CN1764462B - T-type calcium channel blockers - Google Patents
T-type calcium channel blockers Download PDFInfo
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- CN1764462B CN1764462B CN200480008085.2A CN200480008085A CN1764462B CN 1764462 B CN1764462 B CN 1764462B CN 200480008085 A CN200480008085 A CN 200480008085A CN 1764462 B CN1764462 B CN 1764462B
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Abstract
There is provided a T-type calcium channel blocker that is optically active 1,4-dihydropyridine compound, a pharmaceutically acceptable salt thereof or a solvate thereof, of formula (1) wherein R<1> and R<2> are independently of each other C1-6 alkyl group or R<1> and R<2> together form -CR<5>R<6>-CR<7>R<8>-, -CR<5>R<6>-CR<7>R<8>-CR<9>R<10>- or -CR<5>R<6>-CR<7>R<8>-CR<9>R<10>-CR<11>R<12>-, etc.,X<1> and X<2> are independently of each other O or NR<13>, Ar is optionally substituted phenyl group, etc., R<a> and R<b> are independently of each other C1-6 alkyl group, -L<2>-NR<16>R<17>, CH2O-L<2>-NR<16>R<17>, CN, -L<2>-N(CH2CH2)2NR<16> or NR<16>R<17> etc., Y is C1-20 alkyl group, -L<3>-NR<18>R<19> and * is absolute configuration of R.
Description
Technical field
The present invention relates to a kind of T type calcium channel blocker, it is that 4 absolute configuration of dihydropyridine ring is the optical activity dihydropyridine-5-phosphate derivatives of R configuration, also relates to effective treatment of diseases agent of T type calcium channel blocker or preventive.
Background technology
Known dihydropyridine-5-phosphate derivatives (racemic modification) demonstrates oral antihypertensive function, and is effective (reference example such as patent documentation 1～7) in the improvement of blood circulation diseasess such as angina pectoris, cerebrovascular disorders, vascular hypertension.
Above-mentioned effect mainly is by producing based on the vasorelaxation action of L type calcium channel blocking effect, and this effect and other is many with 1, and the 4-dihydrogen pyridine derivative is that the L type calcium antagonist of representative is the same.
In recent years, it is found that except having L type calcium channel blocking effect, also to have T type calcium channel blocking effect (reference example such as non-patent literature 1) as the efonidipine (racemic modification) of the representative compound of dihydropyridine-5-phosphate derivatives.
Report; The activation of T type calcium channel is relevant with the morbidity of following symptom; That is: cardiac hypertrophy (reference example such as non-patent literature 2), cardiac insufficiency (reference example such as non-patent literature 2), cardiomyopathy (reference example such as non-patent literature 3), be the tachycardia arrhythmia (reference example such as non-patent literature 4), arteriosclerosis (reference example such as non-patent literature 5) of representative with the auricular fibrillation, be renal dysfunction (reference example such as non-patent literature 6), renal insufficiency (reference example such as non-patent literature 6), inflammation and edema (reference example such as non-patent literature 7), hyperaldosteronemia (reference example such as non-patent literature 8), neuropathic pain (reference example such as non-patent literature 9), the epilepsy (reference example such as non-patent literature 10) of representative with the nephritis and kidney disease; Therefore, can think that T type calcium channel hinders
Patent documentation 1: the spy opens clear 61-30591 communique
Patent documentation 2: the spy opens clear 60-69089 communique
Patent documentation 3: the spy opens flat 01-275591 communique
Patent documentation 4: the spy opens clear 61-63688 communique
Patent documentation 5: the spy opens clear 63-233992 communique
Patent documentation 6: the spy opens clear 62-169795 communique
Patent documentation 7: the spy opens clear 62-169796 communique
Non-patent literature 1:Mausumiya H etc., Eur J Pharmcol, the 335th volume, the 15th～21 page (1997 years)
Non-patent literature 2:Mulder P etc., J Am Coll Cardiol, the 29th volume, the 416th～421 page (1997 years)
Non-patent literature 3:Villame J etc., Cardiovasc Drugs Ther, the 15th volume, the 41st～48 page (calendar year 2001)
Non-patent literature 4:Fareh S etc., Circulation, the 100th volume, the 2191st～2197 page (1999 years)
Non-patent literature 5:Noll G and Luscher TF, Cardiology, the 89th volume, the 10th～15 page (1998 years)
Non-patent literature 6:Baylis C etc., Am J Kidney Dis, the 38th volume, the 1292nd～1297 page (calendar year 2001)
Non-patent literature 7:Bilici D etc., Pharmacol Res, the 44th volume, the 527th～531 page (calendar year 2001)
Non-patent literature 8:Lenglet S etc., Endocrinology, the 143rd volume, the 1748th～60 page (2002 years)
Non-patent literature 9:McCallum JB etc., Anesthesiology, the 98th volume, the 209th～216 page (2003 years)
Non-patent literature 10:Porcello DM etc., J.Neurophysiol, the 89th volume, the 177th～185 page (2003 years)
But; With efonidipine (racemic modification) is that the dihydropyridine-5-phosphate derivatives of representative is except treating above-mentioned disease; Hindering factor in the time of also possibly becoming treatment based on the intensive vasorelaxation action of L type calcium channel blocking effect with to the influencing of cardiac function; And, also possibly cause taking place the decline of quality of lifes (Quality of life) such as the headache, fever based on vasorelaxation action, dizzy, edema sometimes.
Hence one can see that, as above-mentioned treatment of diseases medicine, if can find that the blocking effect of L type calcium channel is weak or do not demonstrate the T type calcium channel blocker to the blocking effect of L type calcium channel basically, then is very useful.
