UA79374C2 - T-t??pe calcium channel blockers - Google Patents

Abstract

T-Type calcium channel blockers consisting of optically active 1,4-dihydropyridines, pharmaceutically acceptable salts or solvates thereof, represented by the general formula (1), , (1) wherein R1 and R2 are each independently C1-6 alkyl group, or R1 and R2 are united to form -CR5R6-CR7RR8-, -CR5R6-CR7RR8-CR9R10- or -CR5R6-CR7RR8-CR9R10-CR11R12-, and the like; X1 and X2 are each independently O or NR13; Ar is optionally substituted phenyl group or the like; Ra and Rb are each independently C1-6 alkyl group, L2-NR16R17, CH2O-L2-NR16R17, CN, -L2-N(CH2CH2)2NR16 or NR16R17, or the like; Y is C1-20 alkyl group, , (2) , (3) , (4) , (5) or , (6) and * represents absolute R-configuration.

Description

Description of the invention

The present invention relates to T-type calcium channel blockers, which are optically active derivatives of 2-dihydropyridine-5-phosphonate, in which the absolute configuration of the 4-position on the dihydropyridine ring is

K-configuration. In addition, the present invention relates to therapeutic or prophylactic agents against diseases for which T-type calcium channel blockers are effective.

Dihydropyridine-5-phosphonate derivatives (racemates) are known to exhibit oral antihypertensive activity, being effective for cardiovascular diseases such as angina pectoris, cerebrovascular disease, hypertension, or the like (see, for example, Patent Documents 1-7).

The above action is due to the expansion of blood vessels, mainly based on the blocking action of calcium channels of type I and similar action of calcium antagonists of type I, represented by other numerous derivatives of 1,4-dihydropyridine.

Recently, it was found that efonidipine (racemate), which is a representative compound of 12 dihydropyridine-5-phosphonate derivatives, has a blocking effect on T-type calcium channels in addition to a blocking effect on I-type calcium channels (see, for example, non-patent document 1).

Activation of T-type calcium channels has been described to be involved in cardiomegaly (see, for example, Non-Patent Document 2), heart failure (see, for example, Non-Patent Document 2), cardiomyopathy (see, for example, Non-Patent Document 3), tachyarrhythmia represented by atrial fibrillation (see, for example, non-patent document 4), arteriosclerosis (see, for example, non-patent document 5), renal impairment represented by nephritis/nephropathy (see, for example, non-patent document 6), renal failure (see e.g., non-patent document b), inflammation and edema (see, e.g., non-patent document 7), hyperaldosteronism (see, e.g., non-patent document 8), neurogenic pain (see, e.g., non-patent document 9) and epilepsy (see , for example, a non-patent document 10). Therefore, it is believed that T-type calcium channel blockers are effective for the therapy and prevention of these diseases. Gee)

Patent document 1: UR 61-30591 A (1986).

Patent document 2: UR 60-69089 A (1985).

Patent document 3: UR 1-275591 A (1989).

Patent document 4: UR 61-63688 A (1986). WITH

Patent document 5: UR 63-233992 A (1988). what-

Patent document 6: UR 62-169795 A (1987)

Patent document 7: UR 62-169796 A (1987). and.

Non-patent document 1: Mazitiua N ei ai|.: Yeig ) Rpagtasoi! 335, pp. 15-21 (1997). Gee!

Non-patent document 2: Miideg Rei a).: U. At Soi! Sagaiyo! 29, pp. 416-421 (1997). 3o Non-patent Document 3: Mate .). ei aiI.: Sagaiomazs Ogadz Tpeg 15, pp. 41-48 (2001). in

Non-patent document 4: Raghep Z ei a)i.: Sigschatsop 100, pp. 2191-2197 (1999).

Non-Patent Document 5: Mine! S apa I izspeg TE: Sagaishiodu 89, p. 10-15 (1998).

Non-Patent Document 6: Wowiiizz Seyi a). At U Kiapeu Oiz 38 r.1292-1297 (2001). "

Non-patent document 7: Viiiisi O ei aiI.: Rnaptasoi! Kez 44, pp. 527-531 (2001). Z 50 Non-patent document 8: I epdyei Z ei aI.: EpdosgipoIodu 143, p. 1748-60 (2002). s Non-patent document 9: MeSaiisht UV ei ai.: Apezipesiodu 98, p. 209-216 (2003). z» Non-patent document 10: Rogseyo OM ei ai.:. Meigorpuzio! 89, pp. 177-185 (2003).

However, with the use of dihydropyridine-5-phosphonate derivatives, represented by efodipine (racemate), there is a possibility that the effect of this on the expansion of blood vessels and cardiac function, based on the blocking effect on calcium channels of the I type, becomes an obstacle in the therapy of the above-mentioned diseases In addition, they are responsible for reducing the quality of life, causing headache, paroxysmal feeling of heat, (Te) dizziness, edema or similar disturbance based on dilation of blood vessels.

Based on the above, it is considered very useful to find blockers of T-type calcium channels, which have a weak or almost no blocking effect on I-type calcium channels. -I 20 The authors of this invention conducted vigorous research to solve the above-mentioned problems. As a result, they found that optically active derivatives of dihydropyridine-5-phosphonate, in which the absolute configuration

T» 4-position of the dihydropyridine ring is K-configuration, exerts a weak or almost no blocking effect on I-type calcium channels and shows a selective blocking effect against T-type calcium channels.

The present invention discloses the following. 52 1. T-type calcium channel blocker, which is an optically active derivative of 1,4-dihydropyridine, its

ГФ) a pharmaceutically acceptable salt or its solvate of the formula (1) име) 60 b5 ho her ; with more than 70 N

is coming

Where are you? represent, independently of each other, C 4.v-alkyl group "C. The β-alkyl group can be substituted by a phenyl group (the phenyl probe can be substituted by a C-C-Alkoxy group or a halogen atom), 75 by a C-C-Alkenyl group or by a C»-C-alkynyl group (C-C-Alkenyl group and C-D-alkynyl group can be replaced by a phenyl group (a phenyl group can be replaced by a C. 6b- alkoxy group or a halogen atom))) or -71-MvZrv "VZ and K7 represent, independently of each other, a C 4 c-alkyl group (C. c- the alkyl group can be substituted by a phenyl group (the phenyl group can be substituted by a C. 6-6-alkyl group or a halogen atom) or a phenyl group (where the phenyl group can be substituted by a C.-6-alkyl group or a halogen atom, I! is a C-6-alkylene group (Co. d-alkylene group can be replaced by a C. 3-alkyl group or a phenyl group (a phenyl group can be arbitrarily substituted by a halogen atom, a C. 3-alkyl group or

Si with an alkyl group))) or VK' and VK? together they form -СКРБб-Св'в8-, свРвб-свВ'вВЗ-свУВО- or свев9-св'/в8-свУвВ!о. svV'vV!2. (5-27? represent, independently of each other, a hydrogen atom or

C, b-alkyl group or any two of them, together with the carbon atom connecting them, can form a 5-, 6-c or 7-membered ring); Gee)

