WO1998001121A1 - P/q type calcium channel antagonist - Google Patents

Abstract

A P/Q type calcium channel antagonist comprising a compound represented by general formula (I) or a salt thereof as the active principle, a remedy for diseases caused by the excessive release of neurotransmitters in the nervous system, which comprises the compound (I) as the active principle; a method for treating such diseases by administering the compound (I); the use of the compound (I) in the preparation of drugs for the diseases; and novel compounds useful for the treatment of the diseases.

Description

 Specification

P Z Q-type calcium channel antagonist Technical field

 The present invention relates to a P-type or Q-type calcium channel antagonist and a novel compound having a P-type or Q-type calcium channel antagonism. Background art

 At present, calcium channels that control calcium metabolism in various parts of the body are classified into L-type, T-type, N-type, P-type, and Q-type by pharmacological and electrophysiological methods. .

 Among them, N-type, P-type and Q-type calcium channels are known to exist only in the nervous system and to be involved in the release of neurotransmitters. Normally, this neurotransmitter is stored in synaptic vesicles at the nerve endings.However, when the nerve action potential reaches the nerve endings by signal transmission, calcium channels are activated and calcium Ions flow in, causing synaptic vesicles to fuse to the presynaptic membrane and release neurotransmitters. Released neurotransmitters act on postsynaptic membrane receptors and participate in synaptic transmission.

 At present, calcium ions that cause such neurotransmission are thought to pass through N-type calcium channels and P-type or Q-type calcium channels (hereinafter referred to as PZQ-type calcium channels). It is said that the former is mainly present in the peripheral nerves and the latter is mainly present in the central nervous system.

 In view of the mechanism described above, it is estimated that PZQ-type calcium channel antagonists are very effective for diseases caused by excessive release of neurotransmitters in the nervous system.

As peptide-type P / Q-type calcium channel antagonists, ω-agatoxin IVA extracted from spider venom is known (Nature, (Vol. 355, pp. 827-p. 829, 1992) is a polypeptide with a large molecular weight, shows negative pathological dependence, and is active in normal times. However, it has problems such as the possibility that the activity may be weakened during the disease state.

Examples of non-peptide selective PZQ-type calcium channel antagonists include FTX (International Patent Application Publication No. WO9132777), a plant alkaloid, daurisoline (Neuroreport) (N euroreport), pp. 1499-1492, pp. 199-2) have only been reported to have P-type calcium channel antagonism, and they inhibit P-type calcium channel inhibition. IC ₅ . Was several mM for FTX and 35 μΜ for daurizoline, which was not always satisfactory as a pharmaceutical.

 The present inventors have disclosed in Japanese Patent Application No. 7-261556 that α-eudesmol has a type II calcium channel antagonistic action.

 Under these circumstances, there has been a demand for the development of an excellent non-peptidic Q-Q-type calcium channel antagonist that surpasses conventional P / Q-type calcium channel antagonists. Disclosure of the invention

 The present inventors have conducted intensive studies in order to develop a potent non-peptide PZQ-type calcium channel antagonist, and as a result, have found that the compound represented by the following formula (I) achieves the object. Was completed. That is, the present invention provides, as one mode, the formula (I):

(R

[Wherein, the ring Α may have a substituent and may have a double bond; a 6-membered carbon ring; R ¹ is hydrogen or lower alkyl, and R ² is hydrogen; Or R ¹ and R ² may together form one CH ₂ CH ₂ —;

R ³ is hydrogen, — CR ⁵ R ⁶ OH, — CR ^s R ⁶ O S0 ₇ R ⁷ ,-CR ⁵ R ⁶ COR ⁷ . One CR ⁵ R ⁶ OCOR ⁷ , — CR ⁵ R ⁶ NH R ⁸ , One CR ⁵ = CH ₂ ,-CORK ― COOH, One CONHR ⁵ , One CHR ⁵ R ⁶ , = CR ⁵ R ⁶ , One CR ⁵ = N〇H or lower alkyloxylanil;

R ⁴ is hydrogen or lower alkyl;

R ⁵ and R ⁶ are each independently hydrogen or a lower alkyl which may have a substituent;

R ⁷ is a lower alkyl optionally having substituent (s);

R ⁸ is hydrogen or lower acyl;

Dashed lines indicate that either one has a double bond or neither.]

Or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. Further, the present invention provides a method for treating a disease caused by excessive release of a neurotransmitter in the central nervous system, which comprises administering the compound (I). In yet another aspect, there is provided the use of compound (I) for the manufacture of a medicament for a disease caused by excessive release of a neurotransmitter in the central nervous system. In addition, the formula (I '):

(R

A compound represented by the formula:

a) Α 'ring is

R ′ ′ and R ² ′ together form one CH ₂ CH ₂ —, and R ⁹ ′ and R ¹⁰ ′ are one NH R ¹⁸ ′, and The other is hydrogen or joined together to form = NR ^{2 1} ', where R ³ ', R ', R ¹¹ ', R ¹⁸ 'and R ^{2 1} 'are each ^{R 3 R 4 R 1 1,} R 1 8 and R ^{2 1} synonymous force, b) A' ring

R ² ′ is hydrogen and R ³ ′ is — CR ⁵ ′ R ⁶ ′ 0 SO 2 R ⁷ ′ -CR ⁵ ′ CH ₂ , one C ONHR ⁵ ′ or one CO OH and R ¹ ′ RR ⁵ R ⁶ R ⁷ 'R ⁹ ' R ¹⁰ 'and R ¹¹ ' are each synonymous with R 'R ⁴ R ⁵ R ⁶ R ⁷ , R ⁹ , and R ¹¹ ,

c) A 'ring force

R ² ′ is hydrogen; R ³ ′ is —CR ⁵ “R ⁶ ” OH, wherein R ⁵ ″ and R ⁶ ″ are each independently a lower alkyl which may have a substituent; ), — CR ⁵ "'R ⁶ "' 〇 SO ₂ R ⁷ "or one CR ⁵ '" R ^6, "NHR ⁸ ' (where R ^δ "'and R ⁶ each independently represent hydrogen or a substituent R ⁷ "is lower alkyl which may have a substituent; R ⁸ 'is lower acyl), and a broken line indicates that a double bond is not present on both; ¹ 'R ⁴ ' and R ^{1 1} 'are synonymous with RR ⁴ and R ¹ ', respectively

d) A 'ring is

R ⁹ ′ and R ¹⁰ ′ are each independently hydrogen, —O CH ₂ C〇R ¹⁷ ′ or —NHCOR ¹⁹ ′ COOR ²⁰ ′;

R ¹ 'R ² ' R ³ ', R ⁴ ' R ^{1 1} 'R ¹² ' R ¹⁷ 'R ¹⁹ ' and R ²⁰ 'are R i R ² R ³ R ⁴ , R ^{1 1} , R ^{1 2} R ^{1 7} R ^'9 and R ² ° and synonymous der Power or

e) A * ring is

R ³ ′ is hydrogen, — CR ⁵ ′ R ⁶ ′ OC 0 R ⁷ ′, —CR ⁵ ′ = CH ₂ or alkyloxylanil;

R ⁹ 'and R' ⁵ 'are each independently hydrogen, lower alkyl, lower Arukiruokishi, lower Ashiruokishi, lower alkylsulfonyl O ^{_{carboxymethyl, - OC H 2 C OR 1}} 7', 0 NHR 1 8 ', or _ NHC 0 R ^{1 9} 'CO_〇 R ^{2 0'} or where together such connexion = 0, -〇 CH ₂ CH ₂ 0- or - may form NR ^{2 1} '(where together such connexion = When forming 〇, R ³ ′ is —CR ⁵ ′ R ⁶ ′ OCOR ⁷ ′), R ¹¹ ′ and R ¹⁶ ′ are each independently hydrogen or a lower optionally substituted group. Alkyl, or together may form = CH ₂ or = 0,

R ¹⁵ ′ and R ¹⁶ ′ may together form one O—,

R ¹ ', R ² ', R ', R ⁵ ', R ⁶ ', R ⁷ ', R ¹³ ', R ¹⁴ ', R ¹⁷ ', R ¹⁸ ', R ¹⁹ ', R ^{2 0} 'and R ^{2 1'} are each ^{RR 2, R 4, R 5} , R 6, R 7, R 1 3, R 1 4, R 1 7, R 1 8, R 1 9, R 2 0 and R ^{2 A} compound having the same meaning as ¹ , a pharmaceutically acceptable salt thereof or a hydrate thereof is provided. Furthermore, the present invention also provides a pharmaceutical composition containing the compound (1 ′) as an active ingredient. BEST MODE FOR CARRYING OUT THE INVENTION

 In the present specification, the “carbon 6-membered ring optionally having a double bond” includes a cyclohexane ring, a cyclohexene ring, a cyclohexadiene ring, a benzene ring and the like.

“A 6-membered carbon atom which may have a substituent” means hydroxy, lower alkyl optionally having a substituent, lower alkenyl, lower alkyloxy, lower acyloxy, lower alkylsulfonyloxy, —〇 CH ₂ COR ¹⁷ (R ¹⁷ is hydroxy, Lower Arukiruokishi or ^{_{NH 2), -NH R 1 8}} (R 1 8 is hydrogen, hydroxy, lower alkyl, lower Ashiru or lower alkylsulfonyl), or ^{- NHCOR 1 9 C OO R 20} (R 1 9 is a lower alkylene or lower alkenylene; R ^{2 0} is a lower § ^{alkyl), = 0, = NR 2} 1 (R 2 1 is human Dorokishi, NHT s, may have a lower alkylsulfamoyl Honiruokishi) and = CH ₂ and the like substituents It may have a bond such as one OCH ₂ CH ₂₀ —, one CH ₂ , one or one, etc. between two or more carbon atoms forming a ring.

 “Lower alkyl” means a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. —Butyl, n-pentyl, isopentyl, veopentyl and hexyl. “Lower alkyl optionally having substituent (s)” may be substituted with hydroxy, halogen and the like.

 The term "lower acyl" means an acyl having 1 to 6 carbon atoms, and includes acetyl, propionyl, butyryl, isobutyryl, valeryl, vivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonyl and the like.

 The “lower alkylene” includes alkylene having 1 to 6 carbon atoms and includes, for example, methylene, ethylene, trimethylene, tetramethylene, propylene, ethylethylene and the like.

 The “lower alkenylene” includes alkenylene having 2 to 6 carbon atoms, for example, vinylene, probenylene, butenylene, pentenylene, hexenylene, probezienylene, butegenylene and the like. be able to.

References to "the compound according to the present invention" also include pharmaceutically acceptable salts of compound (I). For example, salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid; organic acids such as formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, and succinic acid Salts of acids; salts of organic bases such as ammonium, trimethylammonium, and triethylammonium; salts of alkali metals such as sodium and potassium; and salts of alkaline earth metals such as calcium and magnesium. it can. The compound according to the present invention also includes a hydrate thereof, and one molecule of the compound (I) may be bound to one or more water molecules.

 All the compounds represented by the above formula (I) have a PZQ-type calcium channel antagonistic action and are useful as a PZQ-type calcium channel antagonist or a pharmaceutical composition.

 [1] Ring A

[Wherein, R ⁹ , R ¹ ° and R ¹⁵ are each independently hydrogen, hydroxy, lower alkyl, lower alkyloxy, lower acyloxy, lower alkylsulfonyloxy, OCH 2 COR ¹⁷ (R ¹⁷ human Dorokishi, lower Arukiruokishi or ^{_{NH 2), - NHR 1 8}} (R 1 8 is hydrogen, arsenate Dorokishi, lower alkyl, lower Ashiru or lower alk alkylsulfonyl), or a NHCOR ^{1 9} C_〇_OR ^2. (R ¹⁹ is lower alkylene or lower alkenylene; R ^{2 Q} is lower alkyl)

R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁶ are each independently hydrogen or lower alkyl which may have a substituent.

Also R ⁹ and R ¹ . And R ⁹ and R ^{1 5} are together a connexion _{= 0, - OCH 2 CH 2} O- or = NR ^{2 1} (R ^{2 1} is human Dorokishi, NHT s, lower alkyl sulfonyl Ruokishi) may be formed ,

R ¹¹ and R ¹⁶ may be taken together to form = CH ₂ , = 〇 or one CH ₂ 〇—, and R ¹⁵ and R ¹⁶ may be taken together to form one O— Is also good. A compound that is

More preferably

a) A ring is

In and, R ¹ and R ² are together a connexion - CH ₂ CH ₂ - to form, 1¾ ³ is -〇 1¾ R ⁶ OH, force an CR ⁵ = CH ₂ or a CHR ⁵ R ⁶

b) ring A

R ¹ is lower alkyl, R ² is hydrogen, R ³ is —CR ⁵ R ⁶ 〇H, —CR ⁵ R ⁶ OS 0 ₂ R ⁷ , -CR ⁵ R ⁶ NHR ^8. -CR ⁵ R ⁶ NHR ⁸ >-CR ⁵ = force, which is CH ₂ or one COR ⁵ ,

c) ring A

And R ^{3 is} -CR ⁵ R ⁶ OH, -CR ⁵ R ⁶ OS 0 ₂ R ⁷ CR ⁵ R ⁶ C〇R one CR ⁵ R ⁶ NHR ⁸ or one COR ⁵ ;

d) A ring is

And RR ² and R ³ are hydrogen, or

e) ring A

And R ³ is hydrogen, — CR ⁵ R ⁶ 〇H, one CR ⁵ R ⁶ OC〇 R ⁷ or — CR ⁵ = CH ₂

 [2] Ring A

A compound that is

More preferably, ring A is

A compound that is

[3] a compound wherein R ¹ is lower alkyl and R ² is hydrogen, or a compound wherein R ¹ and R ² are taken together to form —CH ₂ CH ₂ —,

More preferably, R ¹ and R ² together form _CH ₂ CH ₂ —

[4] R ³ is hydrogen, — CR ⁵ R ⁶ OH, one CR ⁵ R ⁶ OS 0 ₂ R ⁷ ,-CR ⁵ R ⁶ NHR ⁸ , one CR ⁵ = CH ₂ , —COR ⁵ , — CO〇H ,-CHR ⁵ R ⁶ , = CR ⁵ R ⁶ or — a compound in which CR ⁵ = N〇H,

More preferably, compounds wherein R ³ is _CR ⁵ R ⁶ OH, — CR ⁵ R ⁶ NHR ⁸ or one CR ⁵ = CH ₂ ,

Most preferably, a compound wherein R ³ is —C (CH 3) 2 OH, one C (CH ₃ ) = CH ₂ or one CH (CH ₃ ) NH ₂

[5] a compound wherein R ⁴ is hydrogen

[6] Ring A

And R ¹ is lower alkyl and R ² is hydrogen or R ¹ and R

² together form one CH ₂ CH ₂ —, R ³ is hydrogen, one CR ⁵ R ⁶ OH, CR ⁵ R ⁶ OSO ₂ R ⁷ .- CR ⁵ R ⁶ NHR ⁸ , one CR ⁵ = CH ₂ , a compound in which one COR ⁵ , c OOH, one C HR ⁵ R ⁶ , = CR ⁵ R ⁶ or one CR ⁵ = NOH

Three

R ¹ and R ² together form one CH ₂ CH ₂ —, and R ³ —— CR ⁵ R ⁶ 〇H, — CR ⁵ R ⁶ NH R ⁸ or one CR ⁵ = CH ₂ Compounds in which R ⁴ is hydrogen

Is preferred as a PQ-type calcium channel antagonist. Specific examples of preferred embodiments of the compound (I) according to the present invention are as follows.