Present inventors have carried out deep research in order to address the above problem; The result finds; 4 absolute configuration of dihydropyridine ring be the optical activity dihydropyridine-5-phosphate derivatives of R configuration to the blocking effect of L type calcium channel a little less than or do not demonstrate blocking effect basically; And T type calcium channel is demonstrated optionally blocking effect, thereby accomplished the present invention.
Summary of the invention
That is, the present invention provides,
1. a T type calcium channel blocker is the optical activity 1 shown in the formula (1), 4-dihydropyridine compound, its officinal salt or their solvate,
[in the formula, R
1And R
2Represent C independently of one another
1-6Alkyl { this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace), C
2-6Alkenyl or C
2-6Alkynyl (this C
2-6Alkenyl or C
2-6Alkynyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) replace or-L
1-NR
3R
4{ R
3And R
4Represent C independently of one another
1-6Alkyl (this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) or phenyl (this phenyl can be by C
1-6Alkoxyl or halogen atom replace), L
1Expression C
2-6Alkylidene (this C
2-6Alkylidene can be by C
1-3(this phenyl can be by halogen atom, C for alkyl or phenyl
1-3Alkyl or C
1-3Alkoxyl replaces arbitrarily) replace arbitrarily), perhaps R
1And R
2In conjunction with and represent-CR
5R
6-CR
7R
8-,-CR
5R
6-CR
7R
8-CR
9R
10-perhaps-CR
5R
6-CR
7R
8-CR
9R
10-CR
11R
12-(R
5～R
12Represent hydrogen atom or C independently of one another
1-6Alkyl, perhaps any 2 combine and form 5,6 or 7 Yuans rings with substituted carbon atom is common),
X
1And X
2Represent O or NR independently of one another
13(R
13Expression hydrogen atom or C
1-6Alkyl),
Ar representes phenyl, pyridine radicals, furyl or 2,1, and (this phenyl, pyridine radicals, furyl or 2,1,3-Ben Bing oxadiazole-4-base can be replaced arbitrarily by 1 or 2 substituent groups that are selected from following radicals 3-Ben Bing oxadiazole-4-base: NO
2, CF
3, Br, Cl, F, (R representes C to R
1-20Alkyl), OH, OR
14(R
14Expression C
1-6Alkyl), OCHF
2, COOR
14, NH
2, NHR
14, NR
14R
15(R
15Expression C
1-6Alkyl), CONH
2, CONHR
14, CONR
14R
15, COSR
14, SR
14, S (O) R
14, S (O)
2R
14, SO
3H, SO
3R
14, SO
2NH
2, SO
2NHR
14, SO
2NR
14R
15, CN and phenyl oxygen base),
R
aAnd R
bRepresent C independently of one another
1-6Alkyl ,-L
2-NR
16R
17{ R
16And R
17Represent hydrogen atom, C independently of one another
1-6Alkyl (this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) or phenyl (this phenyl can be by C
1-6Alkoxyl or halogen atom replace), L
2Expression C
2-6Alkylidene (this C
2-6Alkylidene can be by C
1-3(this phenyl can be by halogen atom, C for alkyl or phenyl
1-3Alkyl or C
1-3Alkoxyl replaces arbitrarily) replace arbitrarily) ,-CH
2O-L
2-NR
16R
17, Ar
1(Ar
1(this phenyl can be by halogen atom, C for the expression phenyl
1-3Alkyl or C
1-3Alkoxyl replaces arbitrarily)), CH=CHAr
1, CH
2CH (OH) Ar
1, CHO, CN, CH
2OH, CH
2OR
16,-L
2-N (CH
2CH
2)
2NR
16Or NR
16R
17,
Y representes C
1-20Alkyl { this C
1-20Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace), C
2-6Alkenyl or C
2-6Alkynyl (this C
2-6Alkenyl and C
2-6Alkynyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) replace ,-L
3-NR
18R
19{ R
18And R
19Represent C independently of one another
1-6Alkyl (this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) or phenyl (this phenyl can be by C
1-6Alkoxyl or halogen atom replace), L
3Expression C
2-6Alkylidene (this C
2-6Alkylidene can be by C
1-3(this phenyl can be by halogen atom, C for alkyl or phenyl
1-3Alkyl or C
1-3Alkoxyl replaces arbitrarily) replace arbitrarily),
or
(in the formula, o and p represent 3 or 4 independently of one another, and q representes 1,2 or 3), * representes absolute configuration];
2. described as optical activity 1 as above-mentioned 1, the T type calcium channel blocker of 4-dihydropyridine compound, its officinal salt or their solvate,
Y representes-L
3-NR
18R
19{ R
18And R
19Represent C independently of one another
1-6Alkyl (this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) or phenyl (this phenyl can be by C
1-6Alkoxyl or halogen atom replace), L
3Expression C
2-6Alkylidene (this C
2-6Alkylidene can be by C
1-3(this phenyl can be by halogen atom, C for alkyl or phenyl
1-3Alkyl or C
1-3Alkoxyl replaces arbitrarily) replace arbitrarily),
or
(in the formula, o and p represent 3 or 4 independently of one another, and q representes 1,2 or 3), R
aExpression C
1-6Alkyl;
3. described as optical activity 1 as above-mentioned 2, the T type calcium channel blocker of 4-dihydropyridine compound, its officinal salt or their solvate, R
bBe C
1-6Alkyl, CN or NH
2
4. described as optical activity 1 as above-mentioned 1, the T type calcium channel blocker of 4-dihydropyridine compound, its officinal salt or their solvate,
Y representes C
1-20Alkyl { this C
1-20Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace), C
2-6Alkenyl or C
2-6Alkynyl (this C
2-6Alkenyl and C
2-6Alkynyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) replace, R
bExpression-L
2-NR
16R
17{ R
16And R
17Represent hydrogen atom, C independently of one another
