CN102372692B - Dihydropyridine derivative - Google Patents
Dihydropyridine derivative Download PDFInfo
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- CN102372692B CN102372692B CN201110245007.6A CN201110245007A CN102372692B CN 102372692 B CN102372692 B CN 102372692B CN 201110245007 A CN201110245007 A CN 201110245007A CN 102372692 B CN102372692 B CN 102372692B
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- methyl
- dihydropyridine
- benzyl
- nitrae
- isosorbide
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- 0 CC1=C(*)C(c2ccccc2Cl)C(C(O)=O)=C(COCC*)N1 Chemical compound CC1=C(*)C(c2ccccc2Cl)C(C(O)=O)=C(COCC*)N1 0.000 description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N BrCc1ccccc1 Chemical compound BrCc1ccccc1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- GWKNCILEWGLYSM-UHFFFAOYSA-N CC(C)(C)OC(N1CC(CC(C2)OC(C)=O)C2C1)=O Chemical compound CC(C)(C)OC(N1CC(CC(C2)OC(C)=O)C2C1)=O GWKNCILEWGLYSM-UHFFFAOYSA-N 0.000 description 1
- ZKXCMDBKBXJMBK-UHFFFAOYSA-N CC(C)(C)OC(N1CCC2(CC(CO)C2)CC1)=O Chemical compound CC(C)(C)OC(N1CCC2(CC(CO)C2)CC1)=O ZKXCMDBKBXJMBK-UHFFFAOYSA-N 0.000 description 1
- ZELJLECFTLYULH-UHFFFAOYSA-N CC(C)CNCc1ccccc1 Chemical compound CC(C)CNCc1ccccc1 ZELJLECFTLYULH-UHFFFAOYSA-N 0.000 description 1
- SZYWZQJFUAMMBM-UHFFFAOYSA-N CC(NC(C)=C(C1c2cccc([N+]([O-])=O)c2)C(OC2C(C3)N(Cc4ccccc4)CC3C2)=O)=C1C(OC)=O Chemical compound CC(NC(C)=C(C1c2cccc([N+]([O-])=O)c2)C(OC2C(C3)N(Cc4ccccc4)CC3C2)=O)=C1C(OC)=O SZYWZQJFUAMMBM-UHFFFAOYSA-N 0.000 description 1
- GBZLGIQGYNMCHE-UHFFFAOYSA-N CC(NC(COCCN)=C(C1c2ccccc2Cl)C(OC(C2)CC3C2CN(Cc2ccccc2)C3)=O)=C1C(OC)=O Chemical compound CC(NC(COCCN)=C(C1c2ccccc2Cl)C(OC(C2)CC3C2CN(Cc2ccccc2)C3)=O)=C1C(OC)=O GBZLGIQGYNMCHE-UHFFFAOYSA-N 0.000 description 1
- WJMGEWXPRVDNJN-UHFFFAOYSA-N CC(OCC(C1)CC(C2)C1CN2C(c1ccccc1)c1ccccc1)=O Chemical compound CC(OCC(C1)CC(C2)C1CN2C(c1ccccc1)c1ccccc1)=O WJMGEWXPRVDNJN-UHFFFAOYSA-N 0.000 description 1
- JAMHTKXZOQLSDQ-UHFFFAOYSA-N CCOC(C(C1C(N2C(c3ccccc3)c3ccccc3)=O)C1C2=O)=O Chemical compound CCOC(C(C1C(N2C(c3ccccc3)c3ccccc3)=O)C1C2=O)=O JAMHTKXZOQLSDQ-UHFFFAOYSA-N 0.000 description 1
- RLINDRDQLDGCNP-UHFFFAOYSA-N O=CC(C1C(N2Cc3ccccc3)=O)C1C2=O Chemical compound O=CC(C1C(N2Cc3ccccc3)=O)C1C2=O RLINDRDQLDGCNP-UHFFFAOYSA-N 0.000 description 1
- AVUAEJJTHLWQOS-UHFFFAOYSA-N OC1C(C2)N(Cc3ccccc3)CC2C1 Chemical compound OC1C(C2)N(Cc3ccccc3)CC2C1 AVUAEJJTHLWQOS-UHFFFAOYSA-N 0.000 description 1
- AUBJWMXFVGCAGR-UHFFFAOYSA-N OC1C(C2)NCC2C1 Chemical compound OC1C(C2)NCC2C1 AUBJWMXFVGCAGR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of medicine, particularly relates to a dihydropyridine derivative disclosed in a general formula (I) and clinically-acceptable salt thereof, wherein R1, R2, R3, R4, R5, X or n is defined as in a specification. The invention also relates to a preparation method of the compounds and the application of the compounds in preparing medicines capable of treating hypertension.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to dihydrogen pyridine derivative, its pharmacy acceptable salt or its steric isomer, the preparation method of these compounds, and the purposes of these compounds in the hypertensive medicine of preparation treatment.
2, background technology
Dihydropyridine calcium ion channel blocker is the medicine that has been used for the treatment of cardiovascular disorder since 20 century 70s, its by with protein receptor binding, optionally block Ca
2+interior stream, reduces Ca in cell
2+concentration, thus cardiovascular function changed, the heart, the cerebrovascular are played a protective role.Dihydropyridine calcium ion channel blocker has the blood vessel selectivity of height, and antihypertensive effect is clear and definite, applied widely, is widely used clinically, has become first-selected antihypertensive drugs.
Listing kind great majority are L-type calcium ion channel blockers, according to its effect length and pharmacological characteristic, are mainly divided into three generations.The first-generation is mainly traditional fugitive retarding agent, represent that medicine is nifedipine (nifedipine), this class medicine peak time is short, acting duration is short, often repeatedly take medicine day by day, in one day, can cause the very great fluctuation process of blood pressure, cause that heartbeat is overrun, peripheral vasodilation, glandular secretion, increase the risk that ischemic heart disease occurs, there is obvious heart negative effects (conductivity effect, chronotropismus and Negative Inotropic Effect), the danger that hyperpietic has a heart attack is increased; Can cause reflectivity sympathetic activation, cause myocardial oxygen consumption to increase, easily bring out irregular pulse, myocardial infarction, can not effectively reduce the M & M of cardiovascular and cerebrovascular disease.Second on behalf of middle effect retarding agent, has good pharmacokinetics character and blood vessel selectivity.Its coronary vasodilation is stronger, has longer plasma half-life, acts on the length of holding time, it represents that medicine has benidipine (benidipine), this class drug bioavailability is lower, and plasma concentration fluctuation in paddy peak is large, and main side reaction is that peripheral blood vessel expansion causes ankle edema.The third generation is long-acting retarding agent, with acceptor or structural constituent slowly, be firmly combined, onset is slow, effect is lasting, represents that medicine is amlodipine (amlodipine), however its peripheral blood vessel expansion causes that ankle edema incidence is higher.Along with the development of L-type calcium ion channel blocker, pharmacologically active and pharmacokinetics feature all make moderate progress, but the various side effects of long-term prescription are not solved.
Research discovery, L-type calcium channel is mainly distributed in kidney afferent glomerular arteriole, and T-type calcium channel all has distribution at kidney afferent glomerular arteriole and kidney efferent glomerular arteriole.Retardance T-type calcium channel can cause that kidney efferent glomerular arteriole produces diastole effect, reduces capillary pressure, weakens capillary permeability, thereby reduce renal glomerulus pressure, reduces the generation of urine protein, protection kidney; Meanwhile, alleviate liquid filtration, reduce oedema incidence.Research is discovery also, and T-type calcium channel, except regulating blood pressure, can also be dominated cardiac structure, can regulate heartbeat, adjust blood flow rate, has cardioprotection.The result for the treatment of of typical T-type calcium ion channel blocker Mibefradil (Mibefradil) has further confirmed above-mentioned conclusion.
Therefore, in retardance L-type calcium channel, retardance T-type calcium channel; not only produce the hypertensive effect for the treatment of, solve the side effect that L-type calcium ion channel blocker cannot overcome, can also bring into play heart, Renoprotective Effect; and alleviation ankle edema is urgent clinical needs.
3, summary of the invention
The present invention be take and developed that good to have the medicine that hypotensive effect, Renoprotective Effect can alleviate again oedema side effect be target, has found to have the dihydrogen pyridine derivative of L-type and the dual calcium channel retardation of T-type.