X! and X? represent, independently of each other, O or ME "Z (B'Z is a hydrogen atom or

C, in-"alkyl group);

Ag is a phenyl group, a pyridyl group, a furyl group or a 2,1,3-benzoxadiazol-4-yl group "Ezo (a phenyl group, a pyridyl group, a furyl group and a 2,1,3-benzoxadiazol-4-yl group can be arbitrarily substituted by one or two substituents selected from MO", SEz, Bg, SI, E, K (K is a C/4.20-alkyl c. group), OH, OK" (B? is a C/.c- alkyl group), OSNE», SOOV'YA, MN», MNE!YA, MYAZ (VYI represents a S. v-alkyl group), SOMNo, SOMNE"I, SOM B", sov, 8, (ОВ, 5(0)2877, 8ОзН, 5038, о 502МН», 802МНЕ Я, 802Мв В 5, SM and phenyloxy group);

Who are you and V? represent, independently of each other, a C 4 .in-alkyl group, -12-MA'9B17 (Вб in represent, independently of each other, a hydrogen atom, a C. in-alkyl group (a C in-alkyl group can be substituted by a phenyl group (a phenyl group can be substituted by a C. 6-alkyl group or a halogen atom)) or a phenyl group (a phenyl group can be substituted by a C. 6-alkyl group or a halogen atom), 2 is a "y C" y-alkylene group ( The C.sub.3-alkylene group can be arbitrarily substituted by a C..3-alkyl group or a phenyl group (the phenyl group can be arbitrarily substituted by a halogen atom, a C.sub.3-alkyl group or a C.sub.3-alukoxy group))), CH»O- And 2-MV 9817, Ah! (Ag! represents a phenyl group (a phenyl group can be arbitrarily substituted by a halogen atom, a C.i.3-alkyl group or a C..3-alkyl group)), SNUSNAG, snH.sn(OnH)

Ag, sno, sm, СНооН, СНО 5, -.2-(СНоСНоИ»МВ 15 or MA!bВ 17;

M is a C 1 20-alkyl group (C 1.20-alkyl group can be substituted by a phenyl group (phenyl-I group can be substituted by a C 1-20-alkyl group or a halogen atom), a C 1-20-alkenyl group or a C-C 2-alkynyl group (Co. c-alkenyl group and Co. d-alkynyl group can be replaced by a phenyl group (a phenyl group can be replaced by a C. c- alkoxy group or a halogen atom))), -I3-MV 8879878 and E79 are (95) independently of each other, C. c-alkyl group (Ci. c-alkyl group can be substituted by phenyl-1 50 group (phenyl group can be substituted by C. 6-alkyl group or halogen atom) or phenyl group (phenyl group can be substituted by C . 6b-alkoxy group or a halogen atom), IZ is a C" in-alkylene iz" group (a C-6-alkylene group can be arbitrarily substituted by a C.-3-alkyl group or a phenyl group (a phenyl group can be arbitrarily substituted by a halogen atom, C..3-alkyl group or C) c-alkyl group))) o - de - 5 t t GI 60 t. o vay o y vod

AND! b5 (where o and p are equal, independently of each other, to C or 4, d is equal to 1, 2 or 3) and " means the absolute configuration of CI.

2. T-type calcium channel blocker, which is an optically active derivative of 1,4-dihydropyridine, its pharmaceutically acceptable salt, or its solvate, as specified in 1, where U represents -Y. Z-ME 8879 /v/8 and v represent, independently of each other, a C 4 v-alkyl group (the C v-alkyl group can be replaced by a phenyl group (the phenyl group can be replaced by a C. 6-alkyl group or a halogen atom) or a phenyl group (a phenyl group can be replaced by a C 6 -alkoxy group or a halogen atom, C is

Co-alkylene group (Co-alkylene group can be arbitrarily substituted by a C 4-z-alkyl group or a phenyl group (a phenyl group can be arbitrarily substituted by a halogen atom, a C-z-alkyl group or a C-z-alkyl group))) ,

AND

. cha zdo (where o and p equal, independently of each other, C or 4, 4 equals 1, 2 or 3) and Ka is

C, in-"alkyl group.

Q. A T-type calcium channel blocker which is an optically active 1,4-dihydropyridine derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof as set forth in 2, wherein B? is Si. в-alkyl group, CM or p

MN". o 4. T-type calcium channel blocker, which is an optically active derivative of 1,4-dihydropyridine, its pharmaceutically acceptable salt or its solvate, as specified in 1, where M is a Co 3oo-alkyl group

The C 20 -alkyl group can be substituted by a phenyl group (a phenyl group can be substituted

a C 6 -alkoxy group or a halogen atom), a C 6 -alkenyl group or a C 6 -alkynyl group " (C 6 -alkenyl group and C 6 -alkynyl group can be substituted by a phenyl group (a phenyl group can be substituted by a C 6 -alkoxy group or a halogen atom))),

IN? is -Y 2-MV'98!7 uv!5 | v!/ represent, independently of each other, a hydrogen atom, and.

C. d-alkyl group (Ci. c-alkyl group can be substituted by a phenyl group (the phenyl group can be F» substituted by a C. c- alkyl group or a halogen atom)) or a phenyl group (the phenyl group can be m substituted by C. c- an aluoxy group or a halogen atom, and 2 is a C»-alkylene group (a C-alkylene group can be arbitrarily substituted by a C..3-alkyl group or a phenyl group (a phenyl group can be arbitrarily substituted by a halogen atom, C.4.3-alkyl group or Si z-aluoxy group))), СН»О-И12-МВ'ЗВ!! or

Г2-Ж(wearable

VK? is a C ..v-alkyl group. - c 5. T-type calcium channel blocker, which is an optically active derivative of 1,4-dihydropyridine, its pharmaceutically acceptable salt or its solvate, as specified in 2, C or 4, where B! and KV? represent, independently » of each other, a C-C-alkyl group (a C-C-alkyl group can be substituted by a phenyl group (a phenyl group can be replaced by a C-C-Alkoxy group or a halogen atom), Co by an all-alkenyl group or by a C» in-alkynyl group (C»o.in-alkenyl group and Co. vd-alkynyl group can be replaced by a phenyl group (the phenyl group can be replaced by a C. in-alkoxy group or a halogen atom)) or K! and KE together form SERV5-СВ В8., со -св5в5-св"в8-свево. or SERVV5-св"В8-свУв9-св in 2. (85-12 represent, independently of each other, a hydrogen or C atom); in - an alkyl group, or any two of them, together with the carbon atom connecting them, can

To form a 5-, 6- or 7-link ring); -70 XX? represent themselves, both, o.