1-6Alkyl (this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) or phenyl (this phenyl can be by C
1-6Alkoxyl or halogen atom replace), L
2Expression C
2-6Alkylidene (this C
2-6Alkylidene can be by C
1-3(this phenyl can be by halogen atom, C for alkyl or phenyl
1-3Alkyl or C
1-3Alkoxyl replaces arbitrarily) replace arbitrarily) ,-CH
2O-L
2-NR
16R
17Or-L
2-N (CH
2CH
2)
2NR
16, R
aExpression C
1-6Alkyl;
5. described as optical activity 1 as above-mentioned 2,3 or 4, the T type calcium channel blocker of 4-dihydropyridine compound, its officinal salt or their solvate,
R
1And R
2Represent C independently of one another
1-6Alkyl { this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace), C
2-6Alkenyl or C
2-6Alkynyl (this C
2-6Alkenyl and C
2-6Alkynyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) replace, perhaps R
1And R
2In conjunction with and represent-CR
5R
6-CR
7R
8-,-CR
5R
6-CR
7R
8-CR
9R
10-perhaps-CR
5R
6-CR
7R
8-CR
9R
10-CR
11R
12-(R
5～R
12Represent hydrogen atom or C independently of one another
1-6Alkyl or any 2 and 5,6 or 7 Yuans rings of the common formation of the substituted carbon atom of institute), X
1And X
2Be O;
6. described as optical activity 1 as above-mentioned 5, the T type calcium channel blocker of 4-dihydropyridine compound, its officinal salt or their solvate,
Ar is phenyl, 3-nitrobenzophenone, 2-nitrobenzophenone, 3-chlorphenyl, 2-chlorphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-trifluoromethyl, 2-trifluoromethyl or 2, the 3-Dichlorobenzene base;
7. described as optical activity 1 as above-mentioned 6, the T type calcium channel blocker of 4-dihydropyridine compound, its officinal salt or their solvate,
R
1And R
2In conjunction with and represent-CH
2-C (CH
3)
2-CH
2-, X
1And X
2Be O, Ar is the 3-nitrobenzophenone, R
aAnd R
bBe methyl, Y is 2-[benzyl (phenyl) amino] ethyl;
8. a medicine contains each described T type calcium channel blocker of 1～7;
9. effective treatment of diseases of T type calcium channel blocking effect or prophylactic agent contain each described T type calcium channel blocker of 1～7;
10. the medicine of treating or preventing cardiac hypertrophy contains each described T type calcium channel blocker of 1～7;
11. the medicine of treating or preventing cardiac dysfunction contains each described T type calcium channel blocker of 1～7;
12. one kind the treatment or prevent myocardiac medicine, contain each described T type calcium channel blocker of 1～7;
13. the medicine of treating or preventing auricular fibrillation contains each described T type calcium channel blocker of 1～7;
14. the medicine of treating or preventing the tachycardia arrhythmia contains each described T type calcium channel blocker of 1～7;
15. treat or the hardened medicine of prevention of arterial, contain each described T type calcium channel blocker of 1～7 for one kind;
16. the medicine of treating or preventing nephritis contains each described T type calcium channel blocker of 1～7;
17. the medicine of treating or preventing nephropathy contains each described T type calcium channel blocker of 1～7;
18. the medicine of treating or preventing renal dysfunction contains each described T type calcium channel blocker of 1～7;
19. the medicine of treating or preventing renal insufficiency contains each described T type calcium channel blocker of 1～7;
20. the medicine of treating or preventing edema contains each described T type calcium channel blocker of 1～7;
21. the treatment or the medicine of prevention of inflammation contain each described T type calcium channel blocker of 1～7;
22. the medicine of treating or preventing hyperaldosteronemia contains each described T type calcium channel blocker of 1～7;
23. the medicine of treating or preventing neuropathic pain contains each described T type calcium channel blocker of 1～7;
24. the medicine of treating or preventing epilepsy contains each described T type calcium channel blocker of 1～7.
The specific embodiment
Below, the present invention will be described in more detail.
In addition, " n " just representing in this manual, and " i " expression is different, " s " representes the second month in a season, and " t " representes uncle, " c " representative ring.
Each substituent group to described in this description describes.
As halogen atom, can enumerate out fluorine atom, chlorine atom, bromine atoms and iodine atom.
As C
1-3Alkyl can be the C of straight chain, side chain
1-3Alkyl or C
3Cycloalkyl can be enumerated out for example methyl, ethyl, n-propyl group, i-propyl group or c-propyl group etc.
As C
1-6Alkyl can be the C of straight chain, side chain
1-6Alkyl or C
3-6Cycloalkyl, for example, except at above-mentioned C
1-3In the alkyl outside the cited group; Can also enumerate out n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, n-amyl group, 1-methyl-n-butyl, 2-methyl-n-butyl, 3-methyl-n-butyl, 1; 1-dimethyl-n-propyl group, c-amyl group, 2-methyl-c-butyl, n-hexyl, 1-methyl-n-amyl group, 2-methyl-n-amyl group, 1; 1-dimethyl-n-butyl, 1-ethyl-n-butyl, 1; 1,2-trimethyl-n-propyl group, c-amyl group, 1-methyl-c-amyl group, 1-ethyl-c-butyl and 1,2-dimethyl-c-butyl etc.
