JPH01299231A - Remedy for circulatory disease - Google Patents

Abstract

PURPOSE:To obtain a remedy for circulatory diseases useful for treating cardiac incompetence, showing strongly inhibitory action on calmodulin, having durable and strong activity even by oral administration, comprising a thienotriazolodiazepine derivative as an active ingredient. CONSTITUTION:A remedy for circulatory diseases comprising a compound shown by formula I (Ar is pyridine, phenyl, etc.; A is 1-8C alkylene, etc.; R<1>, R<2> and R<3> are H or 1-5C alkyl; R<4>, R<5> and R<6> are H, halogen, OH, 1-8C alkyl, etc.) or a salt thereof (e.g., hydrochloride, sulfate, phosphate, etc.) as an active ingredient. The active ingredient has not only inhibitory action on calcium and/or calmodulin dependent phosphodiesterase but also improving action on erythrocyte deformation ability and vasodilating action on coronary blood vessel. The compound shown by the formula in an amount effective for treatment is properly blended with an excipient, extender, etc., made into tablet, pill, etc., and can be safely administered orally or parenterally. A dose is usually 0.1-100mg per adult daily and administered dividedly 1-several times.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to coronary vasodilators, heart failure therapeutics, or Concerning drugs for treating circulatory system diseases such as cerebral vasodilators.

[Conventional technology]

The fact that certain chenotriazolodiazepine compounds have central nervous system effects such as anxiolytic activity and anticonvulsant activity has been reported, for example, by ^rzneim, Forsch, (Drug
Res,) No. 28tL (11), p. 1165, 1
Known since 978. Also, JP-A-61-87
No. 684 and other publications disclose that similar compounds have platelet activating factor antagonistic effects.

Furthermore, Japanese Patent Application No. 62-289983 describes PAFs substituted with an aralkyl side chain at the 2-position, which are effective for oral administration, have a long duration of action, and have less central depressant effects such as sedative and muscle relaxant effects. A series of novel cheno (3,2-f) (1°2, 43 triazolo (4,3-a) (1,4) diazepine compounds with antagonistic effects is disclosed).

[Problem to be solved by the invention]

By the way, the recent increase in the mortality rate due to circulatory system diseases is
It has been recognized that research and development of effective drugs is a pressing issue, but these prior chenotriazolodiazepine compounds, apart from antagonizing PAF-derived effects, have no direct cardiovascular effects. There are no known beneficial effects on

[Means to solve the problem]

Therefore, the present inventors have conducted extensive research with the aim of developing a drug that has a useful effect on cardiovascular diseases, and have found a compound represented by the following general formula (1) and its pharmacological properties. The acid addition salts tolerated by Calmodiniline have a strong calmodiniline inhibitory effect, calcium/calmodiniline-dependent phosphogesterase inhibitory effect, red blood cell deformability improving effect, etc., and are used as inhibitors of intracellular calcium physiology involving calmodiniline. It is useful for various diseases, and because it also has coronary vasodilatory effects and vertebral blood flow increasing effects, it is useful for the treatment of heart failure, ischemic heart disease, cerebral circulation disorders, and various circulatory system diseases based thereon. We also found that these effects are effective and sustained even when administered orally,
The present invention has now been completed.

That is, the present invention is based on (1) the general formula (wherein Ar is pyridyl, phenyl, or as a substituent halogen, hydroxyl group, straight or branched alkyl having 1 to 5 carbon atoms, and phenyl having 1 to 3 members arbitrarily selected from straight chain or branched alkoxy; A is alkylene having 1 to 8 carbon atoms; or phenyl having 1 to 3 carbon atoms;
R1, Rz, and R3 are the same or different and represent hydrogen or a straight or branched chain having 1 to 5 carbon atoms; Branched alkyl, R4, Bs, Rh are the same or different, hydrogen, halogen, hydroxyl group, carbon number 1-8
straight-chain or branched alkyl, straight-chain or branched alkoxy having 1 to 8 carbon atoms, phenyl, phenoxy,
1 arbitrarily selected from aralkyl, aralkyloxy, or a halogen on the aromatic ring, a hydroxyl group, a straight-chain or branched alkyl having 1 to 5 carbon atoms, and a straight-chain or branched alkoxy having 1 to 5 carbon atoms. Contains as an active ingredient a chenotriazolodiazepine derivative represented by phenyl, phenoxy, aralkyl or aralkyloxy having ~3 substituents and a pharmacologically acceptable acid addition salt thereof. A drug for treating circulatory system diseases.