Concrete technical scheme, provides the compound shown in following general formula (I), its pharmacy acceptable salt or its steric isomer:
Wherein, R
1be selected from and be not substituted or by 1 to 3 substituting group Q
1the following group replacing:
6-10 unit also encircles C
0-6alkyl, the volution C of 6-10 unit
0-6alkyl or the bridged ring C of 6-10 unit
0-6alkyl, and the carbon atom in described and ring, volution or bridged ring can be by 1～3 O, S (O)
m, N (H)
m, NCH
3or C (O) replacement,
Q
1independently selected from:
(1) halogen atom, hydroxyl, amino, carboxyl, carbonyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, or by halogen atom, hydroxyl, amino replacement or unsubstituted C
1-6alkyl or C
1-6alkoxyl group,
(2) aryl C
0-6alkyl, the heterocyclic radical C that 3-8 unit is saturated
0-6alkyl, the undersaturated heterocyclic radical C of 5-8 unit
0-6alkyl, two (aryl) C
1-6alkyl, two (heterocyclic radical that 3-8 unit is saturated) C
1-6alkyl or two (the undersaturated heterocyclic radical of 5-8 unit) C
1-6alkyl, described aryl or heterocyclic radical can also be further by halogen atom, hydroxyl, amino, two (C
1-6alkyl) amido, C
1-6alkyl, C
1-6alkoxyl group or halo C
1-6alkoxyl group replaces;
X is O or NR
6, R
6be selected from hydrogen atom or C
1-6alkyl;
R
2be selected from by halogen atom, hydroxyl, amino or C
1-6alkoxyl group replaces or unsubstituted C
1-6alkyl, C
3-6cycloalkyl C
0-6alkyl, or the saturated heterocyclic radical C of 3-8 unit
0-6alkyl;
R
3be selected from hydrogen atom, halogen atom, hydroxyl, cyano group, nitro or C
1-6alkylamidoalkyl;
N is selected from 1,2 or 3;
R
4and R
5respectively independently selected from amino, cyano group, is not substituted or by 1 to 3 substituting group Q
2the C replacing
1-6alkyl, C
2-6thiazolinyl or C
2-6alkynyl, and carbon atom wherein can be by 1～3 O, S (O)
m, N (H)
m, NCH
3or C (O) replacement,
Q
2be selected from halogen atom, hydroxyl, amino or carboxyl;
M is selected from 0,1 or 2.
Be preferably:
Wherein, R
1be selected from and be not substituted or by 1 to 2 substituting group Q
1the following group replacing:
C
1-6alkyl, 6-10 unit is saturated and encircle C
0-6alkyl, the saturated volution C of 6-10 unit
0-6alkyl or the saturated bridged ring C of 6-10 unit
0-6alkyl, and the carbon atom in described and ring, volution or bridged ring can be by 1～3 O, S (O)
m, N (H)
m, NCH
3or C (O) replacement,
Q
1independently selected from:
(1) halogen atom, hydroxyl, amino, carboxyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, or by halogen atom, hydroxyl, amino replacement or unsubstituted C
1-6alkyl or C
1-6alkoxyl group,
(2) aryl C
0-6alkyl, the saturated or undersaturated heterocyclic radical C of 5-6 unit
0-6alkyl, two (aryl) C
1-6alkyl or two (the saturated or undersaturated heterocyclic radical of 5-6 unit) C
1-6alkyl, described aryl or heterocyclic radical can also be further by halogen atom, hydroxyl, amino, two (C
1-6alkyl) amido, C
1-6alkyl, C
1-6alkoxyl group or halo C
1-6alkoxyl group replaces;
X is O or NR
6, R
6be selected from hydrogen atom or C
1-6alkyl;
R
2be selected from by halogen atom, hydroxyl, amino or C
1-6alkoxyl group replaces or unsubstituted C
1-6alkyl, or C
3-6cycloalkyl C
0-6alkyl;
R
3be selected from hydrogen atom, halogen atom, cyano group or nitro;
N is selected from 1 or 2;
R
4and R
5respectively independently selected from amino, cyano group, is not substituted or by 1 to 2 substituting group Q
2the C replacing
1-6alkyl, and carbon atom wherein can be by 1～3 O, S (O)
m, N (H)
mor C (O) replacement,
Q
2be selected from halogen atom, hydroxyl or amino;
M is selected from 0,1 or 2.
Be preferably:
Wherein, R
1be selected from and be not substituted or by 1 to 2 substituting group Q
1the following group replacing:
And the carbon atom on ring can be by 1～3 O, S (O)
m, N (H)
m, methyl or C (O) replace,
P is selected from 0,1 or 2,
Q
1independently selected from:
(1) halogen atom, hydroxyl, amino, carboxyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, or by halogen atom, hydroxyl, amino replacement or unsubstituted C
1-6alkyl or C
1-6alkoxyl group,
(2) aryl C
0-6alkyl, the saturated or undersaturated heterocyclic radical C of 5-6 unit
0-6alkyl, two (aryl) C
1-6alkyl or two (the saturated or undersaturated heterocyclic radical of 5-6 unit) C
1-6alkyl, described aryl or heterocyclic radical can also be further by halogen atom, hydroxyl, amino, two (C
1-6alkyl) amido, C
1-6alkyl, C
1-6alkoxyl group or halo C
1-6alkoxyl group replaces;
X is O or NR
6, R
6be selected from hydrogen atom or C
1-6alkyl;
R
2be selected from by halogen atom, hydroxyl or C
1-6alkoxyl group replaces or unsubstituted C
1-6alkyl;
R
3be selected from hydrogen atom, halogen atom, cyano group or nitro;
N is selected from 1 or 2;
R
4and R
5respectively independently selected from amino, cyano group, is not substituted or by 1 to 2 substituting group Q
2the C replacing
1-6alkyl, and carbon atom wherein can be by 1～3 O, S (O)
m, N (H)
mor C (O) replacement,
Q
2be selected from halogen atom, hydroxyl or amino;
M is selected from 0,1 or 2.
Be preferably:
Wherein, R
1be selected from and be not substituted or by 1 to 2 substituting group Q
1the following group replacing:
P is selected from 0,1 or 2,
Q
1independently selected from:
(1) halogen atom, hydroxyl, amino, carboxyl, C
1-4alkyl amine group, two (C
1-4alkyl) amido, or by halogen atom, hydroxyl, amino replacement or unsubstituted C
1-4alkyl or C
1-4alkoxyl group,
(2) phenyl, phenyl C
1-4alkyl, two (phenyl) C
1-4alkyl, pyridyl, pyridyl C
1-4alkyl, two (pyridyl) C
1-4alkyl, furyl, furyl C
1-4alkyl, thienyl, thienyl C
1-4alkyl, pyrryl, pyrryl C
1-4alkyl, imidazolyl, imidazolyl C
1-4alkyl, thiazolyl, thiazolyl C
1-4alkyl, isothiazolyl, isothiazolyl C
1-4alkyl, oxazolyl, oxazolyl C
1-4alkyl, pyrazinyl, pyrazinyl methyl, two (pyrazinyl) methyl, pyrimidyl, Pyrimidylmethyl or two (pyrimidyl) methyl, described Q
1can also be further by halogen atom, hydroxyl, amino, two (C
1-4alkyl) amido, C
1-4alkyl, C
1-4alkoxyl group or halo C
1-4alkoxyl group replaces;
(3) piperidyl, piperidyl C
1-4alkyl, piperazinyl, piperazinyl C
1-4alkyl, morpholinyl, morpholinyl C
1-4alkyl, pyrrolidyl, pyrrolidyl C
1-4alkyl, described Q
1can also be further by halogen atom, hydroxyl, amino, two (C
1-4alkyl) amido, C
1-4alkyl, C
1-4alkoxyl group or halo C
1-4alkoxyl group replaces;
X is O or NR
6, R
6be selected from hydrogen atom or C
1-4alkyl;
R
2be selected from by halogen atom, hydroxyl or C
1-4alkoxyl group replaces or unsubstituted C
1-4alkyl;
R
3be selected from hydrogen atom, halogen atom, cyano group or nitro;
N is selected from 1 or 2;
R
4and R
5respectively independently selected from amino, cyano group, is not substituted or by 1 to 2 substituting group Q
2the C replacing
1-4alkyl, and carbon atom wherein can be by 1～3 O, S (O)
m, N (H)
mor C (O) replacement,
Q
2be selected from halogen atom, hydroxyl or amino;
M is selected from 0,1 or 2.
Be preferably:
Wherein, R
1be selected from and be not substituted or by 1 to 2 substituting group Q
1the following group replacing:
P is selected from 0,1 or 2,
Q
1independently selected from phenyl, benzyl, styroyl, two (phenyl) methyl, pyridyl, pyridylmethyl, two (pyridyl) methyl, furyl, furyl methyl, thienyl, thienyl methyl, pyrryl, pyrryl methyl, imidazolyl, imidazolyl methyl, thiazolyl, thiazolyl methyl, oxazolyl, oxazolyl methyl, pyrazinyl, pyrazinyl methyl, two (pyrazinyl) methyl, pyrimidyl, Pyrimidylmethyl or two (pyrimidyl) methyl, described Q
1can also further by fluorine atom, chlorine atom, hydroxyl, amino, two (methyl) amido, methoxyl group or trifluoromethoxy, be replaced;
X is O or NR
6, R
6be selected from hydrogen atom, methyl or ethyl;
R
2be selected from methyl, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl;
R
3be selected from hydrogen atom, fluorine atom, chlorine atom, cyano group or nitro;
N is selected from 1 or 2;
R
4and R
5respectively independently selected from amino, cyano group, is not substituted or by 1 to 2 substituting group Q
2the methyl, ethyl, propyl group or the butyl that replace, and carbon atom wherein can be by 1～3 O, S (O)
m, N (H)
mor C (O) replacement,
Q
2be selected from fluorine atom, chlorine atom, hydroxyl or amino;
M is selected from 0,1 or 2.