T" 6. T-type calcium channel blocker, which is an optically active derivative of 1,4-dihydropyridine, a pharmaceutically acceptable salt thereof, or a solvate thereof, as specified in 5, where Ag is phenyl, 3-nitrophenyl, 2-nitrophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-trifluoromethylphenyl or 2,3-dichlorophenyl. 59 7. T-type calcium channel blocker, which is an optically active derivative of 1,4-dihydropyridine, its (F) pharmaceutically acceptable salt or its solvate, as specified in b, where B 7 and B? together will form ka -СнН.-с(СН3)»-СН»о., ХХ? represent, both O, Ag represents Z-nitrophenyl, B. C and 2? are both methyl and M is 2-Ibenzyl(phenyl)amino|ethyl. 8. A pharmaceutical preparation containing a T-type calcium channel blocker as described in any one of 1-7. 9. A therapeutic or prophylactic agent against a disease for which a blocking effect on T-type calcium channels is effective, as described in any one of 1-7. 10. A therapeutic or prophylactic agent against cardiomegaly containing a T-type βB calcium channel blocker as described in any one of 1-7. 11. A therapeutic or prophylactic agent against heart failure comprising a T-type calcium channel blocker as described in any one of 1-7. 12. Therapeutic or prophylactic agent against cardiomyopathy containing a calcium channel blocker

T-type as specified in any one of 1-7. 13. A therapeutic or prophylactic agent against atrial fibrillation comprising a T-type calcium channel blocker as described in any one of 1-7. 14. A therapeutic or prophylactic anti-tachycardia/arrhythmia agent comprising a T-type calcium channel blocker as described in any one of 1-7. 15. A therapeutic or prophylactic agent against arterial sclerosis comprising a T-type calcium channel blocker as described in any one of 1-7. 16. A therapeutic or prophylactic agent against nephritis comprising a T-type calcium channel blocker as described in any one of 1-7. 17. A therapeutic or prophylactic agent against nephropathy containing a calcium channel blocker

T-type as specified in any one of 1-7. 18. A therapeutic or prophylactic agent against renal impairment comprising a T-type calcium channel blocker as described in any one of 1-7. 19. A therapeutic or prophylactic agent against renal failure comprising a T-type calcium channel blocker as described in any one of 1-7. 20. A therapeutic or prophylactic anti-edema agent comprising a T-type calcium channel blocker 2o as described in any one of 1-7. 21. A therapeutic or prophylactic anti-inflammatory agent containing a calcium channel blocker

T-type as specified in any one of 1-7. 22. A therapeutic or prophylactic agent against hyperaldosteronism comprising a T-type calcium channel blocker as described in any one of 1-7. ch 23. A therapeutic or prophylactic agent against neurogenic pain comprising a T-type calcium channel blocker as specified in any one of 1-7. i) 24. Therapeutic or prophylactic agent against epilepsy containing calcium channel blocker

T-type as specified in any one of 1-7.

The best method of carrying out the invention will be described in more detail below.

As used herein, "n" means normal, "iso" means isomeric, "second" means secondary, "tert" means tertiary, and "c" means cyclo. co

Each substituent specified in the description is described.

A halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. b"

The C 1 -alkyl group can be a straight chain alkyl group, a branched alkyl (M) group or a C 3 -cycloalkyl group and includes, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a c-propyl group, and so on further.

The C 1 -alkyl group can be a straight chain alkyl group, a branched alkyl group or a C 1 -cycloalkyl group and includes, for example, in addition to the above substituents for "

C-3-alkyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, C c c-butyl group, n-pentyl group, 1-methyl-n-butyl group, 2-methyl-n -butyl group, 3-methyl-n-butyl group, 1,1-dimethyl-n-propyl group, t-pentyl group, 2-methyl-t-butyl group, n-hexyl group, "z" 1-methyl- n-pentyl group, 2-methyl-n-pentyl group, 1,1-dimethyl-n-butyl group, 1-ethyl-n-butyl group, 1,1,2-trimethyl-n-propyl group, t-hexyl group, 1-methyl-cd-pentyl group, 1-ethyl-cd-butyl group and 1,2-dimethyl-t-butyl group and so on. -The C120-alkyl group can be an alkyl group with a straight chain, a branched alkyl group or a C3.20-cycloalkyl group and includes, for example, in addition to the above-mentioned substituents for the C12-alkyl group, an n-heptyl group, 2-d-pentylethyl group, n-octyl group, 2-c-hexylethyl group, oo 3-c-pentyl-n-propyl group, n-nonyl group, 3-c-hexyl-n-propyl group, 4-c -pentyl-n-butyl group,

N-decyl group, 4-c-hexyl-n-butyl group, 5-c-pentyl-n-pentyl group, n-undecyl group, - 5-c-hexyl-n-pentyl group, b-c-pentyl- n-sexyl group, n-dodecyl group, n-tridecyl group, i» n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-nonadecyl group and n-eicosyl and so on.

Co-alkenyl group includes straight-chain or branched groups, specifically, o-ethenyl group, 1-propenyl group, 2-propenyl group, 1-methyl-1-ethenyl group, 1-butenyl group, 2-butenyl group , 3-butenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group,

F) 1-ethylethenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-pentenyl group, ka 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-n- propylethenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1-methyl-3-butenyl group, 2-ethyl-2-propenyl group, 2-methyl-1-butenyl group, 2 -methyl-2-butenyl group, 2-methyl-3-butenyl group,

3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-methyl-3-butenyl group, 1,1-dimethyl-2-propenyl group, 1-isopropylethenyl group, 1,2-dimethyl-1 -propenyl group, 1,2-dimethyl-2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-methyl-1-pentenyl group, 1 -methyl-2-pentenyl group, 1-methyl-3-pentenyl group, 1-methyl-4-pentenyl 65 GrUPU, 1-n-butylethenyl group, 2-methyl-1-pentenyl group, 2-methyl-2-pentenyl group, 2-methyl-3-pentenyl group, 2-methyl-4-pentenyl group, 2-n-propyl-2-propenyl group,

3-methyl-1-pentenyl group, 3-methyl-2-pentenyl group, 3-methyl-3-pentenyl group, 3-methyl-4-pentenyl group, 3-ethyl-3-butenyl group, 4-methyl-i -pentenyl group, 4-methyl-2-pentenyl group, 4-methyl-3-pentenyl group, 4-methyl-4-pentenyl group, 1,1-dimethyl-2-butenyl group, 1,1-dimethyl-3- butenyl group, 1,2-dimethyl-1-butenyl group, 1,2-dimethyl-2-butenyl group, 1,2-dimethyl-3-butenyl group, 1-methyl-2-ethyl-2-propenyl group, 1 -tert-butylethenyl group, 1,3-dimethyl-1-butenyl group, 1,3-dimethyl-2-butenyl group, 1,3-dimethyl-3-butenyl group, 1-isobutylethenyl group, 2,2-dimethyl- 3-butenyl group, 2,3-dimethyl-1-butenyl group, 2,3-dimethyl-2-butenyl group, 2,3-dimethyl-3-butenyl group, 2-isopropyl-2-propenyl group, 70 3, 3-dimethyl-1-butenyl group, 1-ethyl-1-butenyl group, 1-ethyl-2-butenyl group, 1-ethyl-3-butenyl group, 1-n-propyl-1-propenyl group, 1-n -propyl-2-propenyl group, 2-ethyl-1-butenyl group, 2-ethyl-2-butenyl group y, 2-ethyl-3-butenyl group, 1,1,2-trimethyl-2-propenyl group, 1-tert-butylethenyl group, 1-methyl-1-ethyl-2-propenyl group, 1-ethyl-2- methyl-1-propenyl group, 1-ethyl-2-methyl-2-propenyl group, 1-isopropyl-1-propenyl group and 1-isopropyl-2-propenyl group and so on.