 (4aS, 7R, 8aR) 1,3,4,4a, 5,6,7,8,8a-octahydride mouth—7-isopropenyl-1,4a-dimethyl-naphthalene (compound 1 a) (a S, 7 R, 8 a R) — 3, 4, 4 a, 5, 6, 7, 8, 8 a — Kutahidro 7 — (1-hydroxyl 1-methylethyl) — 1, 4a—Dimethylnaphthalene (Compound 1b)

 (4 a S, 7 S, 8 a R) 1, 3, 4, 4 a, 5, 6, 7, 8, 8 a—Hydroxy 7 — (1-hydroxyl 1—methylethyl) 1 1 , 4a—Dimethylnaphthylene (Compound 1c)

(a S, 7 S, 8 a S) 1, 3, 4, 4 a, 5, 6, 7, 8, 8 a — ク タ ク タ 口 7 — (1-hydroxy 1-methylethyl) 1, 1, 4 a—Dimethyl naphtha Len (compound 1d)

 (4 a S, 7 R, 8 a S) — 3, 4, 4 a, 5, 6, 7, 8, 8 a—Hydroxy _ mouth — 7 — (1-hydroxyl — 1—methylethyl) 1,4a-Dimethylnaphthylene (Compound 1e)

 (4aR, 7R, 8aR)-1,2,3,4,4a, 56,7,8,8a-Decahi draw 7 — (1—Hydroxy-1-1-methylethyl) 4a —Methyl-1-methyl-naphthylene (Compound 2a)

 (4 a R, 7 S, 8 a R) 1, 1, 2, 3, 4, 4 a, 5, 6, 7, 8, 8 a — decahi draw 7 — (1-hydroxy-methylethyl) 1 4 a—Methyl-1 methylene-naphthylene (Compound 2b)

 (4aR, 7R, 8aR) — 3,4,4a, 5,6,7,8,8a—Kitahi draw 7 — (1—Hydroxy-1-methylethyl) 1-4a— Methyl — 1 (2 H) — Naphtholenone (Compound 2 c)

 (4aR, 7R) -2,3,4,4a, 5,6,7,8-octahydro-7— (1-hydroxy-1-methylethyl) —1,4a—dimethylnaphthalene (compound 3 a)

 (4 a S, 7 R)-4, 4 a, 5, 6, 7, 8 _ hexahi draw 7 — (1-hydroxy-1-methylethyl) 1, 1, 4 a-dimethyl 2 (3 H) 1 Naphthalenone (Compound 3b)

 (4 a S, 7 R)-2, 3, 4, 4 a, 5, 6, 7, 8-year-old 7-(1-hydroxy-1-methylethyl) 1, 1 a-dimethyl-2 — (2 — p— tosylhidrazono) 1-naphthylene (compound 3 c)

 (2R, 4aS, 7R) 1,2,3,4,4a, 56,7,8-octahidraw 7— (1-hydroxyl-methylethyl) — 14a—dimethyl-2-naphthene Lenol (compound 3d)

(2 S, 4 a S, 7 R) — 2, 3, 4, 4 a, 56, 7, 8 — 1-hydroxyl 7 — (1-hydroxyl-methylethyl) 1 14 a—dimethyl 2 — Naphthalenol (Compound 3e) (4 a S, 7 S) 1, 4 a, 5, 6, 7, 8-hexahydro 7-isopropyl 1,4 a-dimethyl-2 (3 H)-naphthyllenone (compound 4a)

 (4 a S, 7 R) 1, 4 a, 5, 6, 7, 8-hexahydro 7-isopropyl 1, 4 a-dimethyl-2 (3 H)-naphthalenone (compound 4 b)

 (4 a S, 7 S) — 4, 4 a, 5, 6, 7, 8 — hexahydro 7 — isoprobenyl — 1, 4 a — dimethyl-2 (3 H) mononaphthyllenone (compound 4 c )

 (4 a S, 7 R) — 4, 4 a, 5, 6, 7, 8-hexahydro 7-isoprobeluene 1, 4 a-dimethyl-2 (3 H) 1-naphthalenone (compound 4 e)

 (2 S, 4 a S, 7 S) — 2, 3, 4.4 a, 5, 6, 7, 8-year old Kutahi draw 7-isopropenyl-1,4 a-dimethyl-2-naphthalenol (compound 5 a ) (2R, 4aS, 7S) -1-2-amino-2,3,4,4a, 5,6,7,8-hydro-7-isoprodinil-14a- Dimethylnaphthalene (Compound 5b)

 (2 R, 4 a S, 7 S) — 2-Amino-2,3,4,4a, 5,6,7,8-octahiDraw 7-isopropenyl-14a-dimethylnaphthalene-hydrochloric acid Salt (compound 5c)

 (2 R, 4 a S, 7 S) — 2-Acetylamino — 2, 3, 4, 4 a, 5, 6, 7, 7, 8 — Kutahi Draw 7 — Isoprovenile 1, 4 a — Dimethylnaphthalene (Compound 5d)

 (2 R, 4 a S, 7 S) — 2, 3, 4, 4 a, 5, 6, 7, 8 — Draw 7-isopropenyl-1--2-methanesulfonylamino-1,4 a —Dimethyl naphthene (Compound 5e)

 (2 R, 4 a S, 7 S) — 2, 3, 4, 4 a, 5, 6, 7, 8-year old Kutahi Draw 7-isoprovenil 1,4 a-dimethyl-2-naphthalenol (compound 5 f)

(4 a S, 7 S) 1, 2,3,4,4a, 5,6,7,8-octahydro Draw 2—Hydroxyimino 1 7—Isoprovenile 1,4a—Dimethyl-naphthylene (Compound 5 g)

(4 a S, 7 S)-2, 3, 4, 4a, 5, 6, 7, 8 Soprobenyl-1,4a-dimethyl-2- (2-p-tosylhydrazono) -naphtalene (compound 5h)

 (2 S, 4 a S, 7 S) — 2-Amino-2,3,4,4 a, 5,6,7,8—Oktahi Draw 7 _Isopropenyl— 1> 4 a—Dimethylnaphthalene ( Compound 5 i)

 (2 S, 4 a S, 7 S) 1, 2, 3, 4, 4 a, 5, 6, 7, 8 才 ク 夕 1 — 7-isopropenyl-2-methanesulfonylamino 1, 4 a —Dimethylnaphthalene (Compound 5j)

 (IS, 4 a S, 7 S, 8 a S)-3, 4, 4 a, 5, 6, 7, 8, 8 a-ok Yi He Draw 7 — Isoprovenile 1, 4 a — Dimethyl 2 (1H) mononaphthalenone (compound 6a)

 (IS, 2 S, 4 a S, 7 S, 8 a S) 1, 1 2, 3, 4, 4 a, 5, 6, 7, 8, 8 a-decahydro-7-isopropenyl-14-a-dimethyl 2-Naphthalenol (compound 6b)

 (IS, 4 a S, 7 R, 8 a S) 1, 3, 4, 4 a 5, 6, 7, 8, 8 a (1H) 1-naphthylrenone (compound 6c)

 (1 S, 2 S, 4 a S, 7 R, 8 a S) — 1, 2, 3, 4, 4 a, 5, 6, 7, 8, 8 a—Decahi draw 7—Isopropenyl-1, 4a-Dimethyl-2-naphthalenol (compound 6d)

 (IS, 4aS, 7S, 8aS) 1-7 — [(1—trichloroacetyloxy-1-methyl) ethyl] -1,3,4,4a, 5,6,7,8,8a —Ok Yuhi Draw 1, 4a—Dimethyl 2 (1 H) —Naphthalenone (Compound 6 e)

 (4aS, 7R) — 2,3,4,4a, 5,6,7,8-octadraw 7— (1-hydroxyl-methylethyl) —1,4a—dimethylnaphthylene (compound 7 a)

(4 a R, 7 R) — 4, 4 a, 5, 6, 7, 8 — hexahidraw 7 — (1 — hydroxy 1 — methylethyl) 1, 1, 4 a — dimethyl _ 2 (3 H ) One naphthalenone (Compound 7b)

 (2 R, 4 a S, 7 R) One and (2 S, 4 a S, 7 R)-2, 3, 4, 4 a, 5, 6, 7, 8-octa draw 7-(1- Droxy-1 1-methylethyl) 1,4a-Dimethyl-2-naphthalenol (Compound 7c)

 (4aS) 14,4a, 5,6-tetrahydro-7-isopropyl-1,4a-dimethyl-2 (3H) naphthenelenone (compound 8a)

 (4 a S) 1, 2,3,4,4 a, 5,6—Hexahi draw 2 —Hydroxyimino-17-isopropyl-1,4a-Dimethyl-naphthylene (Compound 8b)

 (4 a S) — 2,3,4,4 a, 5,6-hexahydro 7-isopropyl-l 2- (methanesulfonyloxy) imino-1, 4a-dimethylnaphthalene (compound 8c)

 (4 a S) — 2,3,4,4 a, 5,6 —Hexahydr 7-isopropyl-1,4a—dimethyl-1- (2-p-tosylhydrazono) -naphthalene (compound 8d)

(4aS, 7S) 1,3,4,4a, 5,6,7-Hexahidraw 7-Isopropyl 1,1,4a-Trimethyl-2 (1H) -naphtholenone (Compound 9 a)

(4 a S, 7 S) — 3, 4, 4 a, 5, 6, 7 — HexahiDraw 7 — Isoprovenyl 1, 1, 4 a — Trityl-2 (1H) 1-naphthalenone (compound 9 b)

(4aS) 1,3,4,4a, 5,6,7 —Hexahidraw 7 —Isopropylidene —1,1,4a—Trityl-2 (1H) -naphthalenone (Compound 9c)

 (2 S, 4 a S, 7 S) 1 1, 2, 3, 4, 4 a, 5, 6, 7-year old Kutahi Draw 7-isoprovenile 1, 1, 4 a-trimethyl-2- Naphthalenol (compound 9d)

 (2S, 4aS) 1-1,2,3,4,4a, 5,6,7-octahydro-7-isopropylidene-1,1,4a-trimethyl-2-naphthalenol (compound 9e)

(2R, 4aS, 7,8aR) — 1,2,3,4,4a, 5,6,7,8,8a-decahydro 7-isopropenyl-4a-methyl-1 Methylene mono 2 — naphthylenol (compound 10 a)

(2 R, 4 a S, 7 R, 8 a R) — 1, 2, 3, 4, 4 a, 5, 6, 7, 8, 8 a _Decahi Draw 7— (1 —Hydroxy 1 —Methylethyl) -4 a—Methyl-1-methylene— 2 —Naphthalenol (Compound 10 b)

 (4 a R, 7 R) 1, 3, 4, 4 a, 5, 6, 7 — hexahydro 1 7 — (1 — hydroxy 1 — methylethyl) 1, 1, 4 a _ dimethylnaphthylene ( Compound 1 la)

(1 R .4aR, 7R, 8aR) — 1,2,3,4,4a, 5,6,7,8,8a _Decahi draw 7-Isopropenyl-1 4a-methyl- 1, 1 Epoxymethano 1-naphthylene (Compound 12a)

 (1R, 4aR, 7R, 8aR)-1,2,3,4,4a, 56,7,8,8a—Decahidro 7 — (1—Hydroxy-1-methylethyl) 4 a-Methyl-epoxymethanonaphthalene (Compound 12b)

 (1 R, 4 aR, 7 R, 8 aR) 1, 1, 2, 3 4, 4 a, 5, 6, 7, 8, 8 a Naphthalenol (Compound 13a)

 (IS, 4aR, 7R, 8aR) — 1,23,4,4a, 5,6,7,8,8a-decahydro-7—Isopropenyl-14a—dimethyl-1 One-naph renol (Compound 13b)

 (1 R, 4 aR, 7 R, 8 aS)-14, 4 a, 5, 6, 7, 8, 8 a 1,4a-dimethyl-naphthalene (compound 14a)

 (4 a R, 7 R) 1, 4 a, 5, 6 7, 8-hexahydro 1-7-(1-hydroxy-1-methylethyl) 1, 1, 4 a-Dimethylnaphthalene (compound 14) b) (4 a R, 7 R, 8 a R) — 3, 4, 4 a, 5, 6, 7, 8, 8 a—Kitahiro draw 7 — (1-hydroxy-1-methylethyl) 1-4 a-Methyl-1-naphthalenemethanol (Compound 15a)

 (4 a S, 7 S) 1, 4, 4 a, 5, 6, 7, 8-hexahydro-7-isoprobenyl-4 a _ methyl-2 (3 H) 1-naphthalenone (compound 16a)

(4 a S, 7 R) — 4, 4 a, 5, 6, 7, 8 — hexahydro 7-isoprobe-2-lu 4 a—methyl-2 (3 H) — naphthyllenone (compound 16 b) (IS, 2 R, 4 a S, 7 R, 8 a R) — 1, 2 — Epoxy 1, 2, 3, 4, 4 a, 5, 6, 7, 8, 8 a — Decahydro 7 —Isopropenyl-1,4a—dimethylnaphthylene (compound 18)

 (4 a R, 7 R, 8 a S) — 7 — [(1,2 —epoxy-1-methyl) ethyl] — 1, 2, 3, 4, 4 a, 5.6, 7, 8, 8 a —Decahi Draw 4 a—Methyl— 1-methylene-naphthylene (Compound 19)

 (1 S, 4 a S, 7 R) — 2,2-Ethylenedioxy 1.2,3,4,4a, 5,6,7 —Hydrogen draw 7-Isopropenyl-1,4 a—Dimethylnaphthalene (Compound 20)

 (E) 1-4-1 (2,6,6, -trimethyl-2-cyclohexene-11-yl) -1-butene-2-one (compound 21a)

 (E) 1-41 (2,6,6, —trimethyl-2-cyclohexene1-1yl) 1-3-buten-2-ol (Compound 21b)

 (E) 1-Methyl-4— (2,6,6, —trimethyl-12-cyclohexene-1-yl) —3—Butene-2-ol (Compound 21c)

 (E) 14 — (2.6, 6, 1-trimethyl-2-cyclohexene 1-yl) 1-3-butene-12-amine (Compound 21d)

 (E) 1-41 (2, 6, 6, 1-trimethyl-1-cyclohexene-1-yl) 1-3-butene-2-one (compound 22a)

 (E) 1 4 — (2,6,6, — trimethyl-1-cyclohexene 1-yl) 1-3-butene 1 2 —ol (compound 2 2b)

 (E) 12-Methyl-41- (2,6,6, -trimethyl-1-cyclohexene-11-yl) -13-butene-12-ol (Compound 22c)

 (E) 14-(2, 6, 6-trimethyl-1-cyclohexene-1-yl)-3-butene-2-amine (compound 2 2d)

 (E) — 4- (2,6,6,1-trimethyl-1-cyclohexene-1-yl) -3-butene-2-amine—hydrochloride (compound 22 e)

(E) 1—4— (2,6,6, —trimethyl-1-cyclohexene-1—yl) — 3 —Butene—2—On— (E) —Sixime (Compound 2 2 f)

 (E) — 4- (2,6,6,1-trimethyl_1-cyclohexene-1-yl)