More preferably:
Wherein, R
1be selected from and be not substituted or by 1 to 2 substituting group Q
1the following group replacing:
P is selected from 0,1 or 2,
Q
1independently selected from benzyl, two (phenyl) methyl, pyridylmethyl, two (pyridyl) methyl, pyrazinyl methyl, two (pyrazinyl) methyl, Pyrimidylmethyl or two (pyrimidyl) methyl, described Q
1can also further by fluorine atom, chlorine atom, hydroxyl, amino, two (methyl) amido, methoxyl group or trifluoromethoxy, be replaced;
X is O or NR
6, R
6be selected from hydrogen atom or methyl;
R
2represent methylidene, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl;
R
3be selected from hydrogen atom, fluorine atom, chlorine atom or nitro;
N is selected from 1 or 2;
R
4and R
5respectively independently selected from amino, be not substituted or by 1 to 2 substituting group Q
2the methyl, ethyl, propyl group or the butyl that replace, and carbon atom wherein can be by 1～3 O, N (H)
mor C (O) replacement,
Q
2be selected from fluorine atom, chlorine atom, hydroxyl or amino;
M is selected from 0,1 or 2.
" halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" C of the present invention
1-6alkyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkylamidoalkyl " in " C
1-6alkyl " represent the alkyl that contains 1-6 carbon atom of straight or branched, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc.
" C of the present invention
3-6cycloalkyl " refer to the cycloalkyl group that contains 3-6 carbon atom, as cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" C of the present invention
1-6alkoxyl group, halo C
1-6alkoxyl group " in " C
1-6alkoxyl group " refer to term " C
1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.
" C of the present invention
2-6thiazolinyl " refer to straight or branched that the carbonatoms that contains two keys is 2～6 or the thiazolinyl of ring-type, as vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 1-pentenyl, pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, cyclopropenyl radical, cyclopentenyl, cyclohexenyl etc.
" C of the present invention
2-6alkynyl " refer to straight or branched that the carbonatoms that contains triple bond is 2～6 or the alkynyl of ring-type, as ethynyl, proyl, 2-butyne base, valerylene base, 3-pentynyl, 2-hexin base, 3-hexin base, cyclopropyne base, cyclobutyne base, ring pentynyl, hexamethylene alkynyl etc.
" 6-10 unit ring " of the present invention refers to saturated or the undersaturated and ring structure of 6-10 unit, and two or more ring texturees share each other two adjacent atoms and are connected to form.3-azabicyclo [3.1.0] hexane for example, 3-azabicyclo [3.2.0] heptane, octahydro cyclopentyl [c] pyrroles, octahydro-1H-cyclopentyl [c] pyridine, 2-thia dicyclo [3.2.0] heptane, 2-thia dicyclo [4.2.0] octane, 1, 1-dioxo-octahydro cyclopentyl [b] thiapyran, 5, 6-dihydro-4H-pyrroles [2, 3-d] oxazole, dicyclo [3.1.0] hexane, dicyclo [3.2.0] heptane, octahydro pentalene, perhydronaphthalene, 5, 6-glyoxalidine [1, 2-a] pyrazine, 5, 6-dihydro-1, 7-naphthyridines, 5H-pyrroles [3, 4-b] pyridine, 7, 8-dihydropyridine [4, 3-d] pyrimidine, 2, 3, 6, 7-tetrahydrochysene-1H-pyrazoles [4, 3-c] pyridine, 6, 7-thiazoline [5, 4-c] pyridine, 3-methyl-6, 7-dihydro-3H-pyrazoles [4, 5-c] pyridine, benzo [b] furans, different benzo [b] furans, benzo [b] thiophene, benzoxazole, benzothiazole, benzoglyoxaline, indazole, indoles, quinoline, isoquinoline 99.9, 2H-chromogen alkene etc.
" 6-10 unit volution " of the present invention refers to the saturated or undersaturated spirane structure of 6-10 unit, has at least two rings to share an atom and forms.For example 5-azaspiro [2.4] heptane, 6-azaspiro [2.5] octane, 7-azaspiro [3.5] nonane, 8-azaspiro [4.5] decane, spiral shell [2.4] heptane, spiral shell [3.4] octane, spiral shell [4.4] nonane, spiral shell [2.5] octane, spiral shell [3.5] nonane, spiral shell [4.5] decane, 1-oxygen-2,7-diaza spiro [4.4] ninth of the ten Heavenly Stems-2-alkene, spiral shell [3.4] are pungent-5,7-diketone etc.
" 6-10 unit bridged ring " of the present invention refers to the saturated or undersaturated caged scaffold of 6-10 unit, and any two rings share neither direct connected atom and form.Such as dicyclo [2.2.1] heptane, dicyclo [2.2.2] octane, dicyclo [3.2.1] octane, diamantane, 8-azabicyclo [3.2.1] octane, 2-azabicyclo [2.2.2] octane, 2-azabicyclo [2.2.1] heptane, 7-azabicyclo [2.2.1] heptane, 7-oxabicyclo [2.2.1] heptane etc.
" aryl " of the present invention refers to 5～10 yuan of monocycles or the di-aromatics ring that contains phenyl ring, such as phenyl, naphthyl etc.
In " heterocyclic radical that 3-8 unit is saturated " of the present invention finger ring, there is not the 3-8 unit heterocyclic group of unsaturated link(age), for example, ethylenimine, 2H-ethylenimine, diazacyclo propane, azetidine, 1, 2-diazetidine, tetramethyleneimine, imidazolidine, pyrazolidine, hydrogenated pyridine ketone, piperidines, piperazine, oxyethane, dioxirane, thiirane, trimethylene oxide, 1, 2-dioxetane, Thietane, tetrahydrofuran (THF), tetramethylene sulfide, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyrans, 1, 4-dioxane, 1, 3-dioxane, 1, 3-oxathiane, oxaza propane, oxazole, morpholine etc.Wherein, preferred ethylenimine, azetidine, tetramethyleneimine, imidazolidine, pyrazolidine, hydrogenated pyridine ketone, piperidines, piperazine, oxyethane, tetrahydrofuran (THF), tetramethylene sulfide, 1,3-dioxolane, 1,3-dithiolane, tetrahydropyrans, 1,4-dioxane, 1,3-dioxane, 1,3-oxathiane, oxaza Bing Wan, oxazole, morpholine etc.
The 5-8 unit heterocyclic group that contains unsaturated link(age) in " the undersaturated heterocyclic radical of 5-8 unit " of the present invention finger ring, for example, pyrroles, pyrrolin, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, 1,2,3-triazoles, 1,2,4-triazole, tetrazolium, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazines, 1,2,4,5-tetrazine, nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, Isosorbide-5-Nitrae-diazacyclo heptantriene, nitrogen heterocyclic octatetraene, Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-diazacyclo sarohornene, 1,2-dithia cyclobutene, furans, thiophene, 2,5-dihydro-thiophene, 1,2-dithiole, 2H-pyrans, 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, 4H-pyrans, 4H-pyrans-4-ketone, Isosorbide-5-Nitrae-Dioxin, Isosorbide-5-Nitrae-dithia cyclohexadiene, Isosorbide-5-Nitrae-oxathiin, oxepin, thia cycloheptatriene, Isosorbide-5-Nitrae-dioxane sarohornene ， oxazole, 4,5-dihydro-oxazole, isoxazole, 4,5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, thiazole, 4,5-thiazoline, isothiazole, 1,2,3-thiadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles, 2H-1,2-oxazine, 4H-1,2-oxazine, 6H-1,2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 5,6-dihydro-4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine, 4H-1,3-thiazine, 5,6-dihydro-4H-1,3-thiazine, 6H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,4-thiazine, morpholine etc.Preferred azete wherein, 1,2-diazetine, pyrroles, pyrrolin, imidazoles, 4,5-glyoxalidine, pyrazoles, 4,5-pyrazoline, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, nitrogen heterocyclic heptantriene, 1,2-dithia cyclobutene, furans, thiophene, 2,5-dihydro-thiophene, 1,2-dithiole, 2H-pyrans, 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, 4H-pyrans, 4H-pyrans-4-ketone, Isosorbide-5-Nitrae-Dioxin, Isosorbide-5-Nitrae-dithia cyclohexadiene, Isosorbide-5-Nitrae-oxathiin, oxepin, Isosorbide-5-Nitrae-dioxane sarohornene, oxazole, 4,5-dihydro-oxazole, isoxazole, 4,5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, thiazole, 4,5-thiazoline, isothiazole, 1,2,3-thiadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles, 2H-1,2-oxazine, 4H-1,2-oxazine, 6H-1,2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 5,6-dihydro-4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine, 4H-1,3-thiazine, 5,6-dihydro-4H-1,3-thiazine, 6H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,4-thiazine, morpholine, 1,3,4-thiadiazoles.More preferably pyrroles, pyrrolin, imidazoles, 4, 5-glyoxalidine, pyrazoles, 4, 5-pyrazoline, pyridine, pyridazine, pyrimidine, pyrazine, furans, thiophene, 2, 5-dihydro-thiophene, 2H-pyrans, 2H-pyran-2-one, 3, 4-dihydro-2H-pyrans, 4H-pyrans, 4H-pyrans-4-ketone, 1, 4-Dioxin, 1, 4-dithia cyclohexadiene, 1, 4-oxathiin, oxazole, 4, 5-dihydro-oxazole, isoxazole, 4, 5-dihydro-isoxazole, 2, 3-dihydro-isoxazole, 1, 2, 3-oxadiazole, 1, 2, 5-oxadiazole, thiazole, 4, 5-thiazoline, isothiazole, 1, 2, 3-thiadiazoles, 1, 2, 4-thiadiazoles, 1, 3, 4-thiadiazoles etc.