Co-alkynyl group includes straight chain or branched groups, specifically, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group,

3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 1-methyl-3-butynyl group, 2-methyl-33-butynyl group, 3-methyl-1-butynyl group, 1,1-dimethyl-2-propynyl group, 2-ethyl-2-propynyl group, 1-hexynyl

GVUPU, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 1-methyl-2-pentynyl group, 1-methyl-3-pentynyl group, 1-methyl-4-pentynyl group, 2 -methyl-3-pentynyl group, 2-methyl-4-pentynyl group, 3-methyl-1-pentynyl group, 3-methyl-4-pentynyl group, 4-methyl-1-pentynyl group, 4-methyl-2- pentinyl group. 1,1-dimethyl-2-butynyl group, 1,1-dimethyl-3-butynyl group, 1,2-dimethyl-3-butynyl group, 2,2-dimethyl-3-butynyl group, 3,3-dimethyl -1-butynyl group, 1-ethyl-2-butynyl group, 1-ethyl-3-butynyl group, 1-n-propyl-2-propynyl group, 2-ethyl-3-butynyl group, 1-methyl-1- ethyl-2-propynyl group and i) 1-isopropyl-2-propynyl group and so on.

C 1 -C 6 -Alkoxy can be a straight chain, a branched, or

a C3-cycloalkyl group and includes, for example, a methoxy group, an ethoxy group, an n-propoxy group,

Zo isopropoxy group and c-propoxy group and so on.

The C 1 -C 6 -alkyl group can be a straight-chain, branched-chain or -

C3-6-cycloalkyl group and includes, for example, in addition to the above-mentioned substituents for C4-3-alkyloxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, t-butoxy group, n-pentyloxy group, 1-methyl-n -butoxy group, 2-methyl-n-butoxy group, 3-methyl-n-butoxy group, 1,1-dimethyl-n-propoxy group, b»

From t-pentyloxy group, 2-methyl-t-butoxy group, n-hexyloxy group, 1-methyl-n-pentyloxy group, r. 2-methyl-n-pentyloxy group, 1,1-dimethyl-n-butoxy group, 1-ethyl-n -butoxy group, 1,1,2-trimethyl-n-propoxy group, t-hexyloxy group, 1-methyl-t-pentyloxy group, 1-ethyl-t-butoxy group and 1,2-dimethyl-t-butoxy group and so on.

Co-alkylene group includes ethylene group, propylene group, butylene group, pentylene group and hexylene group and so on. 5-, 6- or 7-membered rings include c-pentyl, c-hexyl and c-heptyl and so on. with c Preferable B and B? include the following values, in which the latter is more predominant: ц 1. В! and in together form -"СЕ?Б5-СВ"в8-, -"СВovo-свв8-СсВУв19- or -"СВв8-св'в8и-свВУво-свВ in 12.

B (K5-B" represents, independently of each other, a hydrogen atom or a C 4 c-alkyl group or any two of them, together with the carbon atom connecting them, can form 5-, 6- or 7-membered ring); 2. B! and 82 together form -"СЕ?В5-СВ"В8-сСвЗв 19. (5-29 represents, independently of each other, an atom of this. hydrogen or C. .v-alkyl group); со 3. B and 82 together form -СНо-С(СНаз)2-СНо- or -СНСНи-СНо-СНОН 3-; syu 4. In! and B? represent, independently of each other, a C 1-6-alkyl group (C. c-alkyl group can be replaced by a phenyl group (a phenyl group can be replaced by a C. b-alkyl group or a halogen atom, -and 20 Co c-alkenyl group or C» b-alkynyl group (Co. b-alkenyl group and Co. b-alkynyl group can be

HT" are substituted by a phenyl group (a phenyl group can be substituted by a C. v-alkyl group or a halogen atom))); 5. In! and 82 represents, independently of each other, C. v-alkyl group; 6. In 22, they both represent a methyl group.

Mostly, X! and X? include the following values, in which the latter is more predominant: o 1.X7iX2 represent, both, 0.

Preferably, Ag includes the following values: i) 1. phenyl group, 4-nitrophenyl group, 3-nitrophenyl group, 2-nitrophenyl group, 4-chlorophenyl group, 3-chlorophenyl group, 2-chlorophenyl group, 4-methoxyphenyl group , 3-methoxyphenyl group, 60 2-methoxyphenyl group, 4-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 2-trifluoromethylphenyl group and 2,3-dichlorophenyl group; 2. phenyl group, 3-nitrophenyl group, 2-nitrophenyl group, 3-chlorophenyl group, 2-chlorophenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, 3-trifluoromethylphenyl group, 2-trifluoromethylphenyl group and 2,3-dichlorophenyl group; 65 C. phenyl group, C-nitrophenyl group, 2-nitrophenyl group, C-chlorophenyl group, 2-chlorophenyl group, C-methoxyphenyl group, 2-methoxyphenyl group, C-trifluoromethylphenyl group and

2-trifluoromethylphenyl group; 4. phenyl group, 3-nitrophenyl group, 2-nitrophenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, 3-trifluoromethylphenyl group and 2-trifluoromethylphenyl group.

Preferable KZ includes the following values: 1. C. γ-alkyl group; more preferably, 2. methyl group.

Preferred EC? includes the following values, in which the latter is more predominant: 1. C. v-alkyl group, CM and MH"; 2. methyl group, CM and MH"; 3. 12-Mv'bB!7 "Bb in!" represent, independently of each other, a hydrogen atom, C 4. 6-alkyl group (C. vd-alkyl group can be replaced by a phenyl group (a phenyl group can be replaced

a C 1 -alkyl group or a halogen atom) or a phenyl group (the phenyl group can be substituted

C. b-alukoxy group or a halogen atom), 7 is a C 2. b-alkylene group (the C. b-alkylene group can be arbitrarily substituted by a C..3-alkyl group or a phenyl group (a phenyl group can be arbitrarily substituted by a halogen atom, Ci. with an alkyl group or Ci with an oxy group))), -СНоО-И2-МВЯАВ!!. and

G2-zh(snosNno»Mv 6; 4. -SNYO 12-MA 5817; 5. SNOSNSNOMN».