As C
1-20Alkyl can be the C of straight chain, side chain
1-20Alkyl or C
3-20Cycloalkyl, for example, except at above-mentioned C
1-6Outside the substituent group of enumerating in the alkyl, can also enumerate out n-heptyl, 2-cyclopenta ethyl, n-octyl, 2-cyclohexyl ethyl, 3-cyclopenta-n-pro-pyl, n-nonyl, 3-cyclohexyl-n-pro-pyl, 4-cyclopenta-normal-butyl, positive decyl, 4-cyclohexyl-normal-butyl, 5-cyclopenta-n-pentyl, n-undecane base, 5-cyclohexyl-n-pentyl, 6-cyclopenta-n-hexyl, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, AI3-06523 base, AI3-36122 base and AI3-28404 base etc.
As C
2-6Alkenyl comprises the C of straight or branched
2-6Alkenyl; Can enumerate out vinyl, 1-acrylic, 2-acrylic, 1-methyl isophthalic acid-vinyl, 1-butylene base, crotyl, 3-cyclobutenyl, 2-methyl isophthalic acid-acrylic, 2-methyl-2-acrylic, 1-ethyl vinyl, 1-methyl isophthalic acid-acrylic, 1-methyl-2-acrylic, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-n-propyl ethylene base, 1-methyl isophthalic acid-cyclobutenyl, 1-methyl-2-butene base, 1-methyl-3-cyclobutenyl, 2-ethyl-2-acrylic, 2-methyl-1-butene thiazolinyl, 2-methyl-2-butene base, 2-methyl-3-cyclobutenyl, 3-methyl-1-butene base, 3-methyl-2-butene base, 3-methyl-3-cyclobutenyl, 1; 1-dimethyl-2-acrylic, 1-i-propyl ethylene base, 1; 2-dimethyl-1-acrylic, 1; 2-dimethyl-2-acrylic, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 1-methyl-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-n-butyl vinyl, 2-methyl-1-pentene thiazolinyl, 2-methyl-pentenyl, 2-methyl-3-pentenyl, 2-methyl-4-pentenyl, 2-n-propyl group-2-acrylic, 3-methyl-1-pentene thiazolinyl, 3-methyl-pentenyl, 3-methyl-3-pentenyl, 3-methyl-4-pentenyl, 3-ethyl-3-cyclobutenyl, 4-methyl-1-pentene base, 4-methyl-pentenyl, 4-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1; 1-dimethyl-crotyl, 1; 1-dimethyl-3-cyclobutenyl, 1; 2-dimethyl-1-butylene base, 1; 2-dimethyl-crotyl, 1; 2-dimethyl-3-cyclobutenyl, 1-methyl-2-ethyl-2-acrylic, 1-s-butyl vinyl, 1; 3-dimethyl-1-butylene base, 1; 3-dimethyl-crotyl, 1; 3-dimethyl-3-cyclobutenyl, 1-i-butyl vinyl, 2; 2-dimethyl-3-cyclobutenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2; 3-dimethyl-3-cyclobutenyl, 2-i-propyl group-2-acrylic, 3; 3-dimethyl-1-butylene base, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-cyclobutenyl, 1-n-propyl group-1-acrylic, 1-n-propyl group-2-acrylic, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-cyclobutenyl, 1,1,2-trimethyl-2-acrylic, 1-tert-butyl group vinyl, 1-methyl isophthalic acid-ethyl-2-acrylic, 1-ethyl-2-methyl isophthalic acid-acrylic, 1-vinyl-2-methyl-2-acrylic, 1-i-propyl group-1-acrylic and 1-i-propyl group-2-acrylic etc.
As C
2-6Alkynyl comprises the C of straight or branched
2-6Alkynyl; Can enumerate out acetenyl, 1-propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl isophthalic acid-butynyl, 1; 1-dimethyl-2-propynyl, 2-ethyl-2-propynyl, 1-hexyn, 2-hexyn, 3-hexyn, 4-hexyn, 5-hexyn, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentene alkynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentene alkynyl, 4-methyl-valerylene base, 1; 1-dimethyl-2-butyne base, 1; 1-dimethyl-3-butynyl, 1; 2-dimethyl-3-butynyl, 2; 2-dimethyl-3-butynyl, 3,3-dimethyl-ethyl acetylene base, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 1-n-propyl group-2-propynyl, 2-ethyl-3-butynyl, 1-methyl isophthalic acid-ethyl-2-propynyl and 1-i-propyl group-2-propynyl etc.
As C
1-3Alkoxyl can be the C of straight chain, side chain
1-3Alkoxyl or C
3Cycloalkyloxy can be enumerated out for example methoxyl group, ethyoxyl, n-propoxyl group, i-propoxyl group and c-propoxyl group etc.
As C
1-6Alkoxyl can be the C of straight chain, side chain
1-6Alkoxyl or C
3-6Cycloalkyloxy is for example except at above-mentioned C
1-3Outside the substituent group of enumerating in the alkoxyl; Can also enumerate out n-butoxy, i-butoxy, s-butoxy, t-butoxy, c-butoxy, n-amoxy, 1-methyl-n-butoxy, 2-methyl-n-butoxy, 3-methyl-n-butoxy, 1; 1-dimethyl-n-propoxyl group, c-amoxy, 2-methyl-c-butoxy, n-hexyloxy, 1-methyl-n-amoxy, 2-methyl-n-amoxy, 1; 1-dimethyl-n-butoxy, 1-ethyl-n-butoxy, 1; 1,2-trimethyl-n-propoxyl group, c-hexyloxy, 1-methyl-c-amoxy, 1-ethyl-c-butoxy and 1,2-dimethyl-c-butoxy etc.
As C
2-6Alkylidene can be enumerated out ethylidene, propylidene, butylidene, pentylidene and hexylidene etc.
As 5,6 or 7 Yuans rings, can enumerate out c-amyl group, c-hexyl and c-heptyl.