3-butene 2-one- (Z) -oxime (compound 22 g)

 4- (2,6,6,1-trimethyl-12-cyclohexene-11-yl) -12-butanone (compound 23a)

 2-Methyl-41 (2,6,6,1-trimethyl-2-cyclohexene-1-yl) —2-butanol (compound 23b)

 4— (2,6,6, —trimethyl-2—cyclohexene-11-yl) _2-butanol (compound 23c)

 4— (2,6,6,1-trimethyl-2-cyclohexene-1-yl) 1-2—butyl methanesulfonate (compound 23d)

 4-(2,6,6, -trimethyl-2-cyclohexene-l-yl) -l-butanamine (compound 23e)

 N— [4- (2,6,6, —trimethyl-2-cyclohexene-1-yl) -12-butylacetamide (compound 23 f)

 (E, E) N- [4- (2,6,6, -trimethyl-l-cyclohexene-l-yl) -l-butyl]-2,4-hexagenamide (compound 23 g) )

4- (2,6,6, -trimethyl-1-cyclohexene-1- (yl) -12-butane nonone (compound 24a)

 4- (2,6,6, —trimethyl-1-cyclohexene-1-yl) -12-butanol (compound 24b)

 4- (2,6,6,1-trimethyl-1-cyclohexene-11-yl) -12-butylmethanesulfonate (compound 24c)

 4 — (2, 6, 6, 6 — trimethyl-1-cyclohexene-1-yl) — 2-butane namine (compound 24d)

 4-(2,6,6, -trimethyl-1 -cyclohexene 1-yl) 1 2 -butane nonoxime (compound 24e)

2,4,4,1-trimethyl_3— (3-methyl-3-butenyl) —2-cyclohexa Xenyl acetate (Compound 25a)

 2,4,4,1-trimethyl-3- (3-tyl-3-butenyl) -1-cyclohexenol (compound 25b)

 2,4,4,1-Trimethyl-3- (3-methyl-3-butenyl) -1-cyclohexene-1-amine (Compound 25c)

 (E) 13- (2,6,6, -trimethyl-1-cyclohexene-1-yl) propenoic acid (Compound 26a)

 3- (2,6,6,1-trimethyl-1-cyclohexene-1-yl) propionic acid (compound 26b)

 (E) -N- (2-methylpropyl) -3- (2,6,6,1-trimethyl-11-cyclohexene-11-yl) -propene amide (Compound 26c)

 4- (2,6,6, -trimethylcyclohexyl) -12-butynone (compound 27) (5R) -11-hydroxyimimino 5-isoprobenil-2-methyl-2-cyclohexene (Compound 28a)

 (5 R) — 1 —Hydroxyiminow 5-Isopropyl-2-methyl-2-cyclohexene (Compound 28 b)

 (Is, 5R) 1-11-ethoxycarbonylmethyloxy-5-isoprobenyl-2-methyl-2-cyclohexene (Compound 29a)

 (I S, 5 R) — 1 —Carboxymethyloxy 5 —isopropenyl — 2-methyl 2-cyclohexene (Compound 29 b)

 (I S, 5 R) 1 1 1-Rubamoylmethyloxy 5-isopropenyl-2-methyl-2-cyclohexene (Compound 29c)

 (1 R, 5 R) 1 1 1 amino-5-isopropenyl-2-methyl-2-cyclohexene hydrochloride (Compound 29 d)

 (1 R, 5 R)-1-(3 -ethoxycarboxyl 1 -oxo 1-2-propenyl) amino 5-isopropenyl-2-methyl-2-cyclohexene (compound 29 e)

(5R) —5-Isopropyl-1,2,2-dimethyl-1-cyclohexanone (Compound 30a) (5R) _5_Isopropenyl—2,2-dimethyl-1-cyclohexanone (Compound 30b)

 (5 R) 1-Hydroxyimino-1-5-isopropylene 2,2-dimethylcyclohexane (Compound 30 c)

 (5 R) — 1-Hydroxyiminow 5-Isopropyl-1,2,2-distylcyclohexane (Compound 30 d)

 (1 R, 5 R) 1-5-Isoproenyl-2,2-dimethyl-1-cyclohexanol (Compound 31 a)

 (1R, 5R) 1-1_amino-5-isopropenyl-2,2-dimethylcyclohexane (Compound 31b)

 (1R, 5R) 1-1-Acetylamino-5-isoprobenyl-2,2-dimethylcyclohexane (Compound 31c)

 (1R, 5R) 1-1-Hydroxyamino-5-isopropenyl-1,2,2-dimethylcyclohexane (Compound 3Id)

 (1 R, 5 R) 1-5-Isoprovenyl 1-methanesulfonyloxy-2,2-dimethylcyclohexane (Compound 31e)

 (IS, 5R) — 5-Isopropenyl-2,2-dimethyl-1-cyclohexanol (Compound 32a)

 (I S, 5 R) — 1-amino-5-isopropenyl-2,2-dimethylcyclohexane (Compound 32 b)

 (IS, 5R) 1-1-Acetylamino-5-isopropenyl-2,2-dimethylcyclohexane (compound 32c)

(IS, 5R) 1-hydroxyamino-5-isopropenyl-2,2-dimethylcyclohexane (compound 32d) In the above specific examples, compounds lb, ld, 4a, 5b, 5c, 5 d, 5e, 5f, 6e, 10a, 20, 21a, 22e, 23a, 23b, 23c, 23d, 23e, 23f. 23 g, 24 a, 2 b, 24 c, 24 d, 25 a, 26 c, 30 c And 31 e are preferred, and compounds 1b, 5b and 24d are more preferred.

 The compound (I) according to the present invention includes known compounds and novel compounds, and the literatures or commercially available products in which the known compounds are described below indicate the name of the sales company.

Compound 1a:

Journal of the Japanese Society of Agricultural Chemistry, 1 98 2, 2, 6, 6, 4 1

Compound 1b:

Journal 'ob' 'organic' chemistry (J. Org. Chem.) 1 9 6 7, 3 2, 2 3 3 5

Compound 1c, Compound 1d, Compound 1e, Compound 2b:

Journal of 'Organic' Chemistry (J. Org. Chem.) 1985, 50, 1359

Compound 2a, Compound 3a:

Helvetica Kimi Power (Helv.Chim.Acta) 1987,70,2187)

Compound 2c:

Journal 'ob' 'natural' products (J. Nat. Prod.) 1994, 57, 1189

Compound 3b:

Indian Journal 'OB' Chemistry (Indian.J.Chem.) 1 9 7 1, 9, 9 5

Compound 3d, compound 3e, compound 14a:

Journal of Bob Chemical _ν Science ( _J. Chem. Soc.) 1963, 2773

Compound 4a:

Journal of Organic, Chemistry (J. Org. Chem.) 1976, 41, 37 05

Compound 4, compound 6c: Journal 'ob''chemical' society (J. Chem. Soc.) 1956, 2670

Compound 4c:

Journal 'Ob Organic Chemistry' (J. Orr. Chem.) 1983, 48, 3334

Compound 4e:

Tetrahedron (Tetrahanedron) 1992, 48, 3112 Compound 5a, Compound 5f:

Journal of American Chemical 'Society (J. Am. Chem. Soc.) 1967, 89, 56, 65

Compound 6a, compound 6, compound 6d (:

Journal 'Ob' Organic 'Chemistry (J. Org. Chem.) 1 986, 51, 4 5 7 3

Compound 7a:

Photochemistry (Phytochem.) 1989, 28, 1909 Compound 7b, Compound 14b:

J.Chem. Canadian 'Journal' Ob 'Chemistry (Canad.J.Chem.)

Compound 7c:

Journal 'Ob' Organic 'Chemistry (J.Or.Chem.) 1 9 6 8, 3 3, 4 3 5

Compound 8a:

Journal 'ob' 'organic' chemistry (J. Org. Chem.) 1 954, 3 4 9 2

Compound 9a:

Tetrahedron (Et r ah e d r o n L e t t e r s) 1 9 7

3, 4 4, 4 3 3 3

Compound 9b, Compound 16a: Tetrahedron 1989, 45, 14447 Compound 9c, Compound 9d, Compound 9e:

Tetrahedron (Tetrahehdron) 1992, 48, 549 7 Compound 10a:

Handbook of Nat'l Rally * O'Ring Ring Compounds (H andbook of Natural 1 y Occuring Commodities) Vol. II, Academic Press New York and London (Academic Press New York and London) 1 9 7 2 Compound 1 0 b:

Phytochemistry (Phytochem.) 199 6, 41, 243 Compound 11a:

Canadian Journal 'ob' Chemistry (Canad. J. Chem.) 19 6 8, 46, 28 17

Compound 1 2a:

Tetrahedron Letters (Tetrahaedron, Lettetters.) 1 9 6 8, 3 2 2 3

Compound 1 2b:

Tetrahedron (Tet r ah e d r on) 1 99 5, 51, 243

Compound 13a:

Chemistry and 'Industry (Chem. Ind.) 196 3, 38 Compound 13b:

Chemistry 'and' Industry (Chem. Ind.) 1964, 1994

Compound 15a:

Photochemistry (Phytochem.) 1998, 27, 3831 Compound 16b:

Tetraedron 1 994, 50, 10073 Compound 21a: Aldrich Chemical Company

Compound 21b:

Helvetica 'Your strength' actor (Helv. Cim. Acta) 1 9 7 3, 5 6, 6 4 1

Compound 21c, Compound 22c:

Journal 'Ob' Organic 'Chemistry (J. Org. Chem.) 1 9 7 7, 4 2, 6 8 2

Compound 21d:

Botany (J.Epp.Bot.) 1997, 30 (1 19) 1 2 0 1

Compound 22a:

Aldrich 'Chemical' Company

Compound 22b, Compound 22d, Compound 22e, Compound 22ί, Compound 22g, Compound 24d:

Helvetica 'Your strength' actor (Helv.Chim.Acta) 1 9 7 3,5,6,1 6 6 2

Compound 23a, Compound 24a:

Tetrahedron 'Letters (T e t r a h e d r o n L e t t e r s) 1 9 7 2, 5 0 3 5

Compound 23c, Compound 24b:

Tetrahedron's (T e t r a h e d r o n L e t t e r s) 1 9 6 9, 1 9 9 5

Compound 23 e:

U.S. Patent 3,046,280

Compound 24e:

Journal 'Ob Essentials' Oil' Research (J. Ess e nnt-〇 i 1. R es.) 1 9 9 1, 3, 1 2 9

Compound 27: Helvetica Kimi Power (Hel v. Chem. A cta) 1 99 3, 76, 20 27

Compound 28a:

Spectroscopy Letters (Spectrosc. Letteras) 1 9 9 1, 24, 2 7 7

Compound 28b:

Indian 'Perfume (Indian) Perfume. 1 9 8 1, 2

5, 1 3

Compound 29d:

Tetrahedron-Letters (T e t r a h e d ro n L e t t e r s)

6, 2 7, 2 2 7

Compound 30a:

Journal of Organics, Chemistry (J. Org. Chem.) 1992, 57, 714

Compound 30b:

Journal 'OB' American Chemical Society (J. Am. Chem. Soc.) 1980, 102, 4784

Compound 31a, Compound 32a:

Journal of American Chemical Society (J Am. Chem. Soc.) 1 98 1, 103, 295

 The above-mentioned group of known compounds has a known structure, but was never known to have P / Q-type calcium channel antagonistic activity.

Among the compounds (I) according to the present invention, a new group of compounds can be represented by the above general formula (I ′). The new compound group (1 ′) is classified into the above groups a) to e) as described above.

a) R ³ ′ is —CR ⁵ = CH ₂ or one CHR ⁵ R ⁶ , and R ⁹ ′ and R ¹⁰ ′ are either NH ₂ , NH C〇CH ₃ or NH SO ゥ R ⁷ , And the other Compounds which are hydrogen or which together form = N〇H, = NNHT s, = NO S〇 ₂ R ⁷ ;

More preferably, R ³ ′ is —CR ⁵ = CH ₂ , R ⁴ ′ is hydrogen, R ⁹ ′ and R ¹ . 'Is a compound in which one is one NH ₂ , one NHC〇CH ₃ or —NHS〇 ₂ CH ₃ and the other is hydrogen

b) R ⁹ 'and R ^{1 (5'} are hydrogen, human Dorokishi or compound is lower Ashiruoki, more preferably R ³ 'is one _{CH (CH 3) OS 0 2} CH 3> - C (CH 3) = CH ₂ , one CONH—i one Bu or one CO〇H compound

c) A compound in which R ³ ′ is —C (CH ₃ ) ₂ OH, one CH (CH ₃ ) 〇S 0 ₂ CH ₃ , one CH (CH 3) NHR ⁸ ′ (where R ⁸ ′ is lower acyl)

d) R ² ′ and R ³ ′ are hydrogen, R ⁴ ′ is lower alkyl, R ⁹ ′ and R ¹⁰ ′ are one hydrogen and the other is one OCH ₂ COR ¹⁷ ′ or A compound that is one NHCOR ¹⁹ 'COOR ²⁰ '

e) R ³ ′ is hydrogen, — CR ⁵ ′ R ⁶ ′ OCOR ⁷ ′ or one CR ⁵ ′ = CH ₂ , and R ⁹ ′ and R ¹⁵ ′ are hydrogen and the other is lower alkylsulfonyl alkoxy or NHR ^{1 8} 'or a, or together a connexion = 〇 one OCH ₂ CH ₂ 0- or form a = N_〇_H, R ^{1 1'} and R ^{1 6} 'are each independently A compound which is hydrogen or lower alkyl optionally having substituent (s),

More preferably R ³ _{'hydrogen, - C (CH 3) 2} OCOCC 1 3 Matahaha one C (CH ₃₎ = a CH _2, R ^9' and R ^{1 5} 'is one of hydrogen, the other lower alk kill sulfonyl O carboxymethyl or where together such connexion = 〇, to form an 〇_CH ₂ CH ₂ 0- or = N_〇_H compound

It is. Particularly preferred are compounds of the types a), b) and c).

Specific examples of the preferred embodiment of the compound (1 ′) include compounds 3c, 5b, 5c, 5d, 5e, 5g, 5h, and 5i in the specific examples of the preferred embodiment of the compound (I). , 5 j, 6 e, 8 b, 8 c, 8 d, 18, 19, 20, 23 b, 23 d, 23 f, 23 g, 24 c, 25 a, 25 b, 25 c, 26 a, 26 b.26 c, 29 a.29 b, 29 c, 29 e, 30 c, 30 d, 31 b, 31 c, 31 d, 31 e, 3 2b, 32 c and 32 d. More preferably, 5b, 5c, 5d.5e, 6e, 20, 23b, 23d, 23f, 23g, 24c, 25a, 26c, 30c And 31 e, most preferably 5 b.

 These novel compounds (1 ') have strong PZQ-type calcium channel antagonistic activity and can be used as PZQ-type calcium channel antagonists or pharmaceutical compositions.

 The new compound group (1 ′) can be synthesized from a known compound by a conventional method using, for example, the following method.

 1) Mix the desired carbonyl compound (for example, compound 3b, 4c, 8a, 30b) with a substituted amino compound such as tosyl hydrazine or hydroxyamine, and mix it in alcohol such as methanol or ethanol. To obtain hydrazone, oxime, and imino compounds (compounds 3c, 5g, 5h, 8b, 8d, 30c, etc.)