Preferred Y includes the following values, in which the latter is more preferred: 1. C..2o-alkyl group /C..2o-alkyl group may be substituted by a phenyl group (a phenyl group may be substituted by a C.v.-alkyl group or an atom a halogen, a Co-alkenyl group or a C»-alkynyl group (a Co-alkenyl group and a Co-alkynyl group can be substituted by a phenyl group (a phenyl group can be substituted by a C-alkoxy group or a halogen atom))); o 2. methyl group, ethyl group, isopropyl group, isobutyl group and methoxyethyl group; 3. 13-Mv 8879 uv8 | вС represent, independently of each other, a C 1 -C-alkyl group (C. C-alkyl group can be substituted by a phenyl group (a phenyl group can be substituted by a C. C- alkyl group or a halogen atom) or a phenyl group (a phenyl group can be substituted by a C. 6-alkyl group or a halogen atom, ! C "f represents a C "5.6-alkylene group (Co. a . arbitrarily substituted by a halogen atom, Si by an alkyl group or by a C. by an oxy group))), co (o)

З5 -- / for | I also chat about your Q. . "» y (where о and р are equal, independently of each other, З or 4, 4 is equal to 1, 2 or 3); -И 4. se) (95) ч я -и с» я о ! ko When optically active 1,4-dihydropyridine derivative used in the present invention is a compound that can form a salt, a pharmaceutically acceptable salt thereof can also be used as an effective component. 60 A pharmaceutically acceptable salt includes hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, benzoates , tartrates, phosphates, lactates, maleates, fumarates, malates, gluconates, salicylates and so on.

Preferably, hydrochlorides and methanesulfonates can be specified.

Solvates are not specifically limited as long as they are pharmaceutically acceptable, specifically they include hydrates and solvates with ethanol and so on. 65 T-type calcium channel blockers that are an optically active derivative of 1,4-dihydropyridine, a pharmaceutically acceptable salt thereof, or a solvate thereof used in the present invention, pharmaceutical preparations containing T-type calcium channel blockers, or therapeutic agents against diseases , for which the blocking action of T-type calcium channels is effective, can be conventionally administered in oral administration forms such as tablets, capsules, powders, granules, pills, syrups and the like, preparations with absorption through the mucous membrane, such as preparations for intrarectal administration, preparations for absorption through the nose, preparations for absorption through the vagina and the like, preparations for absorption through the lungs, preparations for inhalation, ophthalmic solutions, preparations for transdermal absorption or injection.

These drugs can be administered as a single therapeutic agent or as a mixture with another therapeutic agent. They can be introduced as a single component, but usually they are introduced in a 7/0 form of a pharmaceutical composition. These drugs can be obtained by any generally accepted method by adding pharmacologically and pharmaceutically acceptable impurities. That is, impurities such as excipients, lubricants, binders, disintegrants, wetting agents, plasticizers, coating agents, and the like can be used to obtain oral preparations.

Oral liquids may be in the form of an aqueous or oily suspension, emulsion solution, syrup, elixir, and the like, or may be presented as a dry syrup that is diluted with water or another suitable solvent before use. The above liquids may contain conventional additives such as suspending agents, fragrances, diluents or emulsifiers. When the drug is administered intrarectally, it can be administered in the form of a suppository. The suppository may contain suitable base ingredients such as cocoa butter, lauric butter, macrogol, glycerogelatin, witepsol, sodium stearate or a mixture thereof and optionally

May contain emulsifiers, suspending agents, preservatives and the like. For injections, the following components are used: solvents or solubilizing agents, such as distilled water for injection, which can form an aqueous or dissolvable dosage form upon application, saline, 595 glucose solution, propylene glycol, and the like, pharmaceutical ingredients , such as pH regulators, isotonic agents, stabilizers and the like. with

When the pharmaceutical preparations of this invention are administered to a person, the dose is determined depending on the age or condition of the patient. In the case where the patient is an adult, oral administration or intrarectal administration i) is carried out in an amount of about 0.0mg to 1000mg per day per patient, and the injection is given in an amount of about 0.00bmg to 5000mg per day per patient. These values are only examples, and the dose is determined according to the patient's condition. The case in which the present invention is applied includes a case in which the use of compounds having T-type calcium channel blocking activity is expected to improve the patient's condition. uh-

In particular, the compounds of the present invention are effective for the therapy or prevention of cardiomegaly, heart failure, cardiomyopathy, tachyarrhythmia represented by atrial fibrillation, arteriosclerosis, renal impairment represented by nephritis/nephropathy, renal failure, inflammation and edema, Me

From piperaldosteronism, neurogenic pain, epilepsy and the like. M

Optically active derivatives of 1,4-dihydropyridine formula (1) can be obtained with reference to the methods described in UR 1-113398A (1989), UR 2-011592A (1990), Spet. RIagt. Vii., 40(9), 2377-2381 (1992) and Spet.

RNagt. Vii., 40(9), 2370-2376 (1992).

The method of obtaining them is shown in diagram 1. "- с ;" -I se) (95) -I 50 s»

F) name) 60 b5

SAEMA1 in o.m. and Pana vva and ' de Tolusya n ov) (2) (2) from the Separation of de

Kk Kk cha of diastereomers and t chaly 2 (12) dat) n n

Man TNE sm in MAN TNE dak of distereomers - ps s pn pln fl : Shk Shh - y t - (tv, inesp BK) s (22) and - vni: shk - t . 40 (| t shi | shi s " ki g inost (Ba) osn, z ne AK y (Se) I pp noch sti y y s won (1) - 70 n "g" de BE, E, X, X, Va , В, Аг, У and 7 have values similar to those indicated above.

First, styrylphosphonate (2) and an optically active derivative of aminocrotonic acid (3) are called in toluene under conditions of azeotropic dehydration to obtain a derivative of 1,4-dihydropyridine (Ta).

Then the 1,4-dihydropyridine derivative (Ta) is subjected to separation into diastereomers by crystallization or chromatography and so on to obtain (Ta-K), and then (13-K) is subjected to methoxymethylation, thereby obtaining (IB-K), or ( 1a) is subjected to methoxymethylation to obtain (165) and then (15) is subjected to separation into co-diastereomers by crystallization or chromatography and so on, thus obtaining (1B-K).

Then transesterification is carried out and the methoxymethyl group is removed with hydrogen chloride, thereby obtaining an optically active 1,4-dihydropyridine derivative of formula (1).

In addition, according to the methods described in UR. 59-161392A (1984), UR. 60-69089A (1985), UR. 60-248693А (1985), UR 60-258194А (1985), UR. 61-30591A (1986), UR 61-37793A (1986), UR 61-63688A (1986), UR. 61-210092А (1986), ОР 61-254569А (1986), UR. 62-169795A (1987), UR. 62-169796A (1987), UR. 62-195392A (1987), UR. 63-68591A (1988), UR 63-233992 (1988), UR. 1-113398A (1989), OR. 1-275591A (1989), Spet. Ripagt. Vyyy., 40(9), pp. 2362-2369, (1992) and 65 Spet. RIapt. Viiy., 40(9), pp. 2370-2376, (1992) obtain a racemic derivative of 1,4-dihydropyridine and then an optically active derivative of 1,4-dihydropyridine can also be obtained by separation of a racemic derivative by HPLC using an optically active column.

In the following, the present invention will be described on the basis of non-limiting examples.