(2) The therapeutic agent for circulatory system diseases according to (1) above, which is a coronary vasodilator, a heart failure therapeutic, or a cerebral vasodilator.

In the definitions of the above symbols of the compound (1) of the present invention, halogen refers to chlorine, bromine, fluorine, and iodine, and linear or branched alkyl having 1 to 5 carbon atoms refers to methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, tertiary
Butyl, n-pentyl, isopentyl, tertiary pentyl, l-methylbutyl, etc., and linear or branched alkoxy having 1 to 5 carbon atoms include methoxy, ethoxy, n-
Broboxy, isopropoxy, n-butoxy, isobutoxy, tertiary butoxy, n-pentyloxy, isopentyloxy, tertiary pentyloxy, 1-methylbutyloxy, etc.; pyridyl refers to 2-pyridyl, 3-pyridyl, 4-pyridyl, alkylene with 1 to 8 carbon atoms means linear alkylene, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, and alkylene with 1 to 8 carbon atoms.
C1-C8 alkylene substituted with ~5 straight-chain or branched alkyl means alkylene substituted with C1-5 alkyl on the same carbon or on a different carbon. However, methylmethylene, propylene, methyltrimethylene, dimethylethylene, dimethyltetramethylene, ethylethylene, dimethyltrimethylene, etc. are defined as methyl, ethyl, n- propyl, isopropyl, n-butyl,
Isobutyl, tertiary butyl, n-pentyl, isopentyl, l-methylbutyl, n-hexyl, 1-methylpentyl, n-heptyl, 4-methylhexyl, 1-ethylpentyl, 1,4-dimethylpentyl, low octyl,
6-methylheptyl, 2-ethylhexyl, etc., and linear or branched alkoxy having 1 to 8 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-
Butoxy, isobutoxy, tertiary butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy,
n-hebutyloxy, ■-propylbutoxy, n-octyloxy, 5-methylhexyloxy, 2-ethylhexyloxy, 1.6=dimethylhexyloxy, etc., and aralkyl includes benzyl, 1-phenylethyl, 2-
Phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc., aralkyloxy means benzyloxy,
2-phenylethoxy, 3-phenylpropoxy, 4-
Phenylbutoxy, etc., on the aromatic ring, 1 arbitrarily selected from halogen, hydroxyl group, straight chain or branched alkyl having 1 to 5 carbon atoms, and straight chain or branched chain alkoxy having 1 to 5 carbon atoms phenyl having ~3 substituents,
What is phenoxy, aralkyl or aralkyloxy?2
-chlorophenyl, 2-7" romophenyl, 3-fluorophenyl, 2.3-dichlorophenyl, 4-hydroxyphenyl, 2-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-term
Butylphenyl, 4-pentylphenyl, 2.4-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2.4-dimethoxyphenyl, 3.4 .5-trimethoxyphenyl, 2-chlorophenoxy, 2.3-dichlorophenoxy, 4-hydroxyphenoxy, 2-methylphenoxy, 4-butylphenoxy, 2.4-dimethylphenoxy, 2-methoxyphenoxy, 4-methoxyphenoxy , 2,4-dimethoxyphenoxy, 3,4゜5-trimethoxyphenoxy,
2-chlorobenzyl, 2,3-dichlorobenzyl, 4-
Hydroxybenzyl, 2-methylbenzyl, 4-methoxybenzyl, 3,4.5-trimethoxybenzyl, 2-
(2-chlorophenyl)ethyl, 2-chlorobenzyloxy, 2.4-dimethylbenzyloxy, 3.4.5-
Trimethoxybenzyloxy, 2-(2-chlorophenyl)ethoxy, 2-(2,4-dimethylphenyl)ethoxy, etc.