 2) A compound having a suitable hydroxy compound (compounds 5a, 23c, 25b, etc.) is reacted with an azidating agent such as diphenylphosphoryl azide or hydrazic acid under Mitsunobu reaction conditions. A sulfonyl compound such as 23d is reacted with an azide such as sodium azide to form an azide compound, which is then reduced using a reducing agent such as lithium aluminum hydride, tin chloride, magnesium enol, and triphenylphosphine. And a method for obtaining an amino compound (compounds 5b, 23e, 25c, etc.)

 3) A method of sulfonylating a compound having a desired hydroxy compound (compounds 8b, 23c, 24b, 31a, etc.) and an amino compound (compounds 5b, 5i, etc.) according to a conventional method (compound 5e, 5j, 8c, 23d, 24c, 31e, etc.)

 4) Use the desired amino compound (compounds 5b, 23e, 29d, 31b, 32b) with an acylating agent such as an anhydride or chloride of a lower carboxylic acid or an active ester. To obtain an amide compound by reacting a compound having a carboxylic acid such as 26a, 29b with ammonia, an amine, etc. (compounds 5d, 23f, 23g, 29e, 31 c, 32c, 26c, 29c etc),

5) Oxime compounds (compounds 5 g, 30 c, etc.) were treated with sodium hydroxide, lithium aluminum hydride, sodium cyanoborohydride, titanium trichloride, and borax. A method for obtaining a hydroxyamino compound and an amino compound by reducing with an appropriate reducing agent such as Z-trifluoroacetic acid (compounds 5i, 31b, 31d, 32b, 32d, etc.)

 6) Reduce the carbonyl compound (compounds 4e, 8a, etc.) by perch (Birch) or by using a reducing agent such as lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydride, etc. A method for obtaining a compound (compounds 6d, 8e, etc.),

 7) Addition of an organic acid such as trichloroacetic acid or dichloroacetic acid to a compound having a double bond (Compound 6a, etc.) to give an acyloxy compound (Compound 6e, etc.); , Sulfuric acid, sulfonic acids such as protonic acid, boron trifluoride, titanium tetrachloride or other Lewis acids, and triphenylphosphine-iodine complex to form the corresponding hydroxy compound (compound 11b, 1 5b etc.),

9) A method of epoxidizing or catalytically reducing a compound having a double bond (compound 1a, 30c, etc.) by a commonly used method (compounds 18, 19, 30d, etc.),

 10) ketalization, methylation, or olefination of carbonyl compounds (compounds 4c, 23a, 40, etc.) using commonly used methods (compounds 20, 23b. 25a, etc.),

 11) A method of hydrolyzing an ester compound (compounds 25a, 29a, etc.) according to a conventional method to form a carboxylic acid (compounds 25b, 29b, etc.)

 12) A method of reacting a carbonyl compound (compounds 22a, 24a, etc.) with an oxidizing agent such as sodium hypochlorite to obtain a carboxylic acid (compounds 26a, 26b, etc.)

13) A method of reacting a compound having hydroxy (such as compound 41) with an alkylating agent such as bromide or ethyl acetate to obtain an ether compound (such as compound 29a). The P / Q-type calcium channel antagonist of the present invention can be applied to diseases caused by excessive release of neurotransmitters. Glutamate, aspartate and the like are known as neurotransmitters whose release is related to the PZQ-type calcium channel, such as diseases to which antagonist glutamate can be applied. Can be used for

 Specific indications include, for example, ischemic neuronal damage such as stroke, spasticity, epilepsy, head trauma (TBI), Huntington's disease amyotrophic lateral sclerosis (ALS), dementia due to Alzheimer's disease, AIDS Can cause dementia and migraines. Furthermore, since the analgesic effect is observed by intraventricular administration and intraspinal administration of ω-agatoxin IVA, which is a P / Q type calcium channel antagonist, the Ρ / Q type calcium channel antagonist of the present invention is also used as an analgesic. Can be applied. When the PZQ-type calcium channel antagonist of the present invention is administered as a medicine, it can be safely administered by either the oral or parenteral method. Oral administration may be carried out according to a conventional method by preparing a tablet, granule, powder, capsule, pill, solution, suspension, syrup, buccal or sublingual formulation, and administering the formulation. For parenteral administration, any commonly used dosage form, such as injections for intramuscular administration, suppositories, transdermal absorbents, inhalants, etc., can be suitably administered. Administration is preferred.

 The pharmaceutical composition of the present invention requires various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants and diluents suitable for the final dosage form in an effective amount of the active ingredient. Can be prepared by mixing. In the case of injections, the preparation may be prepared by sterilizing with an appropriate carrier.

Specifically, as an excipient, lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose, etc., as a binder, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc. Disintegrators include carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate, and lubricants include talc, magnesium stearate or macrogol. As a suppository base, cocoa butter, macrogol, methylcellulose, or the like can be used. In addition, when preparing a liquid formulation or an emulsion or suspension injection, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are appropriately added. Oral administration You may add a flavoring agent, a fragrance and the like.

 It is desirable to set the dose in consideration of the patient's age, body weight, administration route, type and degree of disease, etc., but when orally administered to humans as a PZQ-type calcium channel antagonist, On the other hand, lJg to 200 mg / kg / day may be administered once or several times a day, and when administered parenterally, it may vary greatly depending on the administration route. 1 g to 20 mg / kg / day may be administered once or several times a day. Example

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Example 1 Synthesis of compound 3c

 To a solution of compound 3b (41 mg, 0.173 mm o 1) in ethanol (0.5 ml) at room temperature under a nitrogen atmosphere was added tosyl hydrazine (39 mg, 0.208 mm o 1). The mixture was refluxed for 2 hours. After concentration, the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. Each organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, and further recrystallized from getyl ether-hexane to obtain compound 3c (33 mg, 47%).

^{1 H - NMR: δ (CDC} 1 3) 1. 00 (3 Η, s), 1. 2 1 (3 H, s), 1. 2 2 (3 H, s), 1. 7 9 (3 Η , s), 1.0—2.2 (m, 10Η), 2.42 (3Η, s), 2.83 (1Η, d,] = 14.1Η), 7. 3 1 (2Η, d, 8.1 1), 7.38 (1Η, brs), 7.88 (2Η, d, J = 8.1 Hz) ρ ρ m. Example 2 Synthesis of compound 5b

 Compound 5a (1.23 g, 5.6 mmol) in dry toluene (8 ml) was added to a solution of triphenylphosphine (1.76 g, 6.7 mmol) and getyl azodicarbonate under ice-cooling. 1 ml, 6.7 mmo 1) and diphenylphosphoryl azide (1.45 ml, 6.7 mmo 1) were sequentially added, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 20 minutes. After completion of the reaction, the residue obtained by concentrating the solvent under reduced pressure was separated and purified by silica gel column chromatography (silica gel 125 g; hexane: ethyl acetate = 1100: 1), and the azide compound (546 mg) was obtained. , 40%).

The above compound (500 mg, 2.0 mmo 1) was dissolved in a mixed solvent of THF (4 ml) and water (0.4 m 1), and triphenylphosphine (644 mg, 2.45 mm o 1) was dissolved. Was added and stirred at 60 t for 4 hours. After completion of the reaction, ethyl acetate was added to the reaction solution, and the mixture was dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure was separated and purified by silica gel column chromatography (silica gel 5 g; chloroform: methanol = 5: 2) to obtain compound 5b (400 mg, 91%).

L S I — MS (m / z): 2 20 [M + H]

Elemental analysis (< _{1 δ} Η ₂₅ Ν · 1 Η 5 Η ₂₀ )

Calculated values: C, 80.80%; H, 11.40%; N. 6.28%

Measured value: C, 81.08%; H, 11.40%; N, 6.37%

_{^{1 HNMR: δ (CDC 1 3}} ) 1. 0 5 (3 H, s), 1. 7 0 (3 H, s), 1.

7 7 (3Η, brs), 2.15 (1Η, m), 2.1 (1Η, brs), 2.

6 8 (1 Η, d t,] = 2.4, 15.0), 3.04 (1 b, b rs), 4. 7

4 (1 Η, s), 4.78 (1 Η, s) p pm.

¹³ C ΝΜ R: d (CDC 1 a) 18.0, 23.2, 23.8, 23.9, 28.3, 28.7, 34.1, 34.9, 3 6.6, 41.0, 51.5, 10.7, 127.3, 13.5.9, 148.0 pp m.

IR: v max (CHC 1 ₃ ) 2 9 26, 1 6 39, 1 576, 1 4 5 1, 1 3 7 1. 1 2 39, 1 1 3 6, 1 09 1, 890 cm Example 3 Synthesis of compound 5c

To a solution of compound 5b (380 mg, 1.7 mmol) in chloroform (6 ml) was added a 4N solution of hydrogen chloride in monoethyl acetate (0.5 m to 2 mmol) to precipitate The crystals were collected by filtration to give compound 5c (350 mg, 79%). Elemental analysis (as C ₁₅ H _{2 C} NC 1.1 / 10 H ₂ 〇)

Calculated values: C, 69.93%; H, 10.25%; N, 5.44%; C1, 13.76%

Measured value: C, 69.87%; H, 10.22%; N, 5.68%; C1, 13.

6 8%

IR: V ma X (KB r) 3 4 3 4, 2 9 3 0, 1 6 4 6, 1 6 0 1, 1 5 1 2, 1 4 5 5, 1 3 7 3, 9 8 0, 8 9 3 cm- ¹ . Example 4 Synthesis of Compound 5d

 To a compound 5b (2.2 mg, 0.1 mmol) at room temperature under nitrogen atmosphere, add pyridine (0.1 ml) and acetic anhydride (4.7 a1, 0.05 mmol) and stir for 50 minutes. did. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 5d (2.5 mg, 96%) as a white solid.

¹ H-NMR: <5 (CDCI ₃ ) 1.07 (3H, s), 1.68 (3H, s), 1.72 (3Η, s), 1.99 (3 Η, s), 1.2—1.4 (4Η, m), 1.6—2.0 (4Η, m), 2.1—2.2 (1Η, m), 2.4 4 (1Η, brs), 2.72 (1Η, dd, J = 2.1, 1 5. 5. Η ζ), 4.2—4.3

(1Η, m), 4.68 (1Η, s), 4.81 (1Η, s), 5.3-5.4

Example 5 Synthesis of Compound 5e (1Η, m) ρ ρ m. To a solution of compound 5b (10 mg, 0.045 mmo 1) in chloroform (1 ml) was added a saturated aqueous solution of sodium hydrogen carbonate (0.8 ml), methanesulfonyl chloride (0.8 ^ 1, 0.1 mmO1) was added, and the mixture was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was separated and purified by silica gel column chromatography (silica gel 5 g; hexane: ethyl acetate = 4 :) to obtain compound 5e (11 mg, 82%).

^{. 1 H - NMR: δ (} CDC 1 3) 1. 0 6 (3 H, s), 1 7 0 (3 H, s), 1. 7 8 (3 H, brs), 2. 1 5 (l 2.4.3 (1 H, brs),

2.71 (1H, dt, J = 2.4, 14.7), 3.01 (3H, s), 3.69 (1H, m), 4.23 (1 H, d, J = 8.1), 4.62 (1H, s), 4-

7 8 (1 H, s) p pm. Example 6 Synthesis of 5 g of Compound

 Hydroxyamine hydrochloride (49 mg, 0.70 mmo1) and pyridine were added to a solution of compound 4c (51 mg, 0.234 mmol) in ethanol (0.5 ml) at room temperature under a nitrogen atmosphere. (7.5.09.33 mmo 1) was added and stirred for 3 hours. Further, hydroxyamine hydrochloride (49 mg, 0.70 mmo 1) and pyridine (75.51> 0.933 mmo 1) were added, and the mixture was stirred for 4 hours. After concentration, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure was purified by silica gel column chromatography to give compound 5 g (47 mg,

86%).

H-NMR: δ (CDCI ₃ ) 1.09 (3H, s), 1.70 (3H, s), 1.86 (3H, s), 1.2—1.9 (6 H, m), 2.2-2.4 (2 H, m), 2.49 (1 H, brs), 2.88 (1 H, d, J = 16.0 Hz ), 3. 0 3 (1H, dt, J = 3.6, 18.0 Hz), 4.67 (1H, s), 4.78 (1H, s), 9.45 (1 H, brs) pp m. Example 7 Synthesis of Compound 5 h

 Compound 4c (109 mg, 0.5 mmo 1) was reacted in the same manner as in Example 1, and the crude product was purified by silica gel column chromatography to give Compound 5 h (133 mg , 7 1%).

^{.. 1 Η - NMR: δ} (CDC 1 3) 1 0 2 (3 H, s), 1 6 9 (3 H, s),

I. 82 (3H, s), 2.43 (3H, s), 1.2—2.4 (10H, m), 2.84 (1H, d, J = 1 5.8 Hz), 4.61 (1H, s), 4.76 (1

II, s), 7.18 (1H, s), 7.31 (2H, d, J = 8.6Hz), 7.89 (2H, d,) = 7.6 H z) p m.Example 8 Synthesis of Compound 5 i

 A solution of 5 g (44 mg, 0.188 mmo1) of the compound in methanol (1.5 m1) was added to a solution of sodium cyanoborohydride (37 mg, 0.56 6 mmo1) and ammonium acetate (160 mg, 2.07 mmo1) were added, and an aqueous solution of titanium trichloride (0.32 ml) was added dropwise. After stirring at room temperature for 40 minutes, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted twice with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue concentrated under reduced pressure was purified by silica gel column chromatography to obtain compound 5i (25 mg, 61%).

^{... 1 Η - NMR:} . (5 (CDC 1 3) 1 1 3 (3 H, s), 1 7 1 (3 H, s), 1 7 5 (3 H, s), 1 1 - 2 0 (8 H, m), 2.1 — 2.2 (1 H, m), 2.41 (1 H, brs), 2.68 (1 H, d,] = 15.0 Hz), 3.32 (1H, brs), 4-71 (1H, s), 4.77 (1H, s) p m. Example 9 Synthesis of compound 5 j

 To a solution of compound 5i (14 mg, 0.064 mmol) in chloroform (lml) was added a saturated aqueous solution of sodium hydrogen carbonate (0.5 ml), and then methanesulfonyl chloride (0 t :) under a nitrogen atmosphere. After adding 10 μm, the mixture was stirred at Ot: for 30 minutes and at room temperature for 40 minutes. Further, methanesulfonyl chloride (10 m 1, 0.127 mmo 1) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, and extracted twice with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 5j (3.4 mg, 18%).

¹ H-NMR: δ (CDC 1 a) 1.10 (3 Η, s), 1.56 (3 H, s), 1.71 (3 H, s), 1.75 ( 3H, s), 1.0—2.0 (8H, m). 2.1—2.3 (1H, m), 2.43 (1H, brs), 2.68 ( 1 H, dt, 3 = 2.1, 15.0 Hz), 2.01 (3H, s), 3.8—3.9 (1H, m), 4.0—4 1 (1 H, m), 4.70 (1 H, m), 4.77 (1 H, m) ppm. Example 10 Synthesis of Compound 6 d

Lithium (26.0 mg, 3.75 mmo 1) was added to and dissolved in liquid ammonia (20 ml) under a nitrogen atmosphere at 178 t. Next, a THF solution (2 ml) of compound 4e (232 mg) and t-butyl alcohol (64.6 mg, 0.87 mmol) was added, and after refluxing for 3 hours, THF (10 ml) was added. . The reaction solution was heated to room temperature to distill off liquid ammonia, and further heated under reflux for 10 minutes. After cooling on ice, getyl phosphate (0.69 ml, 4.8 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Further, getyl phosphate (0.31 ml, 2.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was converted into a saturated aqueous ammonium chloride solution (20 ml). Poured and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 6d (19 mg, 8%).