Racemic efonidipine, synthesized according to the method described in UR 63-233992A (1988), was separated by HPLC with the use of a column for the separation of optically active isomers, obtaining the K-form and the Z-form of efonidipine (2-I(benzyl(phenyl)amino| )ethyl ether 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3 -pyridinecarboxylic acids), which were used as samples.

Separation conditions TOP 70 Column: SNIKAI SEG OS (produced by Oaise! Spetisai! Ipdivigiev, Tsa.).

The size of the column: 20 cm.

Eluent: methanol.

Column temperature: room temperature.

Flow rate: 7bOml/min.

At the same time, compounds as examples other than the above compound efonidipine were synthesized as follows.

Compounds that have diethylphosphonyl in the 5-position of the dihydropyridine ring (272) were synthesized with reference to the preparation method described in UR 60-69089A (1985) and UR. 60-248693 A (1985).

Compounds that have 5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl (271) in the 5-position of the dihydropyridine ring were synthesized with reference to the preparation method described in OP 62-169795 (1987 ) and Spet. Rpagt. Howl.,

Z0(9), pp. 2362-2369 (1992).

Compounds that have 4,6b-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl (73, 74) in the 5-position of the dihydropyridine ring were synthesized with reference to the preparation method described in the OP. 63-68591A (1988) and Spet. RNagt. Vyi., 40(9), pp. 2370-2376 (1992).

In addition, the following compound (1-a) was obtained by the method shown below. high school

And about

Mi V non " OD kit E

N m k2) (U (chu 11g) so

After mixing 8.05 g (19.3 mmol) of compound (3), 1.64 g (21.3 mmol) of ammonium acetate and 80 mL of ethanol, the resulting mixture was refluxed under heating for 45 minutes. 7.23 g (21.3 mmol) of compound (2) is added to the resulting reaction solution and the resulting mixture is further boiled under reflux under heating for 3 hours. After cooling, the solvent is distilled off under reduced pressure and 100 ml of toluene and 5 bbml of 1095 aqueous sodium carbonate solution are added, then the resulting mixture is shaken and left to stand, as a result of which phase separation occurs. The organic phase is washed with 2095 sodium chloride solution, dried over magnesium sulfate (anhydrous), and then the solvent is distilled off under reduced pressure. The residue was purified by chromatography on silica gel (from a mixture of hexane-ethyl acetate, 4:11, v/v, to ethyl acetate), obtaining 6.04 g (yield 4290) of compound (4) in the form of a yellow amorphous substance. is" (Compound (3) is obtained by the method described in EP 0599220A1).

M5 t/2 738 (M'1), "YAN NMR (SOSIi) 5 (m.h): 0.87 (ZN, s), 1.08 (ZN, s), 2.39 (ZN, d) , 2.42 (2Н, t), 3.51-3.73 (4Н, m), 3.69 (ЗН, с), 4.21-4.31 (2Н, m), 4.56 (1Н , d), 4.70 (1H, d) 4.93 (1H, d), 7.17-7.49 (16H,

Sh- M), 7.62 (1H, d), 8.02 (1H, d), 8.11 (1H, m) so After dissolving 500 mg (0.678 mmol) of compound (4) in 5 ml of methanol, add 500 mg of (1.37 mmol) of 1095 NCI in meon and the resulting mixture is refluxed under heating for 2.5 hours. After cooling on standing, the solvent is distilled off under reduced pressure and 20 ml of -I 20 chloroform and 1 Oml of 1095 aqueous sodium carbonate solution are added, and the resulting mixture is shaken and left to stand, as a result of which phase separation occurs. The organic phase is washed with water, dried over magnesium sulfate (anhydrous), and then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel (from a mixture of hexane-ethyl acetate, 20:11, to ethyl acetate, then with a mixture of chloroform-methanol, 5:1 vol./06b), obtaining 21 bmg (yield 6495) of compound (1-a) in in the form of a yellow 22 oil product. (FI M5 t/2 495 (M") "H NMR (SOCIz) 5 (m.h.): 0.89 (ZN, s), 1.04 (ZN, z) 2.46 (ZN, d) , 3.00-3.03 (2H, m), 3.54-3.74 (4H, m), 3.68 (ZH, s), 4.09-4.27 (2H, m), 4.61 (1H, d), 4.66 (IN, d), 4.89 (1H, d), 7.40 (1H, dd), 7.65 (1H, d), 8.01 (1H , d), 8.10 (1H, m), 8.47 (1H, ear. m).

Example 1 of a pharmacological test (effect on Ca (calcium) channels of I-type and T-type expressed in 60 mammalian cells (VNK cells))

Test method

In this test, the electrophysiological assessment was performed using BNK cells (kidneys of baby hamsters), in which Ca channel I-type or Ca channel T-type (c4c) were expressed by the method of UUakatogi Mei ai. (Muakatogi Mei a: 9) Hi! Spec 273, 34857-34867, 1998), based on the patch-clamp method with whole cells. Each current of Ca ions was measured using a patch-clamp amplifier in the form of an inward current, when a depolarizing pulse (10 mV in the I-type Ca channel, 20 mV in the T-type Ca channel) was applied to the cells maintained at a membrane potential of -80 mV ). The optically active K-form or 5-form of efonidipine was dissolved in the extracellular solution and applied by perfusion. 5 minutes after application

Any option in the current of Ca ions was measured. The results show Ca current inhibition (95) by the compound of this invention compared to Ca current (10095) in the filler control.

K-form of efonidipine (mean value 4 standard error) 70 in z y y scha y

In the shade and

Efonidipine C-form (mean - standard error)

You Skhnu Klyitrytsiya huk (their shl face her her And 1 kasha in

Fo al Z go - - l -t.Y.shchyufB g 'i wai z

The results

The optically active K-form showed concentration-dependent inhibition at a concentration of 0.1 µM or more for the T-type Ca channel and did not show any inhibition for the I-type Ca channel even at a concentration of 10 µM. On the other hand, the Z-form showed a strong inhibition for type I Ca-channels, which is as high as 55.6-7.195 Ga at iMm. Based on these results, it was concluded that the K-form of efonidipine has a high selectivity for the T-type Ca channel.

In addition, I-type Ca channel inhibition was elicited by only one optically active form, the 5-form, whereas T-type Ca channel inhibition was elicited by both optically active forms to equal levels. This confirmed that, if the 1,4-dihydropyridine derivative in the racemate form shows a blocking effect for T-type Ca-channels, then one (B-form) of the optically active products will be a compound with high selectivity for Ca-channels T-type. m

Example 2 of a pharmacological test (effect on T-type Ca channels expressed in mammalian cells (VNK cells)) (ze)

Test method b

Similar to the procedure of example 1 of the pharmacological test, the inhibition of T-type Ca-channels by compounds of the formula ych-mvo-sn was measured at a drug concentration of 10 mM, the results are shown in the table below.