Particularly preferred compound comprises:
The present invention also provides the preparation method of above-claimed cpd:
Reaction equation:
Reactions steps:
The preparation of step 1 intermediate 1
Method 1:
Raw material 1 (1 equivalent), raw material 2 (1.3 equivalent) and raw material 3 (1 equivalent) are dissolved in ethanol, return stirring a few hours, cooling, there is Precipitation, suction filtration, filter cake washing with alcohol, dry, obtain intermediate 1.
Method 2:
Raw material 1 (1 equivalent), raw material 2 (1.1 equivalent) and raw material 4 (1.1 equivalent), bicarbonate of ammonia (1.5 equivalent) are dissolved in ethanol-water mixed solvent, in 55 ℃ of-80 ℃ of stirred for several hour, cooling, there is Precipitation, suction filtration, filter cake washing with alcohol, dry, obtain intermediate 1.
The preparation of step 2 intermediate 2
Method 1:
Intermediate 1 is dissolved in to methyl alcohol, under stirring, adds NaOH saturated aqueous solution.In 75 ℃ of vigorous stirring reactions, decompression steams after most of methyl alcohol, in residuum, adds water, leaches unreacting material, and it is acid with 1M hydrochloric acid, adjusting filtrate pH, separates out solid, filters, dry, obtains intermediate 2.
Method 1:
Intermediate 1 is dissolved in glycol dimethyl ether, then adds wherein 1M sodium hydroxide solution, at room temperature stir, reaction solution dilute with water, it is acid with dilute hydrochloric acid, adjusting pH, has precipitation to form, suction filtration is dry, with ethyl alcohol recrystallization, obtains intermediate 2.
The preparation of step 3 formula I ' compound
In dry reaction flask, centre 2 (1 equivalent) joined to DMF-CH
2cl
2in mixed solvent, drip SOCl at-10 ℃
2(1.5 equivalent), stirs for some time.Add catalyzer DMAP, drip the CH of raw material 5 (1 equivalent)
2cl
2solution, stirring reaction under room temperature, uses 10% sodium carbonate solution, saturated common salt water washing successively, separates organic layer washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, column chromatography purification, obtains formula I ' compound.
R in reaction process
1, R
2, R
3, R
4, R
5, n as mentioned before.
Clinically, formula of the present invention (I) compound can be used with the form of the form of dissociating or its pharmacy acceptable salt.The aobvious alkalescence of formula of the present invention (I) compound, can form acid salt with mineral acid or organic acid.
Formula of the present invention (I) compound or its pharmacy acceptable salt, owing to there being unsymmetrical carbon, can exist with a kind of optically active isomer form, and therefore, the present invention also comprises these optically active isomers and composition thereof.
Formula of the present invention (I) compound or its pharmacy acceptable salt can form pharmaceutical composition with one or more pharmaceutical carriers.Described pharmaceutical composition can be made clinically the conventional formulation using, can be oral or the mode such as administered parenterally be applied to the patient who needs this treatment.As tablet, particle, capsule, powder, injection, inhalation, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, sprays, preparation capable of permeating skin etc.These preparations can pass through ordinary method, add pharmaceutical carrier and are prepared from as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc.
Formula of the present invention (I) compound or its pharmacy acceptable salt are comprising hypertension, heart failure, myocardial infarction, stenocardia, cardiac hypertrophy, myocarditis, cardiovascular fibrosis, pressure receptor dysfunction, too much body fluid and arrhythmia for the preparation of Cardiovarscular, or endocrinopathy, comprise the application in the medicine of former/Secondary cases aldosteronism, Addison's disease, the emerging syndrome in storehouse and Bart's formula syndromes.
Described compound, its pharmacy acceptable salt or its steric isomer and one or more therapeutic active substance of formula of the present invention (I) can form pharmaceutical composition, described therapeutic active substance is selected from angiotensin-ii antagonist or its pharmacy acceptable salt, for example valsartan and losartan; HMG-Co-A reductase inhibitor or its pharmacy acceptable salt, for example fluvastatin and pitavastatin; Aldosterone receptor antagonist (MRA) or its pharmacy acceptable salt, for example spironolactone and eplerenone; Angiotensin-converting enzyme (ACE) inhibitor, for example enalapril; Angiotensin-converting enzyme/neutral endopeptidase (ACE/NEP) double inhibitor or its pharmacy acceptable salt, for example atrial natriuretic peptide; Antidiabetic drug; Diet pill; Diuretic(s); Endothelin receptor antagonists; CETP inhibitor, for example atorvastatin; Na-K-ATP enzyme membrane pump inhibitor; B-adrenergic receptor inhibitor or alpha-adrenergic receptor blocker; Neutral endopeptidase (NEP) inhibitor and inotropic agent.
By pharmacological evaluation, further set forth the compounds of this invention beneficial effect below, but this should be interpreted as to the compounds of this invention only has following beneficial effect.
the pharmacological activity test of test example the compounds of this invention
Trial-product: compound 1, compound 4, compound 7, compound 8, compound 10 and compound 1 self-control, its chemical name and structural formula are as mentioned before;
Lercanidipine: commercial.
L, T-shaped calcium channel inhibitor detect
Experimental technique:
Accurately take trial-product, by 3.162 times of stepwise dilution relations, make respectively final concentration be: 10 μ M, 3 μ M, 1 μ M, 0.3 μ M, 0.1 μ M, 0.03 μ M.
T-type detects: separated Neurons of Cerebral Cortex from suckling mouse, cultivate after 7 days for test.At room temperature apply full cell patch tongs technology record cell plasma electric current.Clamp down on electric current for-90mV, 10s between arteries and veins, is T-shaped calcium current (I from-inward electric current that 20mV starts to activate
ca, T).
L-type detects: separated left compartment muscle cell from cavy, cell in 8 hours for experiment.At room temperature apply full cell patch tongs technology record cell plasma electric current.Clamping down on electric current is-80mV, 10s between arteries and veins, and the inward electric current that starts to activate from 0mV is T-shaped calcium current (I
ca, L).
Liquid (mM) in electrode: CsCl 120, and TEA-Cl 20, CaCl
21, E GTA-CsOH 11, Hepes 10, mg-ATP5, pH7.3;
The outer liquid (mM) of electrode: NaCl 135, and CsCl 5.4, CaCl
21.8, mgCl
21, Hepes 5, and glucose 10, pH7.4.
Experimental result and conclusion:
Table 1 the compounds of this invention is active to the inhibition of L-type, T-type calcium channel
From table 1; it is active that the compounds of this invention all has excellent inhibition to L-type, T-type calcium channel; wherein to L-type calcium channel inhibition activity be better than T-type calcium channel; visible the compounds of this invention is the agent of L-type/T-type calcium channel double blocking; not only can be hypotensive; and also having Renoprotective Effect, side effect is little.
4, embodiment
The embodiment of form, is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.
embodiment 1 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 1)
(1) Isosorbide-5-Nitrae-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, the preparation of 5-pyridine dicarboxylic acid methyl esters
M-nitrobenzaldehyde 5g (0.033mol), methyl acetoacetate 8mL (0.072mol), ethanol 10mL, bicarbonate of ammonia 4g (0.05mol), water 4mL are mixed, in 55-60 ℃, be stirred to without bubble (lasting approximately 1 hour), continue again back flow reaction 1-2 hour, cooling, suction filtration, be dried to obtain yellow solid 8.1g, yield 70.9%.
(2) 5-(methoxycarbonyl)-2, the preparation of 6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid
By 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid methyl esters 3.5g (0.01mol) mixes with methyl alcohol 150mL, the saturated aqueous solution that adds 9g (0.225mol) NaOH under stirring, in 70 ℃ of vigorous stirring reactions 6 hours, decompression steamed after 80mL methyl alcohol, in residuum, add 200mL water, leach unreacting material, with 1mol/L hydrochloric acid, adjust filtrate pH=2.5, separate out yellow solid, filter, dry, obtain khaki color powder, methyl alcohol purifying, obtain yellow solid 1.9g, yield 57.2%.
(3) preparation of 5-hydroxyl six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters
5-oxo six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 1.125g (5.0m mol), sodium borohydride 0.756g (20m mol), methyl alcohol 10mL are mixed, under ice bath, react 3 hours, decompression steams after methyl alcohol, in residuum, add 20mL water, be extracted with ethyl acetate, anhydrous sodium sulfate drying, obtains colorless oil 1.135g after concentrating under reduced pressure.