^{1 H - NMR: δ (CDC} 1 3) 0. 86 (3 H, s), 0. 96 (3 H, d, J = 6. 3 H z), 0. 9 5 - 1. 7 4 (1 2 H, m), 1.73 (3 H, s),

I 7 7—1.93 (1H, m), 3.12 (1H, ddd, J = 5.1, 9.8,

I I. 0 Hz), 4.67-4.70 (2H, m) ppm. Example 11 1 Synthesis of Compound 6e

 To a solution of compound 6a (42 mg, 0.191 mmol) in 1,2-dichloroethane (0.2 ml) was added trichloroacetic acid (94 mg, 0.572 The mixture was stirred at room temperature for 1.5 hours and at 50 for 1.5 hours, and then left at room temperature for 16 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The remaining brew was purified by silica gel column chromatography to obtain compound 6e (25 mg, 34%).

¹ H-NMR: δ (CD CI ₃ ) 0.99 (3 H, d, J = 6.3 H z), 1.09 (3 H, s), 1.58 (3 H, s) , 1.60 (3H, s), 1.7—1.9 (10H, m), 2.1—2.3 (1H, m), 2.36 (1H, ddd, J = 2.4, 5.4, 14.4 Hz), 2.53 (1H, dt, J = 6.9, 14.4 Hz) ppm.

^{1 3 C - NMR: δ (} CDC 1 3) 1 1. 2 9, 1 6. 1 9, 2 1. 60, 2 2. 6 8, 2 3. 2 9, 2 5. 9 5, 3 3. 35, 38.04, 40.32, 41.0, 45.47, 46.74, 50.6, 91.00, 91.38, 160.0.07 , 2 1 2.64 pp m. Example 1 Synthesis of Compound 8b

 Compound 8a (109 mg, 0.5 mmo 1) was reacted in the same manner as in Example 6, and the crude product was purified by silica gel column chromatography to give Compound 8b (83 mg, 71%). ).

^{1 H - NM R: δ (} CDC 1 3) 0. 96 (3 H, s), 1. 09 (6H, d,] = 7. 0 H z), 1. 9 1 (3 H, s), 1.3-1.7 (4H, m), 2.0-2.5 (4H, m), 3.05 (1H, ddd, J = 1.8, 7.5, 18) 0 H z), 6.30 (1 H, s), 9.29 (1 H, brs) pp m. Example 13 Synthesis of Compound 8 c

 To a solution of compound 8b (37 mg, 0.158 mm o 1) in dichloromethane (1 ml) was added triethylamine (33.11, 0.238 mm 1) and methanesulfonyl chloride (14.7 μl, 0.190 mmol) were added, and the mixture was stirred for 30 minutes. The reaction solution was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 8c (52 mg, 100%).

'H - NMR: <5 ( CDC 1 3) 0. 9 7 (3 H, s), 1. 1 0 (6 H, d, J = 7. 2 H z), 1. 3- 1. 7 ( 4 H, m), 1.93 (3 H, s), 2.0-2.7 (4 H, m), 3.04 (1 H, ddd,] = 2.0, 7. 8, 18.4 Hz), 3.18 (3H, s), 6.30 (3H, s) pp m. Example 14 Synthesis of Compound 8d

Compound 8a (109 mg, 0.5 mmo 1) was reacted in the same manner as in Example 1, and the crude product was purified by silica gel gel chromatography to obtain Compound 8d (140 mg, 7 0%). ^{1 H - NMR: 6 (CDC} 1 3) 0. 8 7 (3 H, s), 1. 0 6 (3 H, d, J = 6. 9 H z), 1. 0 6 (3 H, d , J = 6-6 Hz), 1.3 — 1.6 (4H, m), 1.86 (3H, s), 2.41 (3H, s), 2.0— 2.6 (5H, m), 6.24 (1H, s), 7.30 (2H, d, J = 7.8Hz), 7.90 (2H, d, J = 7.8 Hz) pp m. Example 15 Synthesis of Compound 8e

 Compound 8a (109 mg, 0.5 mmol) in ethanol (lml) was added to a 1.5 M diisobutylaluminum hydride-toluene solution at 178: under a nitrogen atmosphere, (0.367 ml and 0.55 mmo 1) were added thereto, followed by stirring for 2 hours. The reaction solution was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 8e (33 mg, 30%).

^{1 Η - NMR:. Δ (} CDC 1 3) 1 - 0 0 (3 Η, s), 1. 0 5 (3 Η, d, J = 6. 6 Η ζ), 1 0 6 (3 Η, d , 1 = 6.6 Η)), 1.3-1.5 (4 Η, m), 1.79 (3 Η, s), 1.6-1.8 (2 Η, m), 1 9-1 2.1 (2Η, m), 2.1-2.4 (2Η, m), 4.11 (1Η, t,) = 8.1 1 ζ), 6.08 (3 Η, s) p pm. Example 16 Synthesis of Compound 10 b and Compound 11 b

Step 1 1 Synthesis of compounds lb and 2a

Triclomouth acetic acid (400 mg, 2.4 mmo 1) was added to the serinene 1a mixture (α: / 3 = about 1: 9) (500 mg, 2.4 mmo 1), and the mixture was added at room temperature. Stirred for hours. The reaction solution was partitioned between hexane and water, and the hexane transition was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure It was dissolved in methanol (5 ml), 1N aqueous sodium hydroxide solution (4 ml) was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water and extracted with hexane. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was purified by column chromatography (Merck, Rover column, size A; hexane: ethyl acetate = 100: 1), and a mixture of compounds 1b and 2a (about 1: 2) (about 1: 2) 280 mg, 65%). Process 1 2 Synthesis of silyl ether mixture 4 2

 A solution of the above mixture (184 mg, 0.83 mmol) in dry dimethylformamide (1 ml) was added to a solution of imidazole (113 mg, 1.65 mmol) under ice cooling and then triethylchlorosilane (16 ml). 6 / zl, 0.99 mmol) and stirred for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The residue that was concentrated under reduced pressure was separated and purified by column chromatography (Merck Co., Ltd., orifice column, size A; hexane: ethyl acetate = 20: 1), and the hydroxy of compounds 1b and 2a was triethylsilyl. Thus, a silyl ether mixture 42 (228 mg, 82%) was obtained.

^{1 H - NM R: δ (} CDC 1 3): 0. 6 8 (s), 0. 7 6 (s), 1. 0 1 (s), 4. 43 (s), 4. 70 (s) , 5.31 (s) ppm. Process 3 (IS, 2 R, 4 a S, 7 I ^ 8 a R)-1,-2-pon-1-7-(1 triethylsilyl 1,2-, 3,4,4a, 5,6,7,8,8a-decahydro-1,4a-dimethyl-naphthalene (compound 36) and (1R, 4 a R, 7 R, 8 a R) 1-7-(1-trimethylsilyl xy-1-methylethyl) 1, 1, 2, 3 4, 4 & _, 5._6, _7, _8, 8 a-] Synthesis of draw 4a-methyl-epoxymethanonaphthene (compound 37)

To a solution of silyl ether mixture 42 (12.1 g, 36 mmo 1) in dry dichloromethane (300 ml) was added sodium hydrogen carbonate (3 g) and m-chloroperbenzoic acid (8 0%) (4.6 g, 21.4 mmo 1) and stirred at 110: 2 for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by vacuum straining was separated and purified by silica gel gel column chromatography (silica gel 110 g; hexane: ethyl acetate = 100: 1), and the non-polar fraction raw material 42 (4.6) g, 38%) and compound 37 (1.58 g, 12%) from the polar fraction, and compound 36 (3.26 g, 26%) from the most polar fraction. Obtained. Compound 3 7

¹ H-NMR δ (CD C .55 (6H, q,] = 7.5 Hz), 0.83 (3H, s), 0.99 (9H, t, J = 7 .5 Hz), 1-13 (3 H, s 1.16 (3 H, s), 2.51 (1 H, d, = 4.5 Hz), 2.70 (1 H, dd, J = 4.5, 1.8 Hz) pp m.

_{IR: vma x (CHC 1 3} ): 2 94 2, 2 8 6 6, 1 4 5 7, 1 3 7 9, 1 2 3 1, 1 1 4 7, 1 0 3 3 c m- 1.

Compound 3 6

^{1 H - NMR δ (CDC 1} 3): 0. 58 (6 H, q, 1 = 7. 5 H z), 0. 7 6 (3 H, s), 0. 9 6 (9H, t, = 7.5 Hz), 1.18 (3H, s), 1.20 (3H, s), 1.23 (3H, s), 2.93 (1H, brs) ppm.

_{IR: vma x (CHC 1 3} ):. 1 4 5 3, 1 38 1, 1 2 3 2, 1 1 4 6, 1 0 3 7, 93 7 c m- 1 Step one 4 Compound 1 0 b and 1 Synthesis of 1 b

To a solution of iodine (14 mg, 0.113 mmo 1) in acetonitrile (1 m 1) was added triphenylphosphine (36 mg, 0.136 mmo l), and the mixture was stirred at room temperature for 5 minutes. Next, compound 36 (40 mg, 0.113 mmo1) was added to the reaction mixture. After stirring at room temperature for 20 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with an aqueous sodium thiosulfate solution and saturated saline, and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was separated and purified by column chromatography (Merck, Rover column, size A; hexane: ethyl acetate = 9: 1 to 2: 1), and the compound 10b (3 mg, 12%) from the polar fraction to give compound lib (20 mg, 74%). Compound 10b

Melting point: 1 3 8-1 40

 E I-M S (m / z): 2 3 8 [M] +

Elemental analysis (C _{1 5} H ₂₆ 〇 ₂ - as 1 Bruno 5 H ₂ 0)

Calculated value: C, 7 4.46%; H, 1 1.00%

Measured value: C, 74.57%; H, 10.87%

^{1 H - NMR: <5 (} CDC 1 3) 0. 69 (3 H, s), 1. 2 1 (6 H, s), 2. 2 7 (1 H, d, 1 0. 8), 1 43 (1H, dd, J = 2.4, 2.7),

4.61 (1 H, s), 4.96 (1 H, s) p pm.

_{IR: vmax (CD C 1 3} ) 3 606, 2 93 8, 2 8 68, 1 64 5, 1 4 6 7, 1 4 5 2, 1 3 8 1, 1 2 3 9, 1 1 4 7, 90 7

Compound 1 1 b

^{1 H - NMR: (5 (} CDC 1 3) 0. 9 7 (3 H, s), 1. 1 9 (3H, s), 1. 2 5 (3 H, s), 1. 80 (3 H , brs), 5.54 (1 H, brs),

5.6 3 (1 H, b rs) p pm. Example 17 Synthesis of Compound 15 a and Compound 15 b

To a solution of compound 37 (100 mg, 0.284 mmo 1) obtained in Example 16 in dry THF (2 ml) was added a 2 M boron trifluoride getyl ether complex dichloromethane solution ( 280 wl, 0.56 mmo 1) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract is washed with a saturated saline solution, Dried with sodium acid. The residue that was concentrated under reduced pressure was separated and purified by column chromatography (Merck, one-mouth column, size A; hexane: ethyl acetate = 1: 1), and compound 15a (4 mg, 6%) was obtained from the nonpolar fraction. The compound 15b (4 mg, 6%) was obtained from the polar fraction. Compound 1 5b

^{1 H - NMR: δ (CDC} 1 a) 1. 0 6 (3H, s), 1. 2 0 (3 Η, s), 1. 2 1 (3 Η, s), 2. 1 2 (2 Η , m), 2.75 (lH, m), 3.41 (II, brs), 4.04 (1Η, d, 3 = 11.4), 4.14 (1Η , d, J = 11.4) ρ ρ m.

IR:. Ν ma χ (C Η C 1 3) 2 9 3 7, 2 849, 1 64 2, 1 4 5 6, 1 3 7 8, 8 9 0 cm- 1 Example 1 8 Compound 1 8 and compound Synthesis of 1 9

 A mixture of selinene 1a (α: / 3 = about 1: 9) (204 mg, 1 mmo 1) in dry dichloromethane (2 ml) solution of sodium bicarbonate (50 mg) and 80% meta-chloroperbenzoic acid ( 208 mg (1 mmo1) was added, and the mixture was stirred under ice cooling for 1.5 hours. The reaction solution was poured into ice water and extracted with S-ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The residue that was concentrated under reduced pressure was separated and purified by column chromatography (Merck Co., Ltd., one-column column, size A; hexane: ethyl ethyl succinate = 20: 1), and the compound 18 (60 mg) was obtained from the nonpolar fraction. , 27%).

E I-M S (m / z): 220 [M] *

_{1 HNMR: δ (CDC 1 3} ) 0. 8 0 (3 H, s), 1. 23 (3 H, s), 1 7 5 (3 H, s), 2. 9 3 (l H, brs) , 4.72 (2 H, brs) ppm. Compound 12a (62 mg, 28%) was obtained from the polar fraction, and compound 19 (19 mg, 8%) was obtained from the most polar fraction.

EI-MS (m / z): 2 20 [M] ¹

^{1 HNMR:. 6 (CDC 1} 3) 0 - 7 2 (3 H, s), 1 3 1 (3 H, s), 2. 3 0 (1 H, d, 1 = 1 3. 2), 2 64 (1Η, m), 2.56 (1H, m), 4.72 (1H, m), 4.44 (1H, brs) pp m.

IR: vmax (CHC 13) 2932, 2845, 1644, 1441, 1378, 889 cm- ¹ . Examples] 9 Synthesis of compound 20

To a solution of tritylsilyl triflate (61, 0.03 mmo1) in methylene chloride (6 ml) was added 1,2-bistrimethylsilyloxane (0.883 ml, 3.6 mmo 1) and a solution of compound 4c (655 mg, 3 mm o 1) in methylene chloride (2 ml) were added, and the mixture was stirred for 1.5 hours. Further, trimethylsilyl triflate (23 / _il, 0.12 mmo) was added, and the mixture was stirred at 178 ° C for 2 hours, and then stirred at 0 for 1.5 hours and at room temperature for 7 hours. . The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 20 (113 mg, 14%).

^{1 H - NMR:. Δ (} CDC 1 3) 0 - 9 9 (3 H, d, J - = 6. 6 H z), 1. 1 0 (3 H, s), 1 7 6 (3 H, s), 1.3-1.6 (511, m), 1.6-1.8 (3H, m), 2.5-2.7 (2H, m), 3.8-4. 0 (4H, m), 4.70 (1H, s), 4.82 (1H, s), 5.26 (1H, brs) PP m. Example 20 Compound 23 Synthesis of b To a solution of compound 23a (200 mg, 1.03 mmo 1) in dry ether (2 ml) was added a 3 M methylmagnesium bromide-getyl ether solution (380 μm) while cooling at 178. 1, 1.1 3 mmol) and stirred at 178 ° C for 4 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ether. The extract was washed with brine and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was separated and purified by silica gel column chromatography (silica gel 35 g; hexane: ethyl acetate = 7: 1) to obtain compound 23b (150 mg, 69%).