Designations 21-24, u1-u7, B1 and A1-A7 used in the table mean the following types of compound substituents: -I se) (95) -I 50 s»

F) name) 60 b5

2: ХЕ p: Her 23: Tu schu t: (8,8 (K.K) o h so spos OM y: so ' cha: chi: wo heard her (8) chi: snsny kat, vynosysny,

А1: З-nitrophenyl, А2: З-chlorophenyl, AZ: 2-nitrophenyl, А4: 2-methoxyphenyl, А5: З-methoxyphenyl, Аб: phenyl, сч , и

AT: 3-trifluoromethylphenyl. Go)

Kotiysuryuin 4- Shshibu | Chizk) nn shishinsy | fiogibudvko --

PA OI week | frame iii 1 Z zo III M | saw rshit 5th

W|WHICH W| everything was decided by 1

IA U: | moty rye for Z o

IIABI Chi | mk ze her o

MAIATI I | what | nan ze 4 z5 I ZHVIATI MI vichi rat kil | ak with h-

IA TI seams ryishit and a

IA Z sh-k rishchtpshit huh?

ILIA1I Zh shk yr and 2

IA M | she ryshnai zay Z « shi|A11 shpl ryshlyt 4 and this is from deli! t | our unit |cSnyanya| ml 4 k FATA TH | met (fl I 2 nya kA t shiya rischshht pa 4

When the above compounds in the racemate form show inhibition of T-type calcium channels, it allows us to predict that one of the optically active products (K-form does not show inhibition of I-type calcium channels)

Ge) is a compound that exhibits selective inhibition of T-type calcium channels.

Example 1 of obtaining granules containing the following components are obtained. - Components of Sisluk dormula (1 10 i

Y" Yanshetoza liu shg

Kukurunkaniy kropman 2 o b, 10 me

GF) The compound of formula (1) and lactose are passed through a boOmesh sieve. Pass the cornstarch through a 120-mesh sieve. The specified components are mixed in a two-cylinder mixer. De hydroxypropyl cellulose, which has a low viscosity (HROS-II), is added to the mixed powders, the resulting mixture is kneaded, granulated (granulation by extrusion, hole 0.5 mm) and then dried. The resulting dried granules are passed through a vibrating sieve 60 (12/vOmesh) to obtain the specified granules.

Example 2 of receiving

Powders for filling capsules containing the following components are obtained. b5

Eosmponents of the formula (1) 10 mo

Lavka, 79 ME

Corn cob 10 mg 9 Steprit magic, 1 mg 104 mg

The compound of formula (1) and lactose are passed through a mesh sieve. Pass the cornstarch through a 120-mesh sieve. The specified components are mixed with magnesium stearate in a two-cylinder mixer. 10 powders of 7/0 b0 mg are filled in hard gelatin capsules Me.

Example From receipt

Granules for filling capsules containing the following components are obtained.

Coipivents Spoluga formuyan (1X 15 mg

Lygova 90 mg to Kukuutyamny krokhial in shg

NRSY, building 190 m

The compound of formula (1) and lactose are passed through a mesh sieve. The corn starch is passed through a 2 o sieve of 120 mesh. The specified components are mixed in a two-cylinder mixer. Hydroxypropyl cellulose, which has a low viscosity (HPO-Y), is added to the mixed powders, the resulting mixture is kneaded, granulated and then dried.

The resulting dried granules are passed through a vibrating sieve (12/bOmesh) to obtain the specified granules. 150 mg of granules are filled into a hard gelatin capsule Mo4.,

Example 4 of obtaining sch 25 Tablets containing the following components are obtained. at

Koniozhny Compound form (I) iy

NPela 90 mg

Crystalline cellulose of thin Zome from beeswax

Schetsach macho Z ng y-

SV -Ma 15 mg so me o

The compound of formula (1), lactose, finely ground crystalline cellulose and СМоО-Ма (sodium salt 32 of carboxymethylcellulose) are passed through a mesh sieve and mixed with each other. Magnesium stearate is added to the mixed powders, thereby obtaining mixed powders for making tablets. The powders are subjected to direct pressing, thus obtaining 15Omg tablets.

Example 5 of getting "

Intravenous drugs are obtained in this way. From 7 "Consumption of forms (I) 100 mg - Hyiprrid of saturated evil kiszhta 1000 she," The solution containing the above components is usually administered intravenously to the patient at a rate of 1 ml per minute.

Industrial applicability -i Since the compounds of this invention have a selective blocking effect on T-type calcium channels, it can be predicted that these compounds can be used for the therapy of cardiomegaly, heart failure, cardiomyopathy, tachyarrhythmia represented by atrial fibrillation, arteriosclerosis, renal impairment, ( 95) represented by nephritis/nephropathy, renal failure, inflammation and edema, hyperaldosteronism, - 50 neurogenic pain or epilepsy, without negative effects on blood pressure, cardiac function and quality of life. Therefore, the present invention can offer therapeutic agents for the aforementioned diseases with a guarantee of efficacy, safety and quality of life, and thus it is very useful, for example, in the field of conservative treatment and medicine.

Claims (8)