(4) preparation of 2-benzyl octahydro cyclopentyl [c] pyrroles-5-alcohol
5-hydroxyl six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 1.135g (5m mol) and 10mL methylene dichloride are mixed, under ice bath, stir, in solution, drip 6mL trifluoroacetic acid, under ice bath, react 2 hours, after concentrating under reduced pressure, be dissolved in 20mL methylene dichloride, add successively Potassium ethanoate 0.19g (5m mol), anhydrous magnesium sulfate 0.6g, under room temperature, stirring reaction is 0.5 hour.In system, add continuation under phenyl aldehyde 1.06g (10m mol) room temperature to stir 2 hours, then in system, add in batches sodium triacetoxy borohydride 3.51g (16.6m mol), under room temperature, stir and spend the night, add 30mL water, adjust pH to neutral, dichloromethane extraction, anhydrous magnesium sulfate drying, gained silica gel column chromatography (sherwood oil: ethyl acetate=2: 1), obtain colorless oil 0.78g, yield 71.8% for residuum after concentrating under reduced pressure.
(5) 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
By 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid 0.22g (0.66m mol) is suspended in DMF 0.33mL, methylene dichloride 2.1mL, drips wherein SOCl under ice bath
20.072mL (0.66m mol), stirs 2 hours.Add DMAP 0.089g (0.728m mol), drip the 0.5mL dichloromethane solution of 2-benzyl octahydro cyclopentyl [c] pyrroles-5-alcohol 0.143g (0.66m mol), continue to stir 4 hours.Use successively 10% sodium carbonate solution, saturated common salt water washing, collected organic layer, dry, gained silica gel column chromatography (sherwood oil: ethyl acetate=1: 2), obtain faint yellow solid 0.144g, yield 41.0% for residuum after concentrating under reduced pressure.
Molecular formula: C
30h
33n
3o
6molecular weight: 531.60 mass spectrums (M+H): 532
1H-NMR(CDCl
3，400MHz)：δ8.14(1H，t)，8.02(1H，dd)，7.66(1H，d)，7.42-7.23(6H，m)，5.70(1H，s)，5.13(1H，s)，4.87(1H，quintet)，3.66(3H，s)，3.63(2H，s)，2.54-2.48(6H，m)，2.39(3H，s)，2.37(3H，s)，2.28-2.05(2H，m)，1.70-1.36(2H，m)。
embodiment 2 3-(2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 2)
(1) preparation of 5-hydroxyl six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters
5-oxo six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 1.125g (5.0m mol), sodium borohydride 0.756g (20m mol), methyl alcohol 10mL are mixed, under ice bath, react 3 hours, decompression steams after methyl alcohol, in residuum, add 20mL water, be extracted with ethyl acetate, anhydrous sodium sulfate drying, obtains colorless oil 1.135g after concentrating under reduced pressure.
(2) preparation of 5-acetoxyl group six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters
In the 20mL dichloromethane solution of 5-hydroxyl six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 0.681g (3.0m mol), add successively acetic anhydride 0.367g (3.6m mol), triethylamine 1.26mL (9mol), DMAP 0.18g (1.5m mol), at room temperature stir 3 hours, add water 10mL, adjust pH to neutral, anhydrous sodium sulfate drying, after concentrating under reduced pressure, obtain oily matter 0.807g, yield 100%.
(3) preparation of acetic acid (2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) ester
5-acetoxyl group six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 0.807g (3m mol) are dissolved in to 10mL methylene dichloride, under ice bath, stir, in solution, drip 6mL trifluoroacetic acid, continue reaction 2 hours, after concentrating under reduced pressure, be dissolved in 20mL acetonitrile, add successively diphenyl methyl chloride 0.911g (4.5m mol), triethylamine 1.68mL (12m mol), sodium iodide 0.911g (6.1mm mol), lucifuge at room temperature stirs 24 hours, after concentrating under reduced pressure, add water 10mL, dichloromethane extraction, organic layer anhydrous sodium sulfate drying, filter, after concentrating under reduced pressure, obtain product 0.857g, yield 85.2%
(4) preparation of 2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-alcohol
In methyl alcohol (20mL) solution of acetic acid (2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) ester 0.335g (1.0m mol), add salt of wormwood 0.414g (3.0m mol), under room temperature, stir 3 hours, after concentrating under reduced pressure, add water 10mL, dichloromethane extraction, organic layer anhydrous sodium sulfate drying, filter, (sherwood oil: ethyl acetate=2: 1) column chromatography, obtains 0.23g colorless oil, yield 78.4% for gained residuum after concentrating under reduced pressure.
(5) 3-(2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
By 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid 0.22g (0.66m mol) is dissolved in DMF 0.33mL, methylene dichloride 2.1mL and stirs, and under ice bath, drips SOCl
20.072mL (0.66m mol), stirs 2 hours.Add DMAP 0.089g (0.728m mol), drip methylene dichloride (0.5mL) solution of 2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-alcohol 0.194g (0.66m mol), continue to stir 4 hours.Use successively 10% sodium carbonate solution, saturated common salt water washing, collected organic layer, dry, concentrating under reduced pressure, with silica gel column chromatography (sherwood oil: ethyl acetate=1: 2), obtain faint yellow solid 0.165g, yield 41.1%.
Molecular formula: C
36h
37n
3o
6molecular weight: 607.70 mass spectrums (M+H): 608
1H-NMR(CDCl
3，400MHz)：δ8.17(1H，t)，8.05(1H，ddd)，7.71(1H，d)，7.51-7.41(5H，m)，7.32-7.28(4H，m)，7.21-7.17(2H，m)，5.72(1H，s)，5.17(1H，s)，4.82(1H，quintet)，4.18(1H，s)，3.70(3H，s)，2.50(2H，d)，2.47-2.37(2H，m)，2.41(3H，s)，2.39(3H，s)，2.30-2.21(3H，m)，2.17-2.08(1H，m)，1.61-1.53(1H，m)，1.46-1.37(1H，m)。
embodiment 3 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2-((2-amino ethoxy) Ji Ji)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 3)
(1) 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2-((2-nitrine oxyethyl group) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester
(4) in concrete operations reference example 5, throw 2-((2-nitrine oxyethyl group) methyl)-4-(2-chloro-phenyl-)-5-(methoxycarbonyl)-6-methyl isophthalic acid, (preparation method is with reference to J.Med.Chem.1986 for 4-dihydropyridine-3-carboxylic acid, 29,1696-1702) 0.208g (0.511mmol), 2-benzyl octahydro cyclopentyl [c] pyrroles-5-alcohol (preparation method is shown in (4) in embodiment 1) 0.094g (0.43m mol), obtain faint yellow solid 103mg, yield 39.8%.
(2) 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2-((2-amino ethoxy) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester
(5) in concrete operations reference example 5, throw 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2-((2-nitrine oxyethyl group) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3,5-dicarboxylic ester 103mg (0.170m mol), obtain 49mg beige solid, yield 49.7%.
Molecular formula: C
32h
38clN
3o
5molecular weight: 580.11 mass spectrums (M+H): 580
embodiment 4 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2,6-methyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 4)
(1) preparation of 5-methylene radical six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters
Under ice bath, methyltriphenylphosphonium bromide 1.424g (4m mol) is scattered in to 8mL anhydrous diethyl ether, add potassium tert.-butoxide 0.448g (4m mol), stir after one hour, the diethyl ether solution (6mL) of 5-oxo six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 0.45g (2mmol) is joined in reaction flask, under ice bath, react 1 hour, then under room temperature, stir 3 hours, add 20mL water, be extracted with ethyl acetate, anhydrous sodium sulfate drying, (sherwood oil: ethyl acetate=5: 1) column chromatography for gained residuum after concentrating under reduced pressure, obtain 1.338g colorless oil, yield 94.8%.
(2) preparation of 5-(methylol) six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters
At-15 ℃, to the borine dimethyl sulphide solution 4.7mL (9.4m mol) that slowly drips 2M in ether (10mL) solution of 5-methylene radical six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 0.423g (1.89m mol), react after two hours, drip at low temperatures the sodium hydroxide solution 2mL of 1mol/L, under room temperature, react after one hour, in reaction system, drip 30% hydrogen peroxide 0.65mL again, under room temperature, stir 1 hour, after concentrating under reduced pressure solvent, be extracted with ethyl acetate, anhydrous sodium sulfate drying, filter, (sherwood oil: ethyl acetate=1: 2) column chromatography for gained residuum after concentrating under reduced pressure, obtain 0.412g colorless oil, yield 90.3%.
(3) preparation of (2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl alcohol
5-(methylol) six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 0.412g (1.7m mol) and 10mL methylene dichloride are mixed, under ice bath, stir, in solution, drip 6mL trifluoroacetic acid, under ice bath, react 2 hours, after concentrated, be dissolved in 10mL methylene dichloride, add Potassium ethanoate 0.167g (1.7m mol), anhydrous magnesium sulfate 0.6g, under room temperature, stirring reaction is after 0.5 hour, in system, add continuation under phenyl aldehyde 0.36g (3.4m mol) room temperature to stir 2 hours, then in system, add in batches sodium triacetoxy borohydride 1.2g (5.1m mol), under room temperature, stir and spend the night, add 30mL water, adjust pH to neutral, dichloromethane extraction, anhydrous magnesium sulfate drying, concentrating under reduced pressure, with silica gel column chromatography (sherwood oil: ethyl acetate=2: 1), obtain colorless oil 0.31g, yield 78.8%.