¹ HNR: 6 (CDC 1a) 0.87 (3H, s), 0.93 (3H, s), 1 2 1 (6H, s), 1.68 (3H, brs) ), 1.96 (2 H, m), 5.30 (1 H, brs) pp m.

IR: max max (CHC1 ₃ ) 3 6 0 5, 2 9 6 5, 2 8 6 8 4 6 8, 1 4 5 5, 1 3 8 4, 1 3 7 0, 9 6 6, 8 18 c m- ¹ . Example 2 1 Synthesis of Compound 23d

To a solution of compound 23c (196 mg, 1.0 mmol) in dry dichloromethane (2 ml) was added triethylamine (208-1.5 mmol) and methanesulfonyl chloride (100 μm). 1, 1.3 mmo1) was added, and the mixture was stirred for 30 minutes under ice cooling and for 30 minutes at room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, separated and purified by silica gel column chromatography (silica gel 35 g; hexane: ethyl acetate = 4: 1) to obtain Compound 23d (273 mg, 10%).

0%).

^{1 H NM R:. Δ (} CDC 1 3) 0. 8 7 (3 Η, s), 0. 9 2 (3 H, s), 1 4 2 (3 H, d, ] = 6.6), 1.67 (3, brs), 2.99 (3, s), 4.76 (1, m), 5.33 (1, brs) ρ ρ m.

1 R: ν ma χ (CHC 13) 2956, 2868, 1450, 1415, 13 84, 1 35 5, 97 0, 9 16, 8 20 cm- ¹ . Example 2 Synthesis of Compound 23 f

In a solution of compound 23e (20 mg, 0.10 mmo 1) in dry dichloromethane (2 ml) was added triethylamine (ll mg, 0.1 mmol), acetyl chloride (8 mg, 0.10 mm). mmo1), and the mixture was stirred for 1 hour under ice cooling. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (silica gel 15 g; hexane: ethyl acetate = 1: 1) to give compound 23f (21 mg, 87%). Obtained.

_{^{1 HNMR: δ (CDC 1 3}} ) 0. 86 (3 H, s), 0. 90 (3 H, s), 1. 1 2 (3 Η, d, J = 6. 9), 1. 66 ( 3Η, brs), 1.96 (3Η, s), 3.92 (1Η, m), 5.30 (1H, brs), 5.25 (111, rs) PP m.

IR:. Les _{ma x (CHC 1 3) 3436} , 2 960, 2 8 64, 1 6 6 0, 1 5 1 2, 1 449, 1 369, 96 1, 906 cm "1 Example 2 3 Compound 2 3 g synthesis

To a solution of sorbic acid (25 mg, 0.225 mm o 1) in dry dichloromethane (3 ml) was added 1,1'-carbonyldiimidazole (40 mg, 0.246 mm o 1), and the mixture was stirred at room temperature. And stirred for 1.5 hours. Next, a solution of compound 23e (4 Omg, 0.20 mmo 1) in dry dichloromethane (1 ml) was added dropwise, and the mixture was stirred at 4 for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (silica gel 35 g; hexane: ethyl acetate = 3: 1) to obtain 23 g (1 Omg, 17%) of a compound. ^{1 HNMR: (5 (CDC 1} a) 0. 8 5 (3 H, s), 0. 9 0 (3 H, s), 1 1 5 (3 H, d, J = 6. 3), 1. 6 5 (3H, brs), 1.83 (3H, d, J = 6.0), 1.94 (2H, brs), 4.01 (1H, m), 5. 29 (1H, brs), 5.22 (1H, brs), 5.70 (1H, d, J = 15.0), 6.00-6.20 (2H , m), 7.17 (1H, dd, J = 9.9, 15.0) PP m. Example 24 Synthesis of Compound 24c

Compound 24b (338 mg, 1.72 mmo 1) was sulfonylated in the same manner as in Example 21 to obtain compound 24c (4337 mg, 93%).

^{1 HNMR: (5 (CDC 1} 3) 0. 9 8 (6 H, s), 1. 4 5 (3 H, d, J = 6. 2), 1. 5 9 (3 Η, s), 1 9 0 (2Η, t, J = 6.2), 3.01 (3Η, s), 4.80 (1Η, dq, J = 6.2, 12.4) pp m .

IR: Les _{max (CHC 1 3) 2 9} 3 3, 2 8 6 6, 1 4 7 3, 1 4 5 6, 1 4 1 4, 1 3 8 3, 1 3 5 7, 1 1 7 3, 9 7 0, 9 16 cm-'. Example 25 Synthesis of Compound 25a

Process 1 1 (E) — 4 1 (3-Acetoxy-2,6,6—trimethyl-1 —Six-Hexane-1 1-yl) 1-3-Butene-2-one (Compound 38) ) And (E) -4-1- (3-Hydroxy-2,6,6-trimethyl-1-cyclohexyl-1-yl) -3-butene-12-one (Compound 39)

To a solution of compound 22a (5 g, 26 mmo1) in chloroform (20 ml) was added N-bromosuccinic acid imide (6.5 g, 36 mmo1) for 40 minutes. Heated to reflux. After cooling, petroleum ether was added and the precipitated succinic acid imide was filtered off. After distilling off the solvent under reduced pressure, the residue was dissolved in dioxane (15 ml), and an aqueous solution of sodium acetate acetate (sodium acetate, 2.5 g, 31 mmol, acetic acid, 8 ml of water, 8 ml) was added. Stirred at room temperature for 6 hours. The reaction solution was poured into ice water and extracted with ether. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was separated and purified by silica gel column chromatography (silica gel 150 g; hexane: ethyl acetate = 4: 1 to 1: 1), and Compound 38 (90%) was obtained from the non-polar fraction.

0 mg, 14%) from the polar fraction to give compound 39 (2.48 g, 46%). Compound 38

^{1 H - NMR: δ (CDC} 1 3): 1. 0 5 (3 H, s), 1. 09 (3 H, s), 1. 7 0 (3 H, s), 2. 0 9 (3 H, s), 2.31 (3H, s), 5.24 (1H, t, J = 4.8), 6.13 (1H, d,] = 16.5) , 7.18 (1

H, d, J- 16.5) p p m.

Compound 3 9

^{1 H - NR: ό (CDC} 1 3): 1. 04 (3 H, s), 1. 0 7 (3 H, s),

I.85 (3H, s), 2.31 (3H, s), 4.01 (1II, brs), 6.12 (1H, d, J = 16.2) , 7. 1 9 (1 H, d,] = 1 6. 2) pp m IR:. vm ax (CHC 1 3): 3 604, 2 9 6 3, 2 8 6 6, 1 6 6 9, 1 6 0 8, 1449, 1 3 6 2, 1 2 5 5, 1 1 7 5, 1 0 2 2, 996, 978 cm ^{1 per} process 2 4— (3-acetoxy — 2, 6,, Synthesis of 6-trimethyl-1-cyclohexene-11-yl-2-butanone (Compound 40)

To a solution of compound 38 (840 mg, 3.28 mmol) in benzene (20 ml) was added chlorotris (triphenylphosphine) rhodium (I) (150 mg, 0.164 mmol) and triethylsilane ( 1.0 m, 6.56 mm o 1) was added, and the mixture was stirred with 6 O: for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was filtered through a silica gel column (silica gel 35 g; hexane: ethyl acetate = 9: 1) to obtain a crude product (1.0 g). The above compound (1.0 g) was dissolved in a mixed solvent of acetone (10 ml) and methanol (10 ml), and a potassium carbonate aqueous solution (potassium carbonate (1.0 g, 7.2 mmol) and water (10 ml)) was dissolved. l) and stirred at room temperature for 6 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was separated and purified by silica gel column chromatography (silica gel 50 g; hexane: g / ethyl acetate = 7: 1) to obtain Compound 40 (400 mg, 48%).

^{1 H - NMR: δ (CDC} 1 3): 0. 98 (3 Η, s), 1. 0 5 (3 H, s), 1. 58 (3 H, s), 2. 0 7 (3 H , s), 2.16 (3H, s), 2.30 (2H, m), 2.54 (2H, m), 5.13 (1H, t, J = 4. 8) ppm.

IR: max max (CHC l ₃ ): 2960, 2868, 1714, 1473, 1437, 1371, 1251, 1161, 1101 5, 961, 866 cm. Step 1 3 Synthesis of Compound 25a

A suspension of methyltriphenylphosphonium iodide (1.2 g, 3 mmol) in dry THF (10 ml) was added to a suspension of ice-cooled lithium-t-butoxide (252 mg, 2.2 mg).

5 mm o! ) Was added and stirred for 20 minutes. The reaction solution was cooled to 160, a solution of compound 40 (380 mg, 1.5 mmol) in dry THF (2 ml) was added, and the mixture was stirred at 160 to 120 for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was separated and purified by silica gel column chromatography (silica gel 50 g; hexane: ethyl acetate = 1: 5: 1) to obtain Compound 25a (32 mg, 86%).

_{^{1 HNMR: δ (CDC 1 3}} ) 0. 9 9 (3 Η, s), 1. 0 7 (3 H, s), 1.

6 2 (3H, s), 1.77 (3H, s), 2.07 (3H, s), 2.30 (2 H, m), 2.03-0.20 (2H, m), 4.72 (2H, s), 5.14 (1H, t, J = 4.5) pp m.

IR: vmax (CHC 1 ₃ ) 2940, 2 86 2, 1 7 1 8, 1 646, 1 4 7 2, 1 4 5 0, 1 3 7 2, 1 2 5 3, 9 60, 8 90 cm ¹ Example 26 Synthesis of Compound 25b

Lithium aluminum hydride (43 mg, 1.14 mmo 1) of compound 25a (285 mg, 1.14 mmol) in dry THF (8 m U solution under ice cooling) was added, and the mixture was heated at the same temperature. The mixture was stirred for 5 hours, saturated saline was added until the reaction solution became cloudy, and the precipitate was removed by filtration, the concentrated solution was concentrated under reduced pressure, and silica gel column chromatography (silica gel 35 g; hexane: ethyl acetate = Separation and purification according to 7: 1) yielded compound 25b (247 mg, quant.).

_{^{1 HNMR: δ (CDC 1 3}} ) 0. 9 8 (3 H, s), 1. 0 5 (3 H, s), 1. 7 6 (3 H, s), 1. 7 7 (3 H, s), 3.90 (1 H, m), 4.71 (2 H, brs) pp m.

IR: vmax (CHC 1 ₃ ) 36 05, 2967, 2864, 164 7, 1 47 1, 1 450, 1 3 7 5, 1 3 6 2, 993, 890 cm- ¹ Example 27 Synthesis of Compound 25c

Compound 25b (228 mg, 1.1 mmo 1) was reacted in the same manner as in Example 2 to obtain compound 25c (131 mg, 57%).

_{^{1 HNMR: δ (CDC 1 3}} ) 0. 9 9 (3 H, s), 1. 04 (3 H, s), 1. 7 3 (3 H, s), 1. 7 6 (3H, s) , 3.09 (1H, t, J = 4.8), 4.71 (2H, s) pp m.

IR: Les _{ma x (CHC 1 3) 2} 93 6, 1 646, 1 5 7 6, 1 5 1 2, 1 4 7 1, 1 4 5 2, 1 3 74, 1 36 1, 98 9, 8 8 9 cm Example 28 Synthesis of compound 26a

Compound 22a (2 g, 10.4 mmo1) was dissolved in a mixed solvent of dioxane (80 ml) and water (20 ml), and the mixture was cooled with ice and an aqueous solution of sodium hypobromite (3N aqueous solution) was added. Sodium oxide (40 ml) and bromine (5 g, prepared from 31 mmol) were added, and the mixture was stirred at the same temperature for 4 hours. Further, a 10% aqueous solution of sodium thiosulfate (16 ml) was added, and the mixture was heated under reflux for 20 minutes. The reaction solution was acidified with a 1N aqueous hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. This was crystallized from ethyl hexane monoacetate to give colorless needle-like compound 26a (1.7 g, 84%).

^{1 Η - NMR: δ (CDC} 1 3) 1. 0 8 (6 H, s), 1. 7 9 (3 H, s), 2. 0 8 (2 H, t, J = 6. 6), 5.85 (1 H, d, J = 16.5), 7.56 (1 H, d, J = 16.5) pp m.

IR: vmax (CHC 1 ₃ ) 2 9 3 5, 2 8 2 6, 1 6 8 5, 1 6 3 3, 1 6 0 7, 1 4 7 7, 1 3 8 6, 1 3 7 5, 1 2 8 1, 9 8 3 cm-Example 29 Synthesis of Compound 26 b

Compound 24a (200 mg, 1.03 mmo 1) was reacted in the same manner as in Example 28 to obtain compound 26b (52 mg, 26%).

^{1 H - NMR: 6 (CDC} 1 3) 1. 0 0 (6 H, s), 1. 6 1 (3 H, s), 1. 9 1 (2 H, t, J = 6. 3), 2.32-2.44 (4 H, m) pp m.IR: max max (CH Cl ₃ ) 2 9 3 1, 2 8 3 1, 1 7 0 6, 1 4 7 3, 1 4 Example ¹ 30 Synthesis of compound 26c

Compound 26a (220 mg, 1.13 mmo 1) was added to a dry THF (8 ml) solution. 1 3- (Dimethylaminopropyl) -3-ethylethyl carposimid hydrochloride (240 mg, 1.24 mmol), and 1-hydroxybenzotriazole (153 mg, 1 .13 mmol) and stirred for 30 minutes under ice-cooling. Then, isobutylamine (120 ^ 1, 1.34 mmo1) was added, and the mixture was further stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was separated and purified by silica gel column chromatography (silica gel 35 g; hexane: ethyl acetate = 4: 1) to obtain a crystalline product. This was recrystallized from hexane to obtain a compound 26c (170 mg, 60%).

¹ H-NMR: δ (in CD C.,) 0.95 (6 H, d, J = 6.6), 1.05 (6 H, s), 1.74 (311, s), 2.03 (2H, t, J = 6.0), 3.19 (2H, t-like), 5.73 (1H, d, J = 15.9), 7. 3 1 (1 H, d,] = 1 5.9), 5.47 (1 H, brs) pp m.

IR: max (CHCI ₃ ) 3449, 2969 2, 2869, 1662, 1623, 1515, 1467, 1387, 9773, 8555 cm ^-1 . Example 3 Synthesis of Compound 29a

To a solution of compound 41 (1.0 g, 6.57 mmol) in THF (1 ml) was added sodium hydride (289 mg, 7.23 mmol) at 0 ° C. in a nitrogen atmosphere. The mixture was heated to room temperature and stirred for 30 minutes. After cooling with ice, ethyl bromoacetate (0.802 m1, 7.23 mmo1) was added, and the mixture was stirred at the same temperature for 40 minutes and at room temperature for 30 minutes. The mixture was cooled again on ice, and sodium hydride (145 mg, 3.61 mmo1) and ethyl bromoperate (0.40 ml, 3.61 mmo1) were added. After stirring for 3 hours, the mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 29a (744 mg, 48%). ^{1 H - NMR:...} .. Δ (CDC 1 3) 1 2 9 (3 H, t, ] = 7. 0 H z), 1 4 - 1 7 (2 H, m) 1 7 2 (3 H, s), 1.78 (3H, s), 1.8-2.1 (2H, m), 2.1—2.3 (2H, m), 4.13 (2 H, s), 4.23 (2H, q, 1 = 7.0 Hz), 4.72 (1H, s), 4.73 (1H, s), 5.56 (1 H, brs) ppm Example 3 Synthesis of compound 29b

Compound 29a (620 mg, 2.60 mmol) in ethanol (6 ml) was added to a 2 NN aH solution (2.6 ml, 5.2 mmol) under a nitrogen atmosphere at 0. ) Was added dropwise and stirred for 40 minutes. After concentration, ice and a 1N aqueous hydrochloric acid solution were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 29b (136 mg, 25%).