Formula of the invention F) ko 1. T-type calcium channel blocker, which is an optically active 1,4-dihydropyridine derivative of the formula (1) 60 b5 (0) shko U - som shera M o no de V i B2 represent, independently of each other, a C 4.6-alkyl group, where the C. v-alkyl group can be replaced by a phenyl group, where the phenyl group can be replaced by C ..65 - an alkoxy group or a halogen atom, a C 6 -alkenyl group or a C" 6 -alkynyl group, where the C" 6 -alkenyl group and the C 8 -alkynyl group can be replaced by a phenyl group, where the phenyl group can be replaced by C. by a c-alkyl group or a halogen atom, or -i11-MVZV", where KZ and BK" represent, independently of each other, a C 4 c-alkyl group, where the C, d-alkyl group can be replaced by a phenyl group, where phenyl the group may be substituted by a C 1 -C 6 -alkoxy group or a halogen atom, or a phenyl group, where the phenyl group may be substituted C. b-alukoxy group or a halogen atom, I! represents a C»-alkylene group, where the C-alkylene group can be substituted by a C-1-3-alkyl group or a phenyl group, where the phenyl group can be arbitrarily substituted by a halogen atom, a C-1-3-alkyl group or C). with a 3-alkyl group, or B! and B? together form -свРв5-св'вВ., -свРвб-св'/в8-свЗво. or -сСВРвб-св'в8З-сВУв osv V. where V?-K!? represent, independently of each other, a hydrogen atom or a C-alkyl group or any two of them, together with the carbon atom connecting them, can form a 5-, 6- or 7-membered ring; X! and X2 represent, independently of each other, O or ME "Z, where BZ represents a hydrogen atom or o C. an alkyl group; Ag represents a phenyl group, a pyridyl group, a furyl group, or a 2,1,3-benzoxadiazol-4-yl group, where the phenyl group, pyridyl group, furyl group, and 2,1,3-benzoxadiazol-4-yl group can be arbitrarily Ж are substituted by one or two substituents selected from MO», СЕз, Вг, СИ, Е, К, where К is a C 4-20-alkyl yh-group, OH, ОВ», where "7 is a C 6-alkyl group, OSNE", SOOV'YA, MN", MNE", MAV U, where V"? represents a C.v-alkyl group, SOMNo, SOMNA!I, SOM YAVA, SOY, 5В81Я, в(0)В1Я, (0»ВЯ, ВОзН,вОзВМ 802МН»о, 802МНА Я, 802МА В», SM and a phenyloxy group ; He»!va and KE? represent, independently of each other, a C 4.v-alkyl group, -12-MV 5877, where Вб and В! represent, independently of each other, a hydrogen atom, С. - an alkyl group, where the C 1-6 alkyl group can be replaced by a phenyl group, where the phenyl group can be replaced by a C 1 -alkoxy group or a halogen atom, or a phenyl group, where the phenyl group can be replaced by a C 1 -aloxy group or a halogen atom , 1? represents a Co-alkylene group, where the Co-d-alkylene group can be arbitrarily substituted by a C-z-alkyl group or a phenyl group, where the phenyl group can be arbitrarily substituted by a halogen atom, Si by a c-alkyl group or with S. z-alkoxy group, CH»O-I 2-MAV 5817, Ag!, where Ag! is a phenyl group, where the phenyl group can be arbitrarily replaced by a halogen atom, a C-alkyl group or a C. z-aluoxy group, СН-СНАГ!, » СНоСН(ОНАГ», СНО, СМ, СНоОН, СНОВ'5, -2 -Щ(СНо СНИ)» MA I or MAV; M is a C 4.20-alkyl group, where the C 20-alkyl group can be replaced by a phenyl group, where the phenyl group can be replaced by a C. v- alkoxy group or a halogen atom, Co -alkenyl group or ß-Со в-alkynyl group, where Со в-alkenyl group and Со.в-alkynyl group can be replaced by a phenyl (Се) group, where the phenyl group can be replaced by a С. в-aloxy group or a halogen atom, - I3-MV'ZVU, where these KV|VZ represent, independently of each other, a C 4-6-alkyl group, where the C 8-alkyl group can be replaced by a phenyl group, where the phenyl group can be replaced by a C. 6b-alkyl group or a halogen atom, - 20 or a phenyl group, where the phenyl group can be replaced by a C. in-aloxy group or a halogen atom, IZ is a Co in-alkylene group, where Co is an alkylene group can be arbitrarily substituted by a C. z-alkyl group or a phenyl group, where the phenyl group can be arbitrarily substituted by a halogen atom, a C.-3z-alkyl group, or a C. z-alkyl group, / xyl ' i) - 3-4 sh- -8 ime) 60 t ! -133-kh M--2 18 b5 zi (СН), - - ОН ие or с / (СНУ р neo; (СН where о and р are equal, independently of each other, З or 4, d is equal to 1, 2 or 3, and "means the absolute configuration of K, its pharmaceutically acceptable salt or its solvate. 2. T-type calcium channel blocker according to claim 1, where U represents -I 2-ME 9879, where "8" and "Kk" represent, independently of each other, a C.v.-alkyl group, where C. 6v-alkyl the group can be substituted by a phenyl group, where the phenyl group can be substituted by a C 6-6-alkyl group or a halogen atom, or a phenyl group, where the phenyl group can be substituted by a C-6-alkoxy group or a halogen atom, I? represents a C-C-alkylene a group where the C. d-alkylene group can be arbitrarily substituted by a C. i. 3-alkyl group or a phenyl group, where the o-phenyl group can be arbitrarily replaced by a halogen atom, a C. c- alkyl group or a C. c. 3-alkyl group, - Д:. - -sen VIV or y V. ' sho (SNI), o V -7o -k ge iy sn where o and r are equal, independently of each other, to Z or 4, d is equal to 1, 2 or 3, and Ka is Ge! C. in-alkyl group. cue 3. T-type calcium channel blocker according to claim 2, where ER is a C.v.-alkyl group, CM or MH." 4. T-type calcium channel blocker according to claim 1, where M is a C.20-alkyl group, where the C.20-alkyl group can be replaced by a phenyl group, where the phenyl group can be replaced by C; a β-alkoxy group or a 60 halogen atom, a Сo.β-alkenyl group or a С»β-alkynyl group, where Сo. β-alkenyl group and C. vd-alkynyl group can be substituted by a phenyl group, where the phenyl group can be substituted by a C. β- alkoxy group or a halogen atom, B? represents -and 2-MV'9877, where K19 Her B!7 represent, independently of each other, a hydrogen atom, a C. d-alkyl group, where the C. to C. alkyl group can be substituted by a phenyl group, where the phenyl group can be substituted by a C. d-alkyloxy group or a halogen atom, or a phenyl group, where the phenyl group can be substituted Si in-alkoxy group or a halogen atom, I? is a C»-alkylene group, where the C-C-alkylene group can be arbitrarily substituted by a C--3-alkyl group or a phenyl group, where the phenyl group can be arbitrarily substituted by a halogen atom, a C-C-alkyl group or a C-C-alkyl group , SNХО-И2-МВ'9В!! or 127-Ш(СНСНО)»МВ 5, and Ka is a C in-alkyl group. 5. Blocker of T-type calcium channels according to any of claim 2, C or 4, where B and B82 represent, independently of each other, a C..v-alkyl group, where the C..v-alkyl group can be substituted by a phenyl group, where the phenyl group can be substituted by a C. v.-alkoxy group or a halogen atom, by a C.v.-alkenyl group or by a C"v-alkynyl group, where the C"v-alkenyl group and the Cvd-alkynyl group can be replaced by a phenyl group , where the phenyl group can be replaced by a C-alkoxy group or a halogen atom, or K' and BK? together form -Ск5рвб.св'в8., stv. sv'v8i-svov o. or -SVRvb-sv'v8Z-svov'o-sv in 2., where KO. represent, independently of each other, a hydrogen atom or a C. v-alkyl group, or any two of them, together with the carbon atom connecting them, can form a 5-, 6- or 7-membered ring; 75 X!iX2 are both 0. b. T-type calcium channel blocker according to claim 5, where Ag is phenyl, 3-nitrophenyl, 2-nitrophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl or 2, 3-dichlorophenyl. 7. T-type calcium channel blocker according to point b, where KE! and BC? together they form -СНо-С(СНая)»-СНо-, Х! them? represent, both, O, Ag represents Z-nitrophenyl, 2 and B? are both methyl, and Y is 2-I(benzyl(phenyl)amino|ethyl. 8. Therapeutic or prophylactic agent against cardiomegaly, heart failure, cardiomyopathy, atrial fibrillation, tachycardia/arrhythmia, arterial sclerosis, nephritis, nephropathy, renal impairment, renal failure, edema, inflammation, hyperaldosteronism, neurogenic pain, epilepsy, which contains a calcium channel blocker T-type channels according to any of claims 1-7. o Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 8, 11.06.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. hE cha (ze) (o) i - - s - y? -I se) (95) -I 50 s» ime) 60 b5