(4) 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2,6-methyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid 0.289g (0.87m mol) is scattered in DMF 0.33mL, methylene dichloride 2.1mL and stirs, and under ice bath, drips SOCl
20.095mL (0.87m mol), stirs 2 hours.Add DMAP 0.104g (0.87m mol), drip methylene dichloride (0.5mL) solution of (2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl alcohol 0.168g (0.727m mol), continue to stir 4 hours.Use successively 10% sodium carbonate solution, saturated common salt water washing, collected organic layer, dry,, gained silica gel column chromatography (sherwood oil: ethyl acetate=1: 2), obtain faint yellow solid 0.194g, yield 48.9% for residuum after concentrating under reduced pressure.
Molecular formula: C
31h
35n
3o
6molecular weight: 545.63 mass spectrums (M+H): 546
1H-NMR(CDCl
3，400MHz)：δ8.12(1H，s)，8.01(1H，dd)，7.66(1H，d)，7.37(1H，t)，7.34-7.21(5H，m)，5.72(1H，s)，5.11(1H，s)，4.09(1H，dd)，4.01(1H，dd)，3.66(3H，s)，3.58(2H，s)，2.57-2.43(4H，?m)，2.39(3H，s)，2.38(3H，s)，2.30-2.20(2H，br?s)，2.10-1.82(3H，m)，1.15-1.02(2H，m).
embodiment 5 3-(2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-((2-amino ethoxy) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 5)
(1) preparation of 5-(acetyl-o-methyl) six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters
In the 20mL dichloromethane solution of 5-(methylol) six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters (preparation method is shown in (2) in embodiment 4) 0.973g (4.0m mol), add successively acetic anhydride 0.494g (4.8m mol), triethylamine 1.69mL (12m mol), DMAP 0.245g (2.0m mol), at room temperature stir 3 hours, add water 10mL, adjust pH to neutral, anhydrous sodium sulfate drying, after concentrating under reduced pressure, obtain oily matter 1.132g, yield 99.9%
(2) preparation of acetic acid (2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl ester
5-(acetyl-o-methyl) six hydrogen cyclopentyl [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 1.132g (4.0m mol) are dissolved in to 12mL methylene dichloride, under ice bath, stir, in solution, drip 8mL trifluoroacetic acid, continue reaction 2 hours, after concentrating under reduced pressure, be dissolved in 20mL acetonitrile, add successively diphenyl methyl chloride 1.224g (6.0m mol), triethylamine 2.26mL (16.1m mol), sodium iodide 0.91g (6.0mm mol), lucifuge at room temperature stirs 24 hours, after concentrating under reduced pressure, add water 10mL, dichloromethane extraction, organic layer anhydrous sodium sulfate drying, filter, after concentrating under reduced pressure, obtain product 1.133g, yield 81.0%
(3) preparation of (2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl alcohol
In methyl alcohol (30mL) solution of acetic acid (2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl ester 1.12g (3.2m mol), add salt of wormwood 1.32g (9.6m mol), under room temperature, stir 3 hours, after concentrating under reduced pressure, add water 10mL, dichloromethane extraction, organic layer anhydrous sodium sulfate drying, filter, (sherwood oil: ethyl acetate=2: 1) column chromatography, obtains 0.58g colorless oil, yield 59.0% for gained residuum after concentrating under reduced pressure.
(4) 3-(2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-((2-nitrine oxyethyl group) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester
By 2-((2-nitrine oxyethyl group) methyl)-4-(2-chloro-phenyl-)-5-(methoxycarbonyl)-6-methyl isophthalic acid, (preparation method is with reference to J.Med.Chem.1986 for 4-dihydropyridine-3-carboxylic acid, 29,1696-1702) 0.208g (0.511m mol) is dissolved in DMF 0.33mL, methylene dichloride 2.1mL stirring, under ice bath, drips SOCl
20.055mL (0.65m mol), stirs 2 hours.Add DMAP 0.055g (0.45m mol), drip methylene dichloride (0.5mL) solution of (2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl alcohol 0.132g (0.43m mol), continue to stir 6 hours.Use successively 10% sodium carbonate solution, saturated common salt water washing, collected organic layer, dry, concentrating under reduced pressure, with silica gel column chromatography (sherwood oil: ethyl acetate=1: 2), obtain faint yellow solid 128mg, yield 42.7%.
(5) 3-(2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-((2-amino ethoxy) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester
By the 3-of 128mg (0.184m mol) (2-diphenylmethylene octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-(2-azido-ethoxyl methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydro-3,5-pyridine dicarboxylate is dissolved in 15mL dehydrated alcohol, in solution, add Lindelar-Pd catalyzer 15mg, pass into hydrogen, stir 2 hours, reacting liquid filtering, except desolventizing obtains after crude product with silica gel column chromatography (methylene dichloride: methyl alcohol=7: 1) obtain 63mg beige solid, yield 51.2%.
Molecular formula: C
39h
44clN
3o
5molecular weight: 669.24 mass spectrums (M+H): 670
1H-NMR(CDCl
3，400MHz)：δ7.88(1H，s)，7.46-7.43(4H，m)，7.40(1H，dd)，7.29-7.11(7H，m)，7.02(1H，td)，5.42(1H，s)，4.83(1H，d)，4.75(1H，d)，4.12(1H，s)，4.15-4.09(1H，m)，4.04-3.99(1H，m)，3.66-3.59(2H，m)，3.63(3H，s)，2.99(2H，t)，2.49-2.42(4H，m)，2.37(3H，s)，2.12-2.05(3H，m)，1.88-1.75(2H，m)，1.12-0.97(2H，m)。
embodiment 6 3-(3-diphenyl-methyl 3-azabicyclo [3.1.0] oneself-6-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 6)
(1) 1-diphenyl-methyl-1H-pyrroles-2, the preparation of 5-diketone
Under room temperature, 7.1g (73m mol) maleimide is dissolved in EtOH (300mL), adds wherein Silver Nitrate (12.4g, 73m mol) DMSO solution, this mixture of vigorous stirring, slowly drips 185mL 0.4N NaOH alcoholic solution in 2h, finish, filter washing with alcohol solid, solid is placed in to water, and vigorous stirring, filters, ethanol is washed, then solid is positioned in acetone, repeats to stir, wash, obtain solid 13.10g, yield 88.0%.
The solid 11g obtaining (54m mol) and diphenyl-chloromethane 9.9g (49m mol) are suspended in 300mL toluene, reflux 1.7 hours.Elimination solid, uses washed with dichloromethane solid, collects organic solvent, is spin-dried for, and obtains solid, and EtOH (80mL) recrystallization, obtains product 8.2g, yield 63.3%.
(2) 3-diphenyl-methyl-2,4-dioxo-3-azabicyclo [3.1.0] oneself-preparation of 6-carboxylic acid, ethyl ester
1-diphenyl-methyl-1H-pyrroles-2,5-diketone (8.2g, 31m mol) be dissolved in dimethylbenzene (150mL) and be heated to backflow, dimethylbenzene (20mL) solution that drips ethyl diazoacetate (3.54g, 31m mol) in 1.5 hours, finishes, continue to reflux 90 minutes, steaming desolventizes, and obtains product 7.8g, yield (72.0%).
(3) preparation of (3-diphenyl-methyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl alcohol
3-diphenyl-methyl-2,4-dioxo-3-azabicyclo [3.1.0] oneself-6-carboxylic acid, ethyl ester (1.3g, 3.7m mol) is dissolved in THF (50mL), at 0 ℃, in half an hour, adds LiAlH in batches
4(0.85g, 22.4m mol), stirs under room temperature 2 hours.Add H
2o (2mL) cancellation, elimination solid, concentrated filtrate, column chromatography obtains product 0.48g yield 46.4%.
(4) 3-(3-diphenyl-methyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
(5) in concrete operations reference example 1, throw 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 0.37g (1.1m mol), (3-diphenyl-methyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl alcohol 0.28g (1.0mmol), obtain product 0.22g, yield 37.1%.
Molecular formula: C
35h
35n
3o
6molecular weight: 593.67 mass spectrums (M+H): 594
1H-NMR(CDCl
3，400MHz)：δ8.11(1H，t)，7.95(1H，dd)，7.66(1H，d)，7.40-7.16(11H，m)，5.71(1H，s)，5.13(1H，s)，4.23(1H，s)，3.98(1H，dd)，3.82(1H，dd)，3.65(3H，s)，2.86(2H，t)，2.390(3H，s)，2.387(3H，s)，2.24-2.20(2H，m)，1.67-1.65(1H，m)，1.29-1.25(2H，m).
embodiment 7 3-(2-(3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) ethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 7)
(1) 3-benzyl 1-2,4-dioxo-3-azabicyclo [3.1.0] oneself-preparation of 6-aldehyde
By 0.23g (1m mol) 3-benzyl-6-(methylol)-3-azabicyclo [3.1.0] oneself-2,4-diketone (preparation method is shown in (3) in embodiment 11) is dissolved in 30mL methylene dichloride, adds MnO
20.53g, (6m mol), refluxes 5 hours, solids removed by filtration, filtrate is concentrated, and column chromatography obtains product 0.12g, yield 52.4%.