As preferred R
1And R
2If, then can enumerate out following group according to stating more preferred order record more backward:
1.R
1And R
2In conjunction with and represent-CR
5R
6-CR
7R
8-,-CR
5R
6-CR
7R
8-CR
9R
10-perhaps-CR
5R
6-CR
7R
8-CR
9R
10-CR
11R
12-(R
5～R
12Represent hydrogen atom or C independently of one another
1-6Alkyl or any 2 and 5,6 or 7 Yuans rings of the common formation of the substituted carbon atom of institute).
2.R
1And R
2In conjunction with and represent-CR
5R
6-CR
7R
8-CR
9R
10-(R
5～R
10Represent hydrogen atom or C independently of one another
1-6Alkyl).
3.R
1And R
2In conjunction with and represent-CH
2-C (CH
3)
2-CH
2-or-CHCH
3-CH
2-CHCH
3-.
4.R
1And R
2Represent C independently of one another
1-6Alkyl { this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace), C
2-6Alkenyl or C
2-6Alkynyl (this C
2-6Alkenyl and C
2-6Alkynyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) replace.
5.R
1And R
2Represent C independently of one another
1-6Alkyl.
6.R
1And R
2All represent methyl or ethyl.
As preferred X
1And X
2If, then can enumerate out following group according to stating more preferred order record more backward.
1.X
1And X
2All represent O.
As preferred Ar, can enumerate out following group.
1. phenyl, 4-nitrobenzophenone, 3-nitrobenzophenone, 2-nitrobenzophenone, 4-chlorphenyl, 3-chlorphenyl, 2-chlorphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-trifluoromethyl, 3-trifluoromethyl, 2-trifluoromethyl and 2, the 3-Dichlorobenzene base.
2. phenyl, 3-nitrobenzophenone, 2-nitrobenzophenone, 3-chlorphenyl, 2-chlorphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-trifluoromethyl, 2-trifluoromethyl and 2, the 3-Dichlorobenzene base.
3. phenyl, 3-nitrobenzophenone, 2-nitrobenzophenone, 3-chlorphenyl, 2-chlorphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-trifluoromethyl and 2-trifluoromethyl.
4. phenyl, 3-nitrobenzophenone, 2-nitrobenzophenone, 3-methoxyphenyl, 2-methoxyphenyl, 3-trifluoromethyl and 2-trifluoromethyl.
As preferred R
b, can enumerate out following group.
1.C
1-6Alkyl.
More preferably,
2. methyl.
As preferred R
aIf, then can enumerate out following group according to stating more preferred order record more backward.
1.C
1-6Alkyl, CN and NH
2
2. methyl, CN and NH
2
3.-L
2-NR
16R
17{ R
16And R
17Represent hydrogen atom, C independently of one another
1-6Alkyl (this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) or phenyl (this phenyl can be by C
1-6Alkoxyl or halogen atom replace), L
2Expression C
2-6Alkylidene (this C
2-6Alkylidene can be by C
1-3(this phenyl can be by halogen atom, C for alkyl or phenyl
1-3Alkyl or C
1-3Alkoxyl replaces arbitrarily) replace arbitrarily) ,-CH
2O-L
2-NR
16R
17With-L
2-N (CH
2CH
2)
2NR
16
4.-CH
2O-L
2-NR
16R
17。
5.-CH
2OCH
2CH
2NH
2。
As preferred Y, if, then can enumerate out following group according to stating more preferred order record more backward.
1.C
1-20Alkyl { this C
1-20Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace), C
2-6Alkenyl or C
2-6Alkynyl (this C
2-6Alkenyl and C
2-6Alkynyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) replace.
2. methyl, ethyl, isopropyl, isobutyl group and methoxy ethyl.
3.-L
3-NR
18R
19{ R
18And R
19Represent C independently of one another
1-6Alkyl (this C
1-6Alkyl can (this phenyl can be by C by phenyl
1-6Alkoxyl or halogen atom replace) replace) or phenyl (this phenyl can be by C
1-6Alkoxyl or halogen atom replace), L
3Expression C
2-6Alkylidene (this C
2-6Alkylidene can be by C
1-3(this phenyl can be by halogen atom, C for alkyl or phenyl
1-3Alkyl or C
1-3Alkoxyl replaces arbitrarily) replace arbitrarily),
or
(in the formula, o and p represent 3 or 4 independently of one another, and q representes 1,2 or 3).
4.
and
In optical activity 1 used in the present invention, when the 4-dihydropyridine compound is can shape salifiable chemical compound, also can use its officinal salt as effective ingredient.
As officinal salt, can enumerate out hydrochlorate, hydrobromate, sulfate, mesylate, acetate, benzoate, tartrate, phosphate, lactate, maleate, fumarate, malate, gluconate and Salicylate etc.
Preferably can enumerate out hydrochlorate and mesylate.
As solvate, so long as pharmaceutically useful, just have no particular limits, specifically, can enumerate out hydrate and ethanol compound.