^{.. 1 H - NMR: 6} (CDC 1 3) 1 5 2 (1 H, ddd, J = 1 0. 3, 1 2. 3, 1 2. 3 Η ζ), 1 7 3 (3 Η, s ), 1.74 (3Η, s), 1.9-2.3 (4Η, m), 4-13 (1H, d, J = 16.5Hz), 4.1 7 (1 H, d, J = 16.5 Hz), 4.1-4.2 (1 H, m), 4.73 (1 H, s), 4.75 (1 H, s), 5.61 (1H, m) pp m. Example 33 Synthesis of Compound 29c

To a solution of compound 29a (119 mg, 0.5 mmol) in ethanol (2 ml) was added 28% aqueous ammonia (2 ml) at room temperature, followed by stirring for 7 hours. After concentration, the residue was purified by silica gel column chromatography to obtain compound 29c (58 m, 55%).

^{1 H - NMR:...} Δ (CDC 1 3) 1 4 - 1 6 (1 H, m), 1 7 3 (6 H, W 9 s), 1.8-2.3 (4 H, m), 3.95 (1 H, d, J = 15.6 Hz), 4.05 (1 H, d, J = 15.6 Hz), 4.07 (1H, brs), 4.73 (1H, s), .75 (1H, s), 5.60 (1H, brs) ), 5.75 (1 H, brs), 6.58 (1 H, brs) pp m. Example 34 Synthesis of Compound 29 e

To a solution of compound 29d (30 mg, 0.2 mmo 1) in pyridine (1 m) at room temperature under a nitrogen atmosphere was added ethyl fumarate chloride (53.31, 0.4 mmol), followed by 30 Stirred for minutes. Further, ethyl chloride fumarate (27 wl, 0.2 mmo1) was added, and the mixture was stirred for 1 hour. The reaction solution was poured into ice and a 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 29e (32 mg, 58%).

^{1 H - NM R: δ (} CDC 1 3) 1 - 3 1 (3 H, t, J = 7. 2H z), 1. 7 0 (3 H, s), 1. 7 2 (3 H, s ), 1.6—1.7 (1H, m), 1.8—2.0 (2H, m), 2.0—2.2 (2H, m), 4.24 (2H , q,) = 7.2 Hz), 4.51 (1H, brs), 4.71 (1H, d,) = 0.6 Hz), 4.75 (1H, t,] = 1.5 Hz,) 5.65 (1 H, brs), 6.11 (1 H, d,) = 8.4 Hz), 6.84 (1 H, d, ] = 15.6 Hz), 6.97 (1H, d, J = 15.6 Hz) pp m. Example 35 Synthesis of Compound 30c

Compound 30b (1.18 g, 7.0 mmo 1) was reacted in the same manner as in Example 6 to obtain compound 30c (1.21 g, 95%).

^{1 H - NMR: 0 (CDC} 1 3) 1. 1 4 (3H, s), 1. 1 6 (3 H, s), 1. 4- 1. 8 (4 H, m), 1. 7 6 (3H, s), 1.89 (1H, dd. J = 12.3, 13.8Hz), 2.0-2.1 (1H, m), 3.30 (1H, ddd, J = 1.5, 3.9, 14 lHz), 4.77 (2H, s), 8.70 (1H, brs) pp m. Example 36 Synthesis of Compound 30d

To a solution of compound 30c (40 mg, 0.24 mmol) in methanol (10 ml) was added 10% palladium on carbon (10 mg), and the inside of the reaction vessel was replaced with hydrogen and contacted for 3 hours. Contact reduced. After filtering off insolubles, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 30d (24 mg, 55%).

^{1 H - NMR: δ (CDC} 1 3) 0. 9 1 (3 H, d, 1 = 7. 0 H z), 0. 9 4 (3 H, d, = 7. 0 H z), 1. 1 1 (3H, s), 1.15 (3H, s)

1.2-1.7 (7H, m), 3.2-3.3 (1H, m), 9.37 (1II, brs) ppm. Example 37 Compound 31b and Compound Synthesis of 3 2 b

To a solution of compound 30c (49 mg, 0.2 mmol) in methanol (2 ml) was added sodium cyanoborohydride (40 mg, 0.6 mmol), ammonium acetate (40 mg, 0.6 mmol) at room temperature under a nitrogen atmosphere. 170 mg, 2.2 mmo 1) were added, and an aqueous titanium trichloride solution (0.34 ml) was added dropwise. After stirring at room temperature for 45 minutes, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain a 7: 3 mixture (13 mg, 39%) of compounds 31b and 32b.

^{. 1 H - NMR: <5} (CDC 1 3) 0. 8 7 (3 H, s), 1 0 1 (3 H, s), 1. 7 2 (3 H, s),

for β-is omer: 2.60 (1H, dd, J = 3.8, 11.6Hz) pp m.

 f o a la s o m e 2.86 (1 H, t,) = 3.6 H z) p p m. Example 38 Synthesis of Compound 31c and Compound 32c

The above mixture of 31b and 32b (10 mg, 0.06 mmo1) was reacted in the same manner as in Example 4 to obtain a 6: 1 mixture of compound 31c and 32c (1 0 mg, 80%).

¹ H-NR: 6 (CD 3 OD) 0.88 (3 layers, s), 0.89 (3 H, s), 1.72 (3 layers, s), 1.95 (3 Η, s),

 f or β-is ο m er: 3.71 (1,, d d d, A. 0, 9.6, 12.3 ζ) ρ ρ m.

 f o r α — isomer: 3.8 — 3.9 (1 Η, m) ρ ρ m. Example 39 Synthesis of Compound 31 1 d and Compound 32 d

Trifluoroacetic acid (1.0 m to 13 mmo1) in THF (2 ml) solution was added to a 1.0 M borane-THF solution (3.0 ml, 3. 0 mmo 1) was added and stirred for 5 minutes. Next, compound 30c (181 mg, 1.0 mmol) was added and the mixture was stirred for 45 minutes. Water (1 ml) was added to the reaction solution, and the mixture was concentrated to about half the volume. After cooling on ice, the mixture was adjusted to pH 10 with a 2N aqueous sodium hydroxide solution and extracted with getyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The residue was purified by silica gel column chromatography to obtain compound 31d (72 mg, 40%) and compound 32d (36 mg, 20). Compound 3 1d

^{. 1 H - NM R: δ} (CDC 1 3) 0. 8 2 (3 Η, s), 1 0 3 (3 H, s),

1.1-1.6 (6H, m), 1.73 (3H, s), 1.9-2.0 (1Η, m), 2.15 (1H, ddt, J = 2.0, 3.6, 12.8 Hz), 2.68 (1H, dd, J = 3.9, 11.4H), 4.70 (2H, s) pp m.

Compound 3 2d

^{. 1 H - NMR: δ (} CDC 1 3) 0. 9 4 (3 H, s), 1. 0 1 (3 H, s), 1. 2- 1 7 (6 H, m), 1. 7 4 (3H, s), 1.97 (1H, ddt, J = 1.6, 3.9, 14.0), 2.1-2.3 (1H, m), 2. 8 1 (1 H, t, 1 = 3.6 H z), 4.74 (2 H, s) pp m. Example 40 Synthesis of Compound 31 e

Compound 31a (46 mg, 0.273 mmo 1) was reacted in the same manner as in Example 21 to obtain compound 31e (57 mg, 85%).

^{.. 1 H - NMR: δ} (CDC to _{3) 0. 9 6 (3 H} , s), 1 0 6 (3 H, s), 1. 2- 1. 8 (5 H, m), 1 7 3 (3H, s), 2.0—2.1 (1H, m), 3.02 (3H, s), 4.45 (1H, dd, J = 4.2, 1 1.7 Hz), 4.72 (1H, s), 4.73 (1H, s) pp m. Example 4 1 Synthesis of Compound 1b

Step 1 Synthesis of compound 2c

Ozone gas was passed through a solution of compound 2a (600 mg, 2.7 mmo1) in dry ethyl acetate (20 ml) under cooling at _78 for 20 minutes, and then nitrogen gas was passed for 10 minutes. After that, triethylamine (7501, 5.4 mmo1) was added to the reaction solution, and the mixture was returned to room temperature and stirred for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was separated and purified by silica gel column chromatography (50 g of silica gel; hexane: ethyl acetate = 1: 1) to obtain Compound 2c (495 mg, 61%). Melting point: 120-121 ° C

[] _D = 5.5 ± 0.9 ° (c = 0.5, black-holm) EI-MS (m / z): 2 2 4 [ΜΓ

C D: λ max (E t OH) 2 89.5 n m (Δ 1.40)

Elemental analysis (as C _{1 4} H _{2 4} 〇 _{2 2)}

Calculated value: C7 4.95%; H10.78%

Obtained value: C, 7 4.67%; H, 10.7%% Process 1 2 (4aR, 7R8aR)-7 1 (1-triethylsilyloxy 1 1-methylethyl) 3 4, 4a, 5 6 7 8, 8a—Oktahi draw 4a—Methyl-1 (2H) —NaphtheneLenone (Compound 33)

A solution of compound 2c (394 / g, 1.76 mmo1) in dry dimethylformamide (2 ml) was added to a solution of imidazole (240 mg, 3.52 mmo1) under ice-cooling. ) And then triethylchlorosilane (384 ml, 2-29 mmol) were added, and the mixture was stirred for 3 hours and 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was separated and purified by silica gel column chromatography (silica gel 35 g; hexane: ethyl acetate = 1: 2: 1) to obtain compound 33 (574 mg, 96%). .

L S I-M S (m / z): 3 3 9 [M + H]

^{1 H - NM R: (5} (CDC 1 3): 0. 5 6 (6 H, q, J = 8. 0 II z), 0. 7 5 (3 Η, s), 0. 9 4 (9 Η, t, J = 7.5 Η ζ), 1.17 (3 Ηs), 1.19 (3Η, s), 1.94 (2Η, m) ρ ρ m.

^{.. 1 3 C - NMR:} δ (CDC 1 3): 6. 8 7. 2 1 6. 9 2 1 5, 2 1 8, 2 2. 7 2 7. 1, 2 8. 1 3 9. 4 , 40.5, 41.0, 41.4, 49.6, 57.6, 75.1, 213.1 ρ m.

IR: vmax (CHC l ₃ ): 2 9 4 6, 2 8 6 8, 1 7 0 0, 1 6 0 0 .1 4 5 9 1 3 8 2, 1 1 5 5, 1 0 3 8, 10 1 5 cm- ¹

C D: λ max (MeOH) 2 88 nm (Δε = -1.36)

Elemental analysis (as _{C 2 .H 3 8 0 2 S} i) Calculated value: C, 70.94%; Η, 11.3 1%

Obtained value: C, 70.64%; H, 11.32% Process 1 3 (4aR, 7R, R) _— 1—Trifluorometanesulfonyloxy-17— (1—Troly Tylsilyloxy 1-methylethyl) 3 ^ _4, 4a, 5,6,7,8,8a —Synthesis of 4-a-hydro-1a-methyl-naphthylene (compound 34)

To a solution of compound 33 (500 mg, 1.48 mmol) in dry THF (10 ml) was added a 2 M lithium diisopropylamide THF solution (8901) under cooling at 178 ° C. , 1.77 mmol) and stirred for 20 minutes. Next, a THF (lml) solution of 2- [N, N-bis (trifluoromethylsulfonyl) amino] -15-chloro-pyridine (699 mg, 1.77 mmo1) was added dropwise, The mixture was stirred at 401: for 30 minutes. Ice water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was separated and purified by silica gel column chromatography (silica gel 53 g; hexane: ethyl acetate = 1100: 1) to obtain compound 34 (540 mg, 78%). .

¹ H-NMR: 6 (CDCI ₃ >: 0.58 (6 H, q, J = 7.5 H z), 0.

8 3 (3 H, s), 0.95 (9 H, t,) = 7.5 Hz), 1.19 (3 H, s) 1.2 0 (3 H, s), 2 . 2 3 (2 H, m ) 5. 6 6 (1 H, s) pp m 1 3 C - NMR:. δ (CDC 1 3): 6. 9, 7 2, 1 5. 3, 2 1. 6, 21.8, 22.3, 27.8, 28.0, 34.3 36.2, 39.2, 46.1 49.9, 74.9, 1 16.9, 1 5 1.1 1 1 2.3, 1 16.5, 1 20.7, 1 25.0 pp m.

_{IR: ymax (C HC 1 3} ): 2 9 5 4, 2 8 7 5, 6 7 5, 1 4 5 5

4 1 3, 1 3 8 2, 1 2 4 4, 1 1 4 1, 10 3 8, 9 49, 8 7 8 cm- ¹ step-4 (4 a R, 7 R, 8 a R) One 7 — (1 — Triethylsilyloxy 1 3,4,4a, 5,6,7__8,8a-octahydridone 1,4a-Dimethylnaphthalene (Compound 35)

To a solution of compound 34 (540 mg, 1.14 mmo 1) in dry THF (8 ml) was added hexamethylphosphoramide (950 mg, 5.05 mmo 1), 1 .1 Methyl zinc oxide-THF solution (2.29 ml, 2.52 mmoi) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was heated to 6 Ot :, tetrakis (triphenylphosphine) palladium (0) (26 mg, 0.0229 mmo 1) was added, and the mixture was further stirred for 10 minutes. The reaction solution was poured into ice water and extracted with ether. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained under reduced pressure was separated and purified by silica gel column chromatography (silica gel 53 g: hexane: ethyl acetate = 200: 1) to obtain compound 35 (366 mg, 95%). .

^{J H -NMR: δ (CDC 1} 3): 0. 5 7 (6 H, q, ] = 7. 8 H z), 0. 7 6 (311, s), 0. 9 5 (9 H, t ,) = 7.8 Hz), 1.17 (3H, s), 1.20 (3H, s), 1.61 (3H, brs), 5.31 (1H , brs) pp m.

¹³ C-NMR: δ (CD C: 6.9, 7.2, 15.6, 21.2, 22.5, 23.1, 24.3, 27.3, 28.3, 32.3, 38.0, 40.4, 46.7, 51.0, 75.5, 120.8, 13.5.6 ρ ρ m.

