methyl or ethyl that is unsubstituted or substituted by 1-3 Q 2 substituents, Q 2 is selected from fluoro, chloro, methyl, methoxy, or methoxy and ethoxy that are substituted by 1-3 fluoro, chloro atoms;
R 3 is selected from hydrogen, chloro or nitro;
R 5 is selected from methyl or ethyl that is unsubstituted or substituted by 1-3 Q 3 substituents, Q 3 is selected from fluoro, chloro, hydroxy or amino;
R 6 is selected from methyl that is unsubstituted or substituted by 1-3 Q 3 substituents, Q 3 is selected from fluoro, chloro, hydroxy or amino;
R 7 and R 8 are each independently selected from hydrogen, and phenyl, benzyl, pyridyl, furyl, thienyl, thiazolyl or pyrrolyl that is unsubstituted or substituted by 1-3 Q 4 substituents, and R 7 and R 8 are not both hydrogen at the same time,
Q 4 is selected from fluoro, chloro, hydroxy, amino, methyl, trifluoromethyl or methoxy;
m is 1;
n 1 is 2, n 2 is 1;
p and q are each independently selected from 0, 1 or 2, wherein when q is 0, neither R 7 nor R 8 is phenyl or benzyl.
3. The compound of claim 1 , a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound is selected from:
Compound
Structure
Chemical Name
2
3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
4
3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
6
3-[1-(2,2-diphenylethyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
8
3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
11
3-[1-(3,3-bis(4-fluorophenyl)propyl)- 3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
14
(4R)-3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
15
(4S)-3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
16
(S)-3-[(S)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
17
(S)-3-[(R)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
18
(4S)-3-[1-(2,2-diphenylethyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
19
(S)-3-[(R)-1-(2,2-diphenylethyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
20
(S)-3-[(S)-1-(2,2-diphenylethyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
27
(4S)-3-[1-(3,3-bis(4-fluorophenyl) propyl)-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
28
(S)-3-[(S)-1-(3,3-bis(4-fluorophenyl) propyl)-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
29
(S)-3-[(R)-1-(3,3-bis(4-fluorophenyl) propyl)-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
31
3-[1-(3,3-diphenylpropyl)-3- ethylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
35
3-[3-difluoromethyl-1-(3,3- diphenylpropyl)pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
36
3-[1-(3,3-bis(4-hydroxyphenyl) propyl-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
38
3-[3-aminomethyl-1-(3,3-diphenylpropyl) pyrrolidin-3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
40
3-[1-(3,3-diphenylpropyl)-3-methyl- pyrrolidin-3-yl] 5-isopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
42
3-[1-(3,3-diphenylpropyl)-3-methyl- pyrrolidin-3-yl] 5-(2-methoxyethyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
43
3-[3-methyl-1-(thiazol-2-ylmethyl) pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
44
3-[3-methyl-1-(pyrid-2-ylmethyl) pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
45
3-[3-methyl-1-(pyrid-3-ylmethyl) pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
46
3-[3-methyl-1-(pyrid-4-ylmethyl) pyrrolidin-3-yl]) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
47
3-[3-ethyl-1-(pyridine-3-ylmethyl) pyrrolidin-3-yl] 5-methyl 2-(2-aminoethoxy)methyl-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
48
3-[3-methyl-1-(pyridine-3-ylmethyl) pyrrolidin-3-yl] 5-methyl 2-(2-aminoethoxy)methyl-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
49
3-[3-methyl-1-(pyridine-2-ylmethyl) pyrrolidin-3-yl] 5-methyl 2-(2-aminoethoxy)methyl-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
50
3-[3-methyl-1-(thiazol-2-ylmethyl) pyrrolidin-3-yl] 5-methyl 2-(2-aminoethoxy)methyl-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
52
(S)-3-[(R)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
53
(S)-3-[(S)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
56
(S)-3-[(R)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2-(2-aminoethoxy)methyl-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
57
(S)-3-[(S)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2-(2-aminoethoxy)methyl-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
58
(R)-3-[(S)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2-(2-aminoethoxy)methyl-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
61
(S)-3-[(R)-1-(3,3-diphenylpropyl)-3- ethylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
62
(S)-3-[(S)-1-(3,3-diphenylpropyl)-3- ethylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
68
(S)-3-[(R)-3-difluoromethyl-1-(3,3- diphenylpropyl)pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
69
(S)-3-[(S)-1-(3,3-bis(4-hydroxyphenyl- propyl)-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
71
(S)-3-[(R)-3-aminomethyl-1-(3,3-diphenyl- propyl)pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
73
(S)-3-[(S)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-isopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
75
(R)-3-[(R)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-(2- methoxyethyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
76
(S)-3-[(R)-3-methyl-1-(thiazol-2- ylmethyl)pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
77
(S)-3-[(S)-3-ethyl-1-(pyridine-3- ylmethyl)pyrrolidin-3-yl] 5-methyl 2-(2-aminoethoxy)methyl-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
78
(R)-3-[(R)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
79
(R)-3-[(S)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate.