Pharmaceutically acceptable acid addition salts of the compound of general formula (1) include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and nitric acid, or salts with maleic acid, fumaric acid, and malic acid. , salts with organic acids such as tartaric acid, succinic acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, paratoluenesulfonic acid, and pamoic acid. “When a compound of the present invention has one or more asymmetric carbon atoms, racemates, diastereoisomers and individual optical isomers may exist, and the present invention encompasses all of them.

Examples of the compound of general formula (1) and its pharmacologically acceptable acid addition salts include compounds as illustrated in the table below.

These compounds are those described in the prior art documents mentioned above.

- Below margin 10°42° ((at3)2-(α2)2- QCI
)l HCH3165-167G"2 saliva 3) 2-(01
2) 2- +CH3HHCH3124-126 [Actions and Effects of the Invention] The calmodiniline inhibitory effects and calcium/calmodiniline-dependent phosphogesterase inhibitory effects of the compound (I) of the present invention and its pharmacologically acceptable acid addition salts are as follows. The test compounds and control compounds used are as follows.

Test compound A: 4-(2-chlorophenyl)-2-(2
-(4-isobutylphenyl)ethyl-9-methyl-6H-cheno (3,2-f) (1,2゜4) triazolo(4,3-a) (1,4] diazepine kt'M compound compound -( 2-chlorophenyl)-2-
(2-(4-n-butylphenyl)ethyl-9-methyl-6H-cheno [3,2-・f) (1,2゜4] triazolo(4,3-a) (1,4) diazepine test compound C: 2-(2-(4-n-butylphenyl)ethyl-9-methyl-4-(2-methylphenyl)-6H-cheno (3,2-f) (1,2°4) triazolo(4, 3-a) (1,4]Diazepine Test Compound D: 4-<2-chlorophenyl)-2-(2
-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-cheno (3,2-f) (1,2,4))
Riazolo(4,3-a)(1,4)diazepine Test Compound E: 2-(2-(4-isobutylphenyl)ethyl)-4-(3,4°5-trimethoxyphenyl)-6,9- Dimethyl-6H-cheno(3,2-f) (1,2,4) ) Riazolo(4,3-a) (1,4) Diazepine control compound: 14-ethoxycarbonyl-(3α.

16α-ethyl)-14,15-eburnamenine [vinpocetine] Pharmacology - Experimental Example 1 Calmodiniline inhibitory effect (NPN fluorescent probe method) Calmodiniline inhibitory effect was measured using nibushtan (Eps
[Biochemical and Biophysical Research Communications (Bio
chem, Biophys, Res, Commun,)
, Vol. 105, p. 1142, 1982] was used with modification.

i.e. 25mM) Lis-HCl buffer (pH 7.0)
1000 units of N-phenol-1-naphthylamine (NPN) 5HM1 calmodulin (bovine brain) and each test compound were added to the solution to make a total volume of 3 ml. After leaving it at room temperature for 1 hour, the fluorescence intensity was measured using a fluorophotometer (ex
, 3501m% elf, 440 nm).

A blank was prepared by adding water instead of calmodiniline. Each test compound was tested in dimethyl sulfoxide or
．． It was dissolved in 5% dimethyl sulfoxide, and the final concentration of dimethyl sulfoxide was 0.25%.

rcs the result. The test compounds A, B and D used were 1.0, 0.85 and 1.3 μM, respectively, expressed as values (50% inhibitory concentration, μM). On the other hand, the control compound vinpocetine was 3.5 μM.