(2) 3-benzyl-6-vinyl-3-azabicyclo [3.1.0] oneself-2, the preparation of 4-diketone
(1) in concrete operations reference example 4, throws 3-benzyl 1-2,4-dioxo-3-azabicyclo [3.1.0] oneself-6-aldehyde 0.55g, (2.4m mol), obtains product 0.388g, yield 71.1%.
(3) preparation of 2-(3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) ethanol
(2) in concrete operations reference example 4, throw 3-benzyl-6-vinyl-3-azabicyclo [3.1.0] oneself-2,4-diketone 0.388g (1.71m mol), obtains product 0.292g, yield 78.6%.
(4) 3-(2-(3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) ethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
(5) in concrete operations reference example 1, throw 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 0.61g (1.84m mol), 2-(3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) ethanol 0.259g (1.19m mol), obtain product 0.237g, yield 37.5%.
Molecular formula: C
30h
33n
3o
6molecular weight: 531.60 mass spectrums (M+H): 532
implement 8 3-(7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 8)
(1) preparation of 7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-ketone
In dry reaction flask, add 1.195g (5.0m mol) 2-oxo-7-azepine [3.5] ninth of the ten Heavenly Stems-7-carboxylic acid tert-butyl ester to be dissolved in 50mLCH
2cl
2,-5 ℃ splash into trifluoracetic acid 34.29mL, stir 1 hour at this temperature, and reaction solution evaporate to dryness adds ether in residue, separates out faint yellow solid 1.145g, yield 90.4%.
By the faint yellow solid (1.145g obtaining, 4.5m mol), salt of wormwood 2.48g (18.0m mol), is dissolved in 15mL DMF, at-15 ℃, splash into benzyl bromine 0.58mL (4.95m mol) and be dissolved in 5mL DMF, under this temperature, stirring reaction is 2 hours, and reaction solution adds water and ethyl acetate, ethyl acetate extraction, organic phase washes with water, saturated nacl aqueous solution washing, organic layer anhydrous sodium sulfate drying, column chromatography purification (EA: CH
2cl
2=1: 2), obtain faint yellow solid 846mg, yield 82.0%.
(2) preparation of 7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-alcohol
In dry reaction flask, add 7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-ketone 0.687g (3.0m mol) to be dissolved in 15mL methyl alcohol,-10 ℃ add in reaction solution by sodium borohydride 0.227g (6.0m mol) in batches, under ice bath, react 1 hour, add water, decompression steams after methyl alcohol, in residuum, add water and methylene dichloride, with dichloromethane extraction, organic phase is washed with saturated nacl aqueous solution, organic layer anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product yellow oil 0.718g.
(3) 3-(7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
In dry reaction flask, by 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid 1.322g (3.98m mol), 2.5mL DMF, 12mL CH
2cl
2stir, drip SOCl at-10 ℃
20.44mL (6.12m mol), stirs 2 hours.Add DMAP 0.422g (4.35m mol), drip 7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-alcohol (0.92g, 3.98m mol) and 3.4mL CH
2cl
2mixed solution, under room temperature, stirring reaction is 2 hours, uses successively 10% sodium carbonate solution, saturated common salt water washing, separate organic layer washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains garnet oily matter, column chromatography purification (EA: CH
2cl
2=1: 2), obtain faint yellow solid 0.885g, yield 40.8%.
Molecular formula: C
31h
35n
3o
6molecular weight: 545.63 mass spectrums (M+H): 546
1H-NMR(CDCl
3，400MHz)：δ8.13(1H，m)，8.02(1H，m)，7.64(1H，m)，7.39(1H，t)，7.32-7.29(4H，m)，7.28-7.25(1H，m)，5.71(1H，s)，5.09(1H，s)，4.93(1H，quintet)，3.65(3H，s)，3.45(2H，s)，2.38(3H，s)，2.37(3H，s)，2.32-2.22(6H，m)，1.87-1.85(1H，m)，1.61-1.56(5H，m)
embodiment 9 3-(7-diphenyl-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 9)
(1) preparation of 7-diphenyl-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-ketone
In dry reaction flask, add 1.195g (5.0m mol) 2-oxo-7-azepine [3.5] ninth of the ten Heavenly Stems-7-carboxylic acid tert-butyl ester to be dissolved in 50mLCH
2cl
2,-5 ℃ splash into trifluoracetic acid 34.29mL, stir 1 hour at this temperature, and reaction solution evaporate to dryness adds ether in residue, separates out faint yellow solid 1.145g, yield 90.4%.
By the faint yellow solid (1.145g obtaining, 4.5m mol), salt of wormwood 2.48g (18.0m mol), sodium iodide 0.742g (4.95m mol) is dissolved in 10mL DMF, at-10 ℃, splash into diphenyl-chloromethane 0.88mL (4.95m mol) and be dissolved in 5mL DMF, under room temperature, stirring reaction is 21 hours, reaction solution adds water and ethyl acetate, ethyl acetate extraction, organic phase washes with water, saturated nacl aqueous solution washing, organic layer anhydrous sodium sulfate drying, column chromatography purification obtains yellow solid 0.25g, yield 18.2%.
(2) preparation of 7-diphenyl-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-alcohol
In dry reaction flask, add 7-diphenyl-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-ketone 0.495g (1.62m mol) to be dissolved in 20mL methyl alcohol,-5 ℃ add in reaction solution by sodium borohydride 0.121g (3.2m mol) in batches, under ice bath, react 25 minutes, add water, decompression steams after methyl alcohol, in residuum, add water and ethyl acetate, be extracted with ethyl acetate, organic phase is washed with saturated nacl aqueous solution, organic layer anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product faint yellow solid 0.591g.
(3) 3-(7-diphenyl-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
In dry reaction flask, by 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid 0.476g (1.43m mol), 2mL DMF, 5mL CH
2cl
2stir, drip 0.12mL (1.67m mol) SOCl at-10 ℃
2, stir 2 hours.Add 0.129g (1.06m mol) DMAP, drip the 3.5mL CH of 7-diphenyl-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-alcohol (0.395g, 1.28m mol) at 0-5 ℃
2cl
2solution, 0-5 ℃ of stirring reaction 2.5 hours, uses 10% sodium carbonate solution, saturated common salt water washing successively, separate organic layer washing, saturated common salt water washing, organic layer anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains garnet oily matter, column chromatography purification (EA: CH
2cl
2=1: 10), obtain faint yellow solid 0.2g, yield 25.1%.
Molecular formula: C
37h
39n
3o
6molecular weight: 621.72 mass spectrums (M+H): 622
1H-NMR(CDCl
3，400MHz)：δ8.12(1H，t)，8.01-7.98(1H，m)，7.64-7.62(1H，m)，7.40-7.35(6H，m)，7.28-7.25(3H，m)，7.19-7.16(2H，m)，5.68(1H，s)，5.07(1H，s)，4.91(1H，quintet)，4.18(1H，s)，3.64(3H，s)，2.38(3H，s)，2.36(3H，s)，2.30-2.18(6H，m)，1.83(1H，m)，1.60-1.58(3H，m)，1.33-1.21(2H，m)
embodiment 10 3-(7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 10)
(1) preparation of 2-methylene radical-7-azaspiro [3.5] ninth of the ten Heavenly Stems-7-carboxylic acid tert-butyl ester
(1) in concrete operations reference example 4, throw 1.68g (15.0m mol) potassium tert.-butoxide, 5.34g (15.0m mol) methyltriphenylphosphonium bromide 2.39g (10.0m mol) 2-oxo-7-azepine [3.5] ninth of the ten Heavenly Stems-7-carboxylic acid tert-butyl ester, obtain yellow solid 1.334g, yield 56.2%.
(2) preparation of 2-methylol-7-azaspiro [3.5] ninth of the ten Heavenly Stems-7-carboxylic acid tert-butyl ester
(2) in concrete operations reference example 4, throw 1.212g (5.107m mol) 2-methylene radical-7-azaspiro [3.5] ninth of the ten Heavenly Stems-7-carboxylic acid tert-butyl ester, obtain crude product yellow-green colour oily matter 1.445g.
(3) (7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methyl alcohol
(3) in concrete operations reference example 4, throw 1.398g (5.47m mol) 2-methylol-7-azaspiro [3.5] ninth of the ten Heavenly Stems-7-carboxylic acid tert-butyl ester, obtain faint yellow oily matter 0.17g, yield 12.7%.
(4) 3-(7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
(4) in concrete operations reference example 4, throw 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 0.234g (0.704m mol), (7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methyl alcohol 0.119g, (0.485m mol), obtain faint yellow solid 0.105g, yield 38.7%.
Molecular formula: C
32h
37n
3o
6molecular weight: 559.65 mass spectrums (M+H): 560
1H-NMR(CDCl
3，400MHz)：δ8.11(1H，t)，8.02(1H，dt)，7.64(1H，dt)，7.38(1H，t)，7.40-7.23(5H，m)，5.74(1H，s)，5.10(1H，s)，4.05-3.97(2H，m)，3.66(3H，s)，3.47(2H，s)，2.50-2.22(4H，m)，2.382(3H，s)，2.378(3H，s)，1.84-1.79(2H，m)，1.50-1.25(7H，m).
embodiment 11 3-(3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 11)
(1) 1-benzyl-1H-pyrroles-2, the preparation of 5-diketone
(1) in concrete operations reference example 6, throws 10.6g (109m mol) maleimide, and 14.5g (85m mol) benzyl bromine, obtains product 3.5g, yield: 22.0%.