4. The compound of claim 1 , a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound is selected from
Compound
Structure
Chemical Name
2
3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
4
3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
6
3-[1-(2,2-diphenylethyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
8
3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2- chlorophenyl)-6-methyl-1,4- dihydropyridine-3,5-dicarboxylate
11
3-[1-(3,3-bis(4-fluorophenyl)propyl)- 3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
14
(4R)-3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
15
(4S)-3-[1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
16
(S)-3-[(S)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
17
(S)-3-[(R)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
18
(4S)-3-[1-(2,2-diphenylethyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
19
(S)-3-[(R)-1-(2,2-diphenylethyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
20
(S)-3-[(S)-1-(2,2-diphenylethyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
27
(4S)-3-[1-(3,3-bis(4-fluorophenyl)propyl)- 3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
78
(R)-3-[(R)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate
79
(R)-3-[(S)-1-(3,3-diphenylpropyl)-3- methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate.
5. A process for preparing the compound of general formula (I) of claim 1 , comprising the following steps:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, n 1 , n 2 , p and q are as defined in claim 1 ;
starting material 2=R 5 MgX, wherein X is Br or I;
starting material 2′=R 5 MgI,
starting material 3=
step 1:
starting material 1 and starting material 2 are subjected to a nucleophilic substitution reaction at a low temperature to produce intermediate 1; or
starting material 1′ and starting material 2′ are subjected to a nucleophilic substitution reaction to produce intermediate 1-1, which is subjected to a salification reaction with an acid HA to produce intermediate 1-2; the resulting intermediate 1-2 and starting material 3 are subjected to a coupling reaction to produce intermediate 1-3; and then intermediate 1-3 is reduced with a reductant to produce intermediate 1;
step 2:
starting material 4, starting material 5 and starting material 6 are subjected to a condensation reaction under reflux in an organic solvent to produce intermediate 2-1, which is hydrolyzed in the presence of a base to produce intermediate 2; and
step 3:
intermediate 2 and an acyl halide agent are reacted at a low temperature, and then the resulting material and intermediate 1 are subject to a hydrolyzation reaction under a basic condition at a low temperature to produce the compound of formula (I).
6. A pharmaceutical composition containing a compound of claim 1 , a pharmaceutically acceptable salt or a stereoisomer thereof.
7. A pharmaceutical composition containing a compound of claim 2 , a pharmaceutically acceptable salt or a stereoisomer thereof.
8. A pharmaceutical composition containing a compound of claim 3 , a pharmaceutically acceptable salt or a stereoisomer thereof.
9. A pharmaceutical composition containing a compound of claim 4 , a pharmaceutically acceptable salt or a stereoisomer thereof.
10. The pharmaceutical composition of claim 6 , further comprising therapeutic agent(s) selected from: angiotensin II antagonists or a pharmaceutically acceptable salt thereof; HMG-Co-A reductase inhibitors or a pharmaceutically acceptable salt thereof; aldosterone receptor antagonists (MRA) or a pharmaceutically acceptable salt thereof; angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) dual inhibitors or a pharmaceutically acceptable salt thereof; antidiabetics; weight-loss drugs; endothelin receptor blockers; CETP inhibitors; Na-K-ATPase membrane pump inhibitors; β-adrenergic receptor inhibitors; α-adrenergic receptor blockers; neutral endopeptidase (NEP) inhibitors and inotropic agents.
11. A pharmaceutical formulation containing a compound of claim 1 , a pharmaceutically acceptable salt or a stereoisomer thereof and one or more pharmaceutically acceptable carriers, in any one of pharmaceutically acceptable dosage forms.
12. A method for treating kidney injury, cardiovascular diseases and/or endocrine diseases, comprising the step of administrating a compound of claim 1 , a pharmaceutically acceptable salt or a stereoisomer thereof to a mammal in need thereof; wherein said diseases are selected from high blood pressure, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy, myocarditis, cardiovascular fibrosis, baroreceptor dysfunction, fluid overload and arhythmia, primary/secondary aldosteronism, Addison's disease, Cushing's syndrome and Bartter's syndrome.
13. The pharmaceutical composition of claim 10 , wherein the angiotensin II antagonists comprise losartan, valsartan, irbesartan, olmesartan, or candesartan.
14. The pharmaceutical composition of claim 10 , wherein the HMG-Co-A reductase inhibitors comprise lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, cerivastatin, Rosuvastatin.
15. The pharmaceutical composition of claim 10 , wherein the aldosterone receptor antagonists (MRA) comprise spironolactone or eplerenone.
16. The pharmaceutical composition of claim 10 , wherein the angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) dual inhibitors comprise captopril, alacepril, enalapril, lisinopril, perindopril, ramipril, quinapril, delapril, cilazapril, benazepril, spirapril, trandolapril, moexipril, imidapril, or fosinopril.
17. The pharmaceutical composition of claim 10 , wherein the antidiabetics comprise metformin, glibenclamide, glipizide, glibornuride, gliclazide, gliquidone, sitagliptin, vildagliptin, saxagliptin, alogliptin benzoate, or linagliptin.
18. The pharmaceutical composition of claim 10 , wherein the endothelin receptor blockers comprise bosentan.
19. The pharmaceutical composition of claim 10 , wherein the β-adrenergic receptor inhibitors comprise metoprolol or carvedilol.
20. The pharmaceutical composition of claim 10 , wherein the α-adrenergic receptor blockers comprise prazosin, terazosin, or doxazosin.
21. A compound of one of the following structures:
Compound
Structure
Chemical Name
5
3-(1-phenylethyl-3-methylpyrrolidin-3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate;
21
(4S)-3-[3-methyl-1-(3- phenylpropyl)pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate;
22
(4S)-3-(3-methyl-1-phenylethylpyrrolidin- 3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate;
or a pharmaceutically acceptable salt or a stereoisomer thereof.