IR: vmax (C II C 1 3): 2 9 1 1, 2 8 7 5, 1 4 5 5, 1 3 7 9, 1 3 6 4, 1 1 4 6, 1 0 4 0, 1 0 1 6 , 9 3 7 cm-Step—5 Synthesis of Compound 1 b

1M tetrabutylammonium fluoride in THF (1.83 ml, 1.83 ml) was added to a dry THF (4 ml) solution of compound 35 (412 mg, 1.22 mmo1). mmo 1) was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (silica gel 35 g; hexane). Separation and purification by sun: ethyl acetate = 7: 1) and further crystallization from pentane gave a colorless needle compound lb (262 mg, 97%). Melting point: 8 7-89 ° C

 [a] D = -8.0 ± 0.5 ° (c = l. 0, black mouth form)

E I -M S (m / z): 2 2 2 [M] «

Elemental analysis (as C! ₅ H _{2 6} 〇)

Calculated value: C, 81.0 2%; H, 11.78%

Measured value: C, 80.95%; H, 11.86%

1 H NMR: δ (CDC 13) 0.77 (3 layers, s) 1.2 1 (3 H, s), 1.

2 2 (3 H, s),] 6 1 (3 H, b rs) 3 2 (1 H, b rs) p p m.

^{1 3 C NM: δ (CDC} 1 3) 1 5. 6, 2 1 2, 2 2., 2 3. 0, 2 4.

3, 26.8, 27.6, 32.2, 37.8.40.1, 46.6, 50.0,

73.0, 12.0, 13.5 ppm.

IR: Les _{max (CHC 1 3) 3 5} 9 6, 2 9 0 8 2 8 4 0, 1 6 3 6, 1 4 5 2, 1 3 7 5, 1 1 5 5, 9 0 9 cm one ^1. Example 4 Synthesis of Compound 2 3 e

Sodium azide (83 mg, 1.28 mmo 1) was added to a solution of compound 23 d (270 mg, 0.98 mm o 1) in dry distilformamide (3 m 1). The mixture was stirred at 70 for 1.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (silica gel 35 g; hexane: ethyl acetate = 40: 1) to obtain an azide compound (196 mg, 90%).

This compound (150 mg, 0.68 mmo 1) was reduced with triphenylphosphine in the same manner as in Example 2 to obtain compound 23e (121 mg, 91%). _{^{1 HNMR: δ (CDC 1 3}} ) 0. 8 7 (3 H, s), 0. 92 (3 H, s), 1. 0 9 (3 H, d, J = 6. 3), 1. 6 8 (3 H, brs), 2.85 (1 H, m), 5.29 (1 H, brs) pp m.

 Hereinafter, in all experiments, compound (I) was dissolved in DMS O (45 mM) and used after appropriately diluting. DMS O was confirmed to have no effect in all experiments.

 1) Preparation of synabutosomes

 Synaptosomes were prepared from the cerebrum of Sprague-Dawely male rats (21-28 days old). The cerebrum was homogenized with the prepared solution (32 OmM sucrose, 15 mM HEPES, 5 mM EDTA, pH 7.4), and the cells were collected.

Centrifuged at 0 X g for 10 minutes. The supernatant was centrifuged at 12,500 × g for 20 minutes, and the precipitate was suspended in a fresh preparation solution. After overlaying it on a 3%, 10%, 15%, or 23% discontinuous Percoll gradient, centrifuge at 32, 500 X g for 5 minutes, and concentrate on 23% barcoal. The fraction was defined as a synaptosome fraction. The fractions basic solution (1 4 5 mM N a C l, 3. 1 mM KC 1, 1. 2 mM Mg C l 2, 0. 4 mM KH 2 PO 4, 0. 5 mM C a C l 2 , 10 mM glucose, l OmM Tr

After washing with 1 s and pH 7.4), the cells were suspended in lmgZm 1 and used for experiments. These operations were performed at 4 t.

2) Calcium ion flow measurement by depolarization stimulation

Compound (1) was added to synaptosomes and incubated at 30 for 1 minute. 1

^{2 5 4 5 C a 2+ 50} 1 of the first Shinabutosomu the (0. 2 5 C i) Basic comprising a solution or a depolarization solution (final concentration of potassium 30 mM) was added, free of glucose after 1 0 seconds free basic solution was added to stop the ^{4 5} C a ² 'flows. This was filtered through a cellulose two traits film of 0. 4 5 mm, counts the remaining ^{4 5} C a ^{2 t} amount on washed twice filter. ^{4 5} C a ² * inflow difference depolarization thorns of by depolarizing solution and basic solution Was ^{4 5} C a ² + inflow by intense.

C a "ion influx inhibitory activity is expressed as percent inhibition of compound (I), assuming that inhibition by 1 M ω-agatoxin I VA (ω-Aga IV), a P-type calcium channel inhibitor, is 100%. It was. further, from the dose-response curve of inhibitory rate calculated 50% inhibition concentration (IC _5.).

Force beam channel current measurement for specificity test

 To exclude the possibility that the effect of compound (I) was a non-specific effect on the membrane, potassium channel current was measured.

Potassium channel currents were recorded as whole-cell force-stream currents from pituitary-derived GH3 cells by the whole-cell patch clamp method. The extracellular fluid 1 5 0 mM N a C 1 , 5 mM KCU 1 mM M g C 1 2, 2 mM C a C 1 2> 1 0 m M glucose, l OmM HE PE S, p H 7. 4 A solution having a composition of 70 mM KC 1, 70 mM K aspartate, 5 mM MgCl ₂ , 10 mM HE PES and pH 7.4 was used as the internal solution of the pipette. Potassium channel current (A current + Delayed rectifier) was measured by applying a voltage-clamp to cells at -9 OmV and applying a depolarizing stimulus up to 80 msec and +10 mV. After the outward current due to the depolarization stimulation was stabilized, the compound (I) was added by replacing the extracellular solution with an extracellular solution containing 45 mM of the compound (I). The specificity of the compound (I) was expressed as a percentage with the current value before treatment being 100%, and it was judged that the specificity was 70% or more.

 Table 1 shows the test results.

table 1

C a ²⁺ influx% of ω-Aga IV K + current inhibitor Compound

 % of

45 M 4.5 M 0.45 M ICso (M)

 control

1 b 109 ± 4.7 61 ± 7,3 26 ± 8.3 2.0 75

1 d 103.0 44.0 41.0 3.0 98

4 a 101.0 56.0 33.0 2.2 b 89.2 ± 9.4 52 ± 7.3 43.5 ± 7.4 2.1-c 123.0 44.0 3.0 4.2 71 d 111.0 56.0 2.0 3.4-e 110.0 76.0 45.0 1.0 f 96.5 40.0 24.0 5.0-e 109.0 36.0 3.0 5.8-a 94.0 69.0 12.0 2.3 85 0 86.0 48.0 44.0 3.0 72 a 60.0 52.0 43.0 3.6 i e100.0 43.0 26.0 4.6-a 80.0 53.0 37.0 2.8 88 b 93.0 39.0 21.0 5.6 88 c 104.0 45.0 34.0 3.3-d 79.0 66.0 19.0 2.5-e 72.0 58.0 10.0 4.1-f 113.0 56.0 5.0 3.6 ― g 78.0 39.0 15.0 1.9 75 a 71.0 49.0 39.0 3.9 73

 93.0 39.0 18.0 5.8 ― c 1 10.0 48.0 1.0 4.3 100 d 107.0 58.0 16.0 2.8 91 a 94.0 43.0 22.5 4.7 86 c 110.0 60.0 22.0 2.3

c 82.0 41.0 28.0 5.7 100 e 102.0 42.0 27.0 4.2 80 The compound (I) according to the present invention has a strong P / Q-type calcium channel antagonist. Formulation Example 1 with obvious anti-activity

 Compound (I) 5 Omg

 Lactose 46 mg

 Corn starch 20mg

 Low-substituted hydroxypropylcellulose 8mg

 Hydroxypropyl methylcellulose 5mg

 Magnesium stearate 1 mg

 Total Γ 3 Omg Effect of the invention

The compound (I) according to the present invention is useful as a PZQ-type calcium channel antagonist and can be used for treating a disease caused by excessive release of a neurotransmitter.

Claims

The scope of the claims

 1. Formula (I)

[Wherein, ring A may have a substituent and may have a double bond, a 6-membered carbon ring; R ¹ is hydrogen or lower alkyl, and R ² is hydrogen, Or R ¹ and R ² may together form one CH ₂ CH ₂ —;

R ³ is hydrogen, one CR ⁵ R ⁶ OH, One _{^{CR 5 R 6 OS 0 2 R}} 7, - CR 5 R 6 COR 7, one ^{CR 5 R 6 OCOR 7, -} CR 5 R 6 NHR 8, one CR ⁵ = CH ₂ , one COR ⁵ , -COOH, one CONHR ⁵ , —CHR ⁵ R ⁶ , = CR ⁵ R ⁶ , one CR ⁵ = NOH or lower alkyloxylanil;

R ⁴ is hydrogen or lower alkyl;

R ⁵ and R ⁶ are each independently hydrogen or a lower alkyl which may have a substituent;

R ⁷ is a lower alkyl optionally having substituent (s);

R ⁸ is hydrogen or lower acyl;

Dashed lines indicate that either one has a double bond or neither.]

Or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

2. Ring A

[Wherein R ⁹ , R ¹ Q and R ¹⁵ are each independently hydrogen, hydroxy, lower alkyl, Lower alkyloxy, lower acyloxy, lower alkylsulfonyloxy, --OCH ₂ COR ¹⁷ (R ¹⁷ is hydroxy, lower alkyloxy or --NH ₂ ), --NH R ¹⁸ (R ¹⁸ is hydrogen, hydroxy, lower Alkyl, lower acyl or lower alkylsulfonyl), or —NH C 0 R ¹⁹ C〇〇R ^{2 G} (R ¹⁹ is lower alkylene or lower alkenylene; R ² is lower alkyl),

R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁶ are each independently hydrogen or lower alkyl which may have a substituent.

Furthermore, R ⁹ and R ^{1 0} and R ⁹ and R ^{1 5} are together a connexion _{= 0, - 0 CH 2 CH} 2 O- or = NR ^{2 1} (R ^{2 1} is human Dorokishi, NHT s, lower alkylsulfonyl Two oxy) may be formed,

R ¹ I and R ¹⁶ may be taken together to form = CH ₂ , = O or one CH ₂ O—, and R ¹⁵ and R ¹⁶ may be taken together to form —〇— Is also good. ]

2. The P / Q-type calcium channel antagonist according to claim 1, which is:

3. The compound of formula (I) is

a) A ring is

R ′ and R ^{2 are} linked to form —CH ₂ CH ₂ —, and ^1-3 are — (: 1 ^ R ⁶ II, one CR ⁵ = CH ₂ or one CHR ⁵ R A force that is ⁶ ,

b) ring A

, And the R ¹ is lower alkyl, R ² is hydrogen, 1¾ ³ is ^{-?. 1 5 1 ^ 6} 01 "1, -CR s R 6 OS O z R 7 one CR ⁵ R ⁶ NHR ⁸ , — CR ⁵ = CH ₂ or one COR ⁵ or

c) ring A

R ^{3 is} CR ⁵ R ⁶ OH, CR ⁵ R ⁶ OS 0 ₂ R-CR ⁵ R ⁶ COR, CR ⁵ R ⁶ NHR ⁸ or COR ⁵ ,

d) A ring is

Where RR ² and R ³ are hydrogen,

e) ring A

_2. The PZQ-type calcium channel antagonist according to claim 1, wherein R ³ is hydrogen, —CR ⁵ R ⁶ OH, CR ⁵ R ⁶ OC〇R ⁷ or CR ⁵ = CH ₂ .

4. The claim 1, 2, or 3, wherein the PZQ-type calcium channel antagonist is an anti-ischemic neuropathy agent, an anti-epileptic agent, an anti-spasmodic agent, a migraine agent or an analgesic agent. Is a PZQ-type calcium channel antagonist according to item 3.

 5. A method for treating a disease caused by excessive release of a neurotransmitter in the central nervous system, which comprises administering compound (I).

 6. Use of compound (I) for the manufacture of a medicament for a disease caused by excessive release of neurotransmitters in the central nervous system.

7. Formula (I '):

A compound represented by the formula:

a) A 'ring is

R ¹ ′ and R ² ′ together form —CH ₂ CH ₂ —, and R ⁹ ′ and R ¹⁰ ′ are one NHR ¹⁸ ′ and the other There is hydrogen, or is 'forms a, R ^3' connexion = NR ^{2 1} a ^{together, R 4 ', R 1 1} ', R 1 8 ' and R ^{2 1'} are each R ^3, R ^{4, R 1 1, R 1} 8 and R ^{2 1} whether synonymous,

b) A 'ring force

R ² ′ is hydrogen, R ³ ′ is —CR ^S ′ R ⁶ ′ OSO ₂ R, —CR ⁵ ′ = CH ₂ , —C ONHR ⁵ ′ or one C OOH, and R ¹ ′, ^{R, R 5 ', R 6} ', R 7 ', R 9', R 1 0 ' and! ? ^{1 1} 'are each ^{R 1, R, R;.} R 6 R 7, R 9, R 1. And is synonymous with R ¹¹ or

c) A * Ring force, '

R ² ′ is hydrogen; R ³ ′ is —CR ⁵ “R ⁶ ” 〇H (where R ⁵ ”and R ⁶ ” are each independently a lower alkyl which may have a substituent; ), — CR ⁵ "'R ⁶ "' 0 SO ₂ R ⁷ "or one CR ⁵ "'R ⁶ "' NH R ⁸ '(where R ⁵ '" and R ⁶ '"are each independently hydrogen or Lower alkyl which may have a substituent; R ⁷ ″ has a substituent Lower alkyl; R ⁸ 'is lower acyl); the dashed line represents the absence of a double bond in both; R, R ⁴ ' and R ¹¹ 'are synonymous with RR ⁴ and R ^11, respectively. Or

d) A 'ring is

R ⁹ ′ and R ^{1 C} ′ are each independently hydrogen, one OCH ₂ COR or —NHCOR ¹⁹ ′ COOR ²⁰ ′;

R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ¹¹ ′ R ¹² ′, R ¹⁷ ′, R ¹⁹ * and R ²⁰ ′ are R ¹ , RRRR ¹ R ² , R ^{1 respectively 7,} R ^{1 9} and R ^2. Is synonymous with or

e) A 'ring is

R ³ 'is hydrogen, CR ⁵ ' R ⁶ 'OCOR ⁷ ', CRCH- or lower alkyloxylanil;

R ⁹ ′ and R ¹⁵ ′ are each independently hydrogen, lower alkyl, lower alkyloxy, lower acyloxy, lower alkylsulfonyloxy, one CH ₂ COR〗 ⁷ ′, one NH R ¹⁸ ′, or one NHCOR ^{1 9} 'C OO R ^{2 0'} is a force or together a connexion = 0,, - OCH ₂ CH ₂ 〇- or - may form NR ^{2 1} '(where together form a connexion = 0 R ³ ′ is —CR ⁵ ′ R ⁶ ′ OC 0 R ⁷ ′), and R ¹¹ ′ and R ¹⁶ ′ are each independently hydrogen or a lower alkyl which may have a substituent. Or together may form = CH ₂ or = 0,

R ¹⁵ ′ and R ¹⁶ ′ may together form one O—,

^{R 1 ', R 2',} R 4 ', R 5', R 6 ', R 7', R 1 3 ', R 14', R 1 7 ', R 1 8', R 1 9 ', R 2 ⁰ 'and R ^21' are each ^{R ', R 2, R 4} , R 5, R 6, R 7, ^{R 1 3, R 1 4,} R 1 7, R 1 8, R 1 9, R 2. And R ^{2 1} synonymous compound, a pharmaceutically acceptable salt or a hydrate thereof.

 8. A pharmaceutical composition comprising the compound according to claim 7 as an active ingredient.