(2) 3-benzyl-2,4-dioxo-3-azabicyclo [3.1.0] oneself-preparation of 6-carboxylic acid, ethyl ester
(2) in concrete operations reference example 6, throw 1-benzyl-1H-pyrroles-2, and 5-diketone 5.3g (28.3m mol), obtains product 4.2g, yield 54.3%.
(3) preparation of (3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl alcohol
(3) in concrete operations reference example 6, throw 3-benzyl-2,4-dioxo-3-azabicyclo [3.1.0] oneself-6-carboxylic acid, ethyl ester 3g (11m mol), obtain product 0.62g, yield 27.7%.
(4) 3-(3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic ester
(5) in concrete operations reference example 1, throw 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 0.61g (1.84m mol), (3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl alcohol 0.224g (1.1m mol), obtain product 0.19g, yield 33.4%.
Molecular formula: C
29h
31n
3o
6molecular weight: 517.57 mass spectrums (M+H): 518
1H-NMR(CDCl
3，400MHz)：δ8.12(1H，s)，7.98(1H，d)，7.67(1H，d)，7.35-7.24(6H，m)，5.74(1H，s)，5.12(1H，s)，3.90(1H，dd)，3.85(1H，dd)，3.66(3H，s)，3.59(2H，s)，2.93(2H，t)，2.38(3H，s)，2.36(3H，s)，2.35-2.32(2H，m)，1.58-1.54(1H，m)，1.30-1.23(2H，m).
embodiment 12 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-[(2-amino ethoxy) methyl]-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester (compound 12)
(1) 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-[(2-nitrine oxyethyl group) methyl]-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester
(4) in concrete operations reference example 5, throw 2-[(2-nitrine oxyethyl group) methyl]-4-(2-chloro-phenyl-)-5-(methoxycarbonyl)-6-methyl isophthalic acid, (preparation method is with reference to J.Med.Chem.1986 for 4-dihydropyridine-3-carboxylic acid 0.203g (0.50mmol), 29,1696-1702), benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl alcohol 0.093g (0.40mmol) (preparation method is shown in (2) in embodiment 4), obtains product 0.124g.
(2) 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-[(2-amino ethoxy) methyl]-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3, the preparation of 5-dicarboxylic ester
(5) in concrete operations reference example 5, throw 3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-((2-nitrine oxyethyl group) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3,5-dicarboxylic ester 0.124g (0.20mmol), obtains product 0.063g.
Molecular formula: C
33h
40clN
3o
5molecular weight: 594.14 mass spectrums (M+H): 594
embodiment 13 6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic acid-3-(2-benzyl-2-azabicyclo [2.2.1] heptane-6-ester)-5-methyl ester hydrochloride (compound 20)
(1) 2-benzyl-2-azabicyclo [2.2.1] heptane-6-alcohol
By 2-azabicyclo [2.2.1] heptane-6-alcohol (1.2g, 10.6mmol) and triethylamine (2.1g, 21.2mmol) be dissolved in 50mL methylene dichloride, under ice-water bath, add benzyl bromine (1.0g, 6.4mmol), rise to room temperature and continue reaction 3h, solvent evaporate to dryness is obtained to crude product, through the separated (methylene dichloride: methyl alcohol=10: 1) obtain anhydrous oily matter 665mg, productive rate 51% of silicagel column.
(2) 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic acid-3-(2-benzyl-2-azabicyclo [2.2.1] heptane-6-ester)-5-methyl esters
By 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (200mg, 0.6mmol) be dissolved in the dry DCM of 5ml, under ice bath, slowly add oxalyl chloride (152mg, 1.2mmol), then drip two DMF, react after 2 hours, be spin-dried for to obtain yellow oil.This oily matter is dissolved in the dry DCM of 15ml, adds 2-benzyl-2-azabicyclo [2.2.1] heptane-6-alcohol (182mg, 0.9mmol), after reaction 2h, to reaction solution, add water, dichloromethane extraction, dry, be spin-dried for, through the separated (DCM: MeOH=60: 1) obtain 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3 of post, 5-dicarboxylic acid-3-(2-benzyl-2-azabicyclo [2.2.1] heptane-6-ester)-5-methyl esters 40mg, productive rate 13%.
(3) 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3, the preparation of 5-dicarboxylic acid-3-(2-benzyl-2-azabicyclo [2.2.1] heptane-6-ester)-5-methyl ester hydrochloride
By 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic acid-3-(2-benzyl-2-azabicyclo [2.2.1] heptane-6-ester)-5-methyl esters (20mg, 0.04mmol) be dissolved in 10mL hydrogen chloride methanol solution, under room temperature, stir 2h.Solvent evaporate to dryness is obtained to yellow solid 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic acid-3-(2-benzyl-2-azabicyclo [2.2.1] heptane-6-ester)-5-methyl ester hydrochloride 22mg, productive rate 100%
Molecular formula: C
29h
32clN
3o
6molecular weight: 554.0 mass spectrums (m/e): 518.2 (M+1)
Ultimate analysis: measured value: C, 62.84%; H, 5.86%; N, 7.55%
Theoretical value: C, 62.87%; H, 5.82%; N, 7.58%
HNMR(400MHz，DMSO)：11.6(s，1H)，8.05(m，2H)，7.40-7.76(m，7H)，5.65(s，1H)，5.40(m，1H)，4.86(s，1H)，4.24(m，2H)，3.92(m，1H)，3.64(s，3H)，3.55(m，1H)，2.85(m，2H)，2.42(s，3H)，2.38(s，3H)，1.89-2.21(m，4H)
With reference to above-mentioned preparation method, can also prepare following compound.
Claims (5)
1. the compound shown in general formula (I), its pharmacy acceptable salt or its steric isomer:
Wherein, R
1be selected from and be not substituted or by 1 to 2 substituting group Q
1the following group replacing:
P is selected from 0,1 or 2,
Q
1independently selected from benzyl, two (phenyl) methyl, pyridylmethyl or two (pyridyl) methyl, described Q
1can also be further by fluorine atom, chlorine atom, hydroxyl or amino replacement;
X is O;
R
2represent methylidene, ethyl, sec.-propyl, trifluoromethyl or methoxy ethyl;
R
3be selected from hydrogen atom, fluorine atom, chlorine atom or nitro;
N is selected from 1 or 2;
R
4and R
5respectively independently selected from amino, be not substituted or by 1 to 2 substituting group Q
2the methyl, ethyl, propyl group or the butyl that replace, and carbon atom wherein can be by 1～3 O, N (H)
mor C (O) replacement,
Q
2be selected from fluorine atom, chlorine atom, hydroxyl or amino;
M is selected from 0,1 or 2.
2. compound, its pharmacy acceptable salt or its steric isomer, wherein compound is selected from:
3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester,
3-(2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester,
3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) 5-methyl 2-((2-amino ethoxy) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3,5-dicarboxylic ester,
3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2,6-methyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester,
3-(2-diphenyl-methyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-((2-amino ethoxy) methyl)-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3,5-dicarboxylic ester,
3-(3-diphenyl-methyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester,
3-(2-(3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) ethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester,
3-(7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester,
3-(7-diphenyl-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester,
3-(7-benzyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester,
3-(3-benzyl-3-azabicyclo [3.1.0] oneself-6-yl) methyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic ester, and
3-(2-benzyl octahydro cyclopentyl [c] pyrroles-5-yl) methyl 5-methyl 2-[(2-amino ethoxy) methyl]-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4-dihydropyridine-3,5-dicarboxylic ester.
3. compound, its pharmacy acceptable salt or its steric isomer, wherein compound is selected from:
4. the pharmaceutical preparation that contains compound, its pharmacy acceptable salt or its steric isomer described in claim 1～3 any one, is characterized in that comprising one or more pharmaceutical carriers.
5. compound, its pharmacy acceptable salt or its steric isomer as described in claim as arbitrary in claim 1～3 comprising hypertension, heart failure, myocardial infarction, stenocardia, cardiac hypertrophy, myocarditis, cardiovascular fibrosis, pressure receptor dysfunction, too much body fluid and arrhythmia for the preparation of Cardiovarscular, or endocrinopathy, comprise the application in the medicine of former/Secondary cases aldosteronism, Addison's disease, the emerging syndrome in storehouse and Bart's formula syndromes.
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| CN101316842A (en) * | 2005-11-29 | 2008-12-03 | 第一三共株式会社 | Acid addition salt of optically active dihydropyridine derivative |
| CN101643469A (en) * | 2008-12-27 | 2010-02-10 | 武汉百科药物开发有限公司 | Synthesis process of barnidipine hydrochloride |
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| CN101215258A (en) * | 2008-01-21 | 2008-07-09 | 中国药科大学 | Dihydropyridines calcium antagonist compounds, preparation method and medical use thereof |
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