Used in the present invention as optical activity 1, the T type calcium channel blocker of 4-dihydropyridine compound, its officinal salt or their solvate, the effective treatment of diseases medicine of T type calcium channel blocking effect that contains the medicine of this T type calcium channel blocker or contain this T type calcium channel blocker usually can be with through mucous membrane absorbent such as oral agents such as tablet, capsule, powder, granule, pill, syrup, rectally preparation, per nasal absorbent, transvaginal absorbent, through the form administration of lung absorbent, inhalant, eye drop, cutaneous permeable agent or injection.1 therapeutic agent administration that this preparation can be used as, also can with other the form administration of mixture of therapeutic agent.These medicines can be with the monomeric form administration, also can be with the form administration of common pharmaceutical composition.These preparations can also add the additive of being allowed in pharmacology, the galenic pharmacy, and with the usual way manufacturing.That is additives such as the excipient that, can use in the oral Preparation to be used always, lubricant, binding agent, disintegrating agent, wetting agent, plasticizer, smears.Oral liquid can be forms such as aqueous or oily suspensions, solution, emulsion, syrup, elixir, perhaps the form of the dry syrup of water or the preparation of other appropriate solvent before use.The aforesaid liquid preparation can also contain the such typical additives of suspending agent, spice, diluent or emulsifying agent.Can be with the suppository form administration when rectally.Suppository can add emulsifying agent, suspending agent, antiseptic etc. as required with suitable material such as cocoa butter, LAURIN DYNASAN 112, Polyethylene Glycol, glycerin gelatine, witepol (ウ イ テ Star プ ゾ one Le), sodium stearate or their mixture as substrate.Injection can use can constitute the aqueous dosage form or when injecting the lysotype dosage form lytic agent such as distilled water for injection, normal saline solution, 5% glucose solution, propylene glycol and even cosolvent, pH regulator agent, etc. preparation compositions such as imbibition agent, stabilizing agent.
When medicine of the present invention is taken to the people; According to patient's age, its dosage of state decision; Usually as far as the adult, being about 0.1～1000mg/ people/sky when oral formulations or drop rectum with drug, is about 0.05mg/～500mg/ people/sky during the injection administration.These numerical value are illustrative, and dosage should decide according to patient's symptom.
As using situation of the present invention, can enumerate the situation that to expect to improve disease through the chemical compound that use has a T type calcium channel blocking activity.Specifically, can be used for cardiac hypertrophy, cardiac insufficiency, cardiomyopathy, be the tachycardia arrhythmia, arteriosclerosis of representative with the auricular fibrillation, be the treatment or the prevention of renal dysfunction, renal insufficiency, inflammation and edema, hyperaldosteronemia, neuropathic pain, the epilepsy etc. of representative with the nephritis and kidney disease.
Optical activity 1 shown in the formula (1); The 4-dihydropyridine compound; Can open flat 01-113398 communique with reference to the spy, the spy opens flat 02-011592 communique, Chem.Pharm.Bull., 40 (9), 2377～2381 (1992) and Chem.Pharm.Bull.; 40 (9), 2370～2376 (1992) described methods are made.
Manufacturing approach is shown in following layout.
Layout 1
(in the formula, R
1, R
2, X
1, X
2, R
a, R
b, Ar, Y be identical with above-mentioned definition with *).
At first, under the azeotropic dehydration condition, in toluene, heat phosphonic acids styrene esters (2) and the amino .beta.-methylacrylic acid derivant (3) of optical activity, obtain 1,4-dihydrogen pyridine derivative (1a).
Then, wait to 1 through crystallization or chromatographic column, 4-dihydrogen pyridine derivative (1a) carries out diastereomer and splits; Obtain (1a-R), carry out methoxyization and obtain (1b-R), perhaps; (1a) carry out methoxyization; After obtaining (1b), carry out diastereomer through crystallization or column chromatography and split, obtain (1b-R).
Then, carry out ester exchange,, can produce the optical activity 1 of formula (1), the 4-dihydropyridine compound through sloughing methoxy with hydrogen chloride.
In addition; Can open clear 59-161392 communique, spy according to the spy opens clear 60-69089 communique, spy and opens clear 60-248693 communique, spy and open clear 60-258194 communique, spy and open clear 61-30591, spy and open clear 61-37793 communique, spy and open clear 61-63688 communique, spy and open clear 61-210092 communique, spy and open clear 61-254596 communique, spy and open clear 62-169795 communique, spy and open clear 62-169796 communique, spy and open clear 62-195392 communique, spy and open clear 63-68591 communique, spy and open that clear 63-233992 communique, spy are opened flat 01-113398 communique, the spy opens flat 01-275591 communique, Chem.Pharm.Bull.; 40 (9); The 2362nd～2369 page (1992) and Chem.Pharm.Bull.; 40 (9), the 2370th～2376 page of (1992) described manufacturing approach produces racemic 1; The 4-dihydropyridine compound; Can also separate with HPLC through using optically active column then, make optically active 1, the 4-dihydropyridine compound.
Below, come at length to explain the present invention with embodiment, still, the present invention does not receive any restriction of these embodiment.
Efonidipine (1 as embodiment; 4-dihydro-2, and 6-dimethyl-5-(5,5-dimethyl-2-oxygen-1; 3; 2-dioxaphosphorinane-2-yl)-4-(3-nitrobenzophenone)-3-picolinic acid 2-[benzyl (phenyl) amino] ethyl ester) R body and S body, use open the synthetic racemic efonidipine of embodiment 25 described methods of clear 63-233992 communique according to the spy after, split chromatographic column with optical isomer and carry out the HPLC preparation and separate the chemical compound that obtains.
HPLC prepares separation condition
Chromatographic column: CHIRALCEL OC (ダ イ セ Le chemical industry (strain) society system)
Column size: 20cm φ * 50cm
Eluent: methanol
Column temperature: room temperature
Flow velocity: 760ml/ minute
In addition, the chemical compound as embodiment outside the above-mentioned efonidipine chemical compound is synthetic according to following method.
5 for dihydropyridine ring is the chemical compound of diethyl phosphonyl (Z2), is to open clear 60-69089 communique and the described manufacturing approach manufacturing of the clear 60-248693 communique of Te Kai with reference to the spy.
5 for dihydropyridine ring is 5,5-dimethyl-2-oxygen-1,3; The chemical compound of 2-dioxaphosphorinane-2-base (Z1); Be to open clear 62-169795 communique and Chem.Pharm.Bull. with reference to the spy, 40 (9), the 2362nd～2369 page (1992) described manufacturing approach is made.
5 for dihydropyridine ring is 4,6-dimethyl-2-oxygen-1,3; The 2-dioxaphosphorinane-(Z3, chemical compound Z4) are to open clear 63-68591 communique and Chem.Pharm.Bull. with reference to the spy to the 2-base; 40 (9), the 2370th～2376 page (1992) described manufacturing approach is made.
In addition, chemical compound (1-a) as follows is to make with following method.
8.05g (19.3mmol) chemical compound (3), 1.64g (21.3mmol) ammonium acetate, 80ml ethanol are mixed reflux 45 minutes.In resulting reactant liquor, add 7.23g (21.3mmol) chemical compound (2), further reflux is 3 hours.After the cooling, distillation removes and to desolvate under reduced pressure, adds the aqueous sodium carbonate of 100ml toluene, 50ml 10%, after the vibration, leaves standstill, separatory.Use 20% saline solution washing organic layer, carry out the drying back with magnesium sulfate (anhydrous) and under reduced pressure, distill except that desolvating.With silica gel column chromatography (hexane-ethyl acetate 4: 1V/V～ethyl acetate) make with extra care residue, obtain the yellow unbodied chemical compound (4) of 6.04g (yield 42%).
(chemical compound (3) is made according to the described method of EP 0599220 A1)
MS?m/z：738(M
++1)，
1H-NMR(CDCl
3)δ(ppm)：0.87(3H，s)，1.08(3H，s)，2.39(3H，d)，2.42(2H，t)，3.51-3.73(4H，m)，3.69(3H，s)，4.21-4.31(2H，m)，4.56(1H，d)，4.70(1H，d)，4.93(1H，d)，7.17-7.49(16H，m)，7.62(1H，d)，8.02(1H，d)，8.11(1H，m)。
500mg (0.678mmol) chemical compound (4) is dissolved in the 5ml methanol, adds 500mg (1.37mmol) 10%HCl-MeOH, reflux 2.5 hours.After the cooling, distillation removes and to desolvate under reduced pressure, adds 20ml chloroform, 10ml 10% aqueous sodium carbonate and vibration, leaves standstill then, separatory.The washing organic layer, after use magnesium sulfate (anhydrous) drying, distillation removes and desolvates under reduced pressure.(hexane-ethyl acetate 20: 1V/V～ethyl acetate, chloroform-methanol 5 then: 1V/V) make with extra care residue, obtain the chemical compound (1-a) of 216mg (yield 64%) yellow oil form with silica gel column chromatography.
MS?m/z：495(M
+)，
1H-NMR(CDCl
3)δ(ppm)：0.89(3H，s)，1.04(3H，s)，2.46(3H，d)，3.00-3.03(2H，m)，3.54-3.74(4H，m)，3.68(3H，s)，4.09-4.27(2H，m)，4.61(1H，d)，4.66(1H，d)，4.89(1H，d)，7.40(1H，dd)，7.65(1H，d)，8.01(1H，d)，8.10(1H，m)，8.47(1H，brm)。
Pharmacological test example 1: (in mammalian cell (bhk cell), expressing the influence of L type and T type Ca (calcium) passage)
Test method
Test is according to people's such as Wakamori M method (Wakamori M etc., J Biol Chem, 273,34857～34867,1998), uses and expresses L type Ca passage or T type calcium channel (α
1G) BHK (babyhamster kidney) cell of (Perez-Reyes E.:J Bioenerg Biomembr 30,313～318,1998), utilize full cell patch pincers (whole cell patch clamp) method to carry out the electrophysiology evaluation.Each Ca ion current be through patch clamp amplifier determine to transmembrane potential remain on-cell of 80mV applies the depolarization pulse, and (L type Ca passage is 10mV, and T type Ca passage is-inward electric current 20mV) time.For optical activity R body, the S body of efonidipine, it is dissolved in the extracellular measures in the solution, pour into and use, measure the variation of using the Ca ion current after 5 minutes.The result representes with respect to the Ca magnitude of current (100%) of control solvent with the Ca magnitude of current suppression ratio (%) of chemical compound of the present invention.
Efonidipine R-configuration (average ± SE)
Efonidipine S-configuration (average ± SE)
[0156]?
The result
Efonidipine optical activity R body when being 0.1 μ M or the concentration more than it, demonstrates the blocking effect that depends on concentration to T type Ca passage, even when being 10 μ M, L type calcium channel is not shown blocking effect yet.On the other hand, the S body is in the following time of concentration of 1 μ M, L type calcium channel demonstrated 55.6 ± 7.1% intensive blocking effect.The result judges thus, and efonidipine R body is high to the selectivity of T type Ca passage.
In addition, only in a kind of optically active body (S body), find the effect of L type Ca carrier frequency channel break, and in two kinds of optically active bodies, all found the effect of T type Ca carrier frequency channel break.Thus, if find 1, the 4-dihydropyridine compound shows the effect of T type Ca carrier frequency channel break through racemic modification, is hinting that then a kind of (the R body) of its optically active body becomes the chemical compound that T type Ca passage is had high selectivity.
Pharmacological test example 2: (to the influence of the T type Ca passage of expression in mammalian cell (bhk cell))
Through the method identical with pharmacological test example 1, to the chemical compound shown in the following formula,
Measure each drug level and be the blocking-up rate of the T type Ca passage of 10 μ M, as shown in the table.
In addition, employed Z1～Z4, Y1～Y7, B1 and A1～A7 represent the substituent kind of above-claimed cpd in the table, and it is as follows.
A1:3-nitrobenzophenone, A2:3-chlorphenyl, A3:2-nitrobenzophenone, A4:2-methoxyphenyl, A5:3-methoxyphenyl, A6: phenyl, A7:3-trifluoromethyl.
Because above-claimed cpd demonstrates T type calcium channel blocking effect through racemic modification, thereby can think that a kind of (the R body: do not show L type calcium channel blocking effect) of its optically active body is to demonstrate the optionally chemical compound of T type calcium channel blocking effect.
Formulation example 1
Manufacturing contains the granule of following composition
Chemical compound 10mg shown in the empirical formula (1)
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
1000mg
Chemical compound shown in the formula (1) and lactose are passed through 60 purpose sieves.Corn starch is passed through 120 purpose sieves.With V-Mixer they are mixed.In mixed-powder, add low-viscosity hydroxypropylcelluloand (HPC-L) aqueous solution, (drying extrusion granulator, aperture 0.5～1mm) afterwards, of kneading, granulate.Use vibrosieve (12/60 order) to sieve resulting dried particles, obtain granule.
Formulation example 2
The capsule that manufacturing contains following composition is filled and to be used powder
Chemical compound 10mg shown in the empirical formula (1)
Lactose 79mg
Corn starch 10mg
Magnesium stearate 1mg
100mg
Chemical compound shown in the formula (1) and lactose are passed through 60 purpose sieves.Corn starch is passed through 120 purpose sieves.Use V-Mixer that they are mixed with magnesium stearate.10 times of powder 100mg are filled in No. 5 hard gelatin capsules.
Formulation example 3
The capsule that manufacturing contains following composition is filled and to be used granule
Chemical compound 15mg shown in the empirical formula (1)
Lactose 90mg
Corn starch 42mg
HPC-L 3mg
150mg
Chemical compound shown in the formula (1) and lactose are passed through 60 purpose sieves.Corn starch is passed through 120 purpose sieves.Use V-Mixer that they are mixed.In mixed-powder, add low viscosity hydroxy propyl cellulose (HPC-L) aqueous solution, after kneading, granulating, drying.Sieved resulting dried particles, carried out granulate with shaking screen (12/60 order), its 150mg was filled in No. 4 hard gelatin capsules.
Formulation example 4
Manufacturing contains the tablet of following composition
Chemical compound 10mg shown in the empirical formula (1)
Lactose 90mg
Microcrystalline Cellulose 30mg
Magnesium stearate 5mg
CMC-Na 15mg
150mg
Chemical compound shown in the formula (1), lactose, microcrystalline Cellulose, CMC-Na (sanlose) through 60 purpose sieves, are mixed.In mixed-powder, add magnesium stearate, obtain preparation and use mixed-powder.Suppress this mixed-powder, obtain the tablet of 150mg.
Formulation example 5
As following, make intravenous formulation.
Chemical compound 100mg shown in the formula (1)
Saturated fatty acid glyceride 1000ml
The solution of mentioned component normally carries out intravenously administrable with the speed of 1 minute 1ml to the patient.
The industry utilizability
Because chemical compound of the present invention has optionally T type calcium channel blocking effect; Thereby can think; It can be produces harmful effect to blood pressure, cardiac function and quality of life, can be used for cardiac hypertrophy, cardiac insufficiency, cardiomyopathy, is the tachycardia arrhythmia, arteriosclerosis of representative with the auricular fibrillation, is the treatment of the renal dysfunction, renal insufficiency, inflammation, edema, hyperaldosteronemia, neuropathic pain, epilepsy etc. of representative with the nephritis and kidney disease.Therefore, the present invention can provide a kind of effectively, safety and considered the above-mentioned treatment of diseases medicine that is used for of quality of life, thereby it is very useful at for example medical treatment, drug world.
Claims (1)
1.T the optical activity 1 shown in the type calcium channel blocker formula (1), 4-dihydropyridine compound or its officinal salt are used to prepare the purposes of the medicine of treating neuropathic pain,
* represent absolute configuration R,
R
1And R
2In conjunction with expression-CH
2-C (CH
3)
2-CH
2-, X
1And X
2Be O, Ar is the 3-nitrobenzophenone, R
aAnd R
bBe methyl, Y is 2-[benzyl (phenyl) amino] ethyl.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP090916/2003 | 2003-03-28 | ||
| JP2003090916 | 2003-03-28 | ||
| JP2003393893 | 2003-11-25 | ||
| JP393893/2003 | 2003-11-25 | ||
| PCT/JP2004/004432 WO2004087172A1 (en) | 2003-03-28 | 2004-03-29 | T-type calcium channel blockers |
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| Publication Number | Publication Date |
|---|---|
| CN1764462A CN1764462A (en) | 2006-04-26 |
| CN1764462B true CN1764462B (en) | 2012-09-26 |
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|---|---|
| CN (1) | CN1764462B (en) |
| UA (1) | UA79374C2 (en) |
| ZA (1) | ZA200507804B (en) |
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| CN102809596B (en) * | 2012-08-21 | 2014-07-09 | 辉源生物科技（上海）有限公司 | Method for recording T type calcium channel current by separating and cultivating newborn rat cortical neural cells |
-
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Non-Patent Citations (3)
| Title |
|---|
| ET AL.Effects of Ca2+ channel antagonists on sinus node:Prolongation of late phase 4 depolarization by efonidipine.European Journal of Pharmacology,335 1.1997,335(1),15-22. |
| Masumiya, Haruko |
| Masumiya, Haruko;ET AL.Effects of Ca2+ channel antagonists on sinus node:Prolongation of late phase 4 depolarization by efonidipine.European Journal of Pharmacology,335 1.1997,335(1),15-22. * |
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|---|---|
| UA79374C2 (en) | 2007-06-11 |
| ZA200507804B (en) | 2007-03-28 |
| CN1764462A (en) | 2006-04-26 |
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