Pharmacological Experiment Example 2 Calcium/calmodulin-dependent phosphogesterase inhibition effect experiments were conducted using the method of Thompson et al. [Advances in Cyclic Nucleotide Research (Advances)]
es in Cyclic Nucleotide R
e5earch) Vol. 10, p. 69, 1979]. That is, 40. /! 200mM) Lissu salt fI1. Buffer (pH 8, 0, containing 25 mM magnesium chloride, 0.5 mM ethylene glycol-bis(β-aminoethyl ether)-N,N'-tetraacetic acid (EGTA)), 20 μl of 10 μM (
3H)-cAMP (250 nCi), test compound and calcium/calmodulin-dependent phosphogesterase (PDE) enzyme solution were added to give a final volume of 200 μl.

Note that the test compound was dissolved in dimethyl sulfoxide to a final concentration of 1%. The reaction was carried out at 37°C for 20 minutes.

After stopping the reaction by heating for 1 minute in a boiling water bath, add snake venom (snake venom, 1/v).
x l ) to 50μ! In addition, the generated 5°-AMP was converted to adenosine by reacting at 30° C. for 10 minutes. Subsequently, 500 μl of AG I-X 8 (methanol: resin = 31) was added, and unreacted cA was removed by standing for 15 minutes while shaking occasionally under water cooling.
MP was adsorbed. Thereafter, centrifugation was performed, and the radioactivity of the supernatant was measured using a liquid scintillation counter.

The effect of the test compound on PDE activity was calculated by calculating the damage rate when calcium/calmodulin was not added using the following formula.

Margin below 1: Inhibition of PDE in the absence of calcium/calmodulin (%) -(1--) X100 a: PD in the presence of test compound and absence of calmodulin
E activity b: Test compound, PDE activity in the absence of calmodulin The results were determined as IC2° values, and the test compounds A, B, C, and E used were each 10.12.8
and 11 μM. On the other hand, the control compound vinpocetine was 88 μM.

Furthermore, the acute toxicity of the compound of the present invention was investigated using six male mice. When the test compound was orally administered and observed for 5 days, no deaths were observed at a dose of 1000 kg/kg.

As is clear from the above pharmacological experiment examples and various pharmacological experiments, the compound of the present invention (N and its pharmacologically acceptable acid addition salts have a strong calmodulin inhibitory effect,
In addition to inhibiting calmodulin-dependent phosphogesterase, it also has effects on improving red blood cell deformability, dilating coronary vessels, and increasing blood flow to the vertebral bones. Even when administered orally, it exhibits long-lasting and strong activity.

Furthermore, this activity is found to be far more potent in inhibiting calcium/calmodulin-dependent phosphogesterase than vinpocetine, which was used as a control.

Therefore, the compound (1) of the present invention and its pharmacologically acceptable acid addition salts can be used as inhibitors of intracellular calcium physiological action involving calmodulin, and also as coronary vasodilators, heart failure therapeutics, and cerebral vasodilators. as heart failure, ischemic heart disease (angina pectoris, myocardial infarction, etc.) or cerebral circulation disorder (
It is useful as a therapeutic agent for cardiovascular diseases such as cerebral infarction, cerebral arteriosclerosis, cerebral hemorrhage, head disorders, etc.) or diseases based thereon (deterioration of spontaneity, depression, memory disorders, etc.).

The compound (r) of the present invention and its pharmacologically acceptable acid addition salts can be prepared in a therapeutically effective amount and pharmaceutical additives such as excipients, diluents, solubilizing agents, etc. as appropriate. mix,
It can be safely administered orally or parenterally as a tablet, pill, powder, capsule, granule, liquid, inhaler, suppository, transdermal absorption agent, or injection. The dosage varies depending on the compound selected, the severity of the disease, age, etc., but it can usually be administered at 0.1 to 100 μ per day for adults, either once or in several divided doses.

〔Example〕

Examples of pharmaceutical compositions containing the compound of the present invention as an active ingredient are given below.

Formulation Example 1 Tablet 1 part of the compound (I) of the present invention, 1.30 parts of milk, 40 parts of crystalline cellulose and 5 parts of cornstarch were thoroughly mixed, and then thoroughly kneaded with a binder made from 2 parts of cornstarch. This mixture was sifted through a 16-mesh screen, and during opening,
After drying at 50°C, it was sieved with 24 meshes. The kneaded powder obtained here, 10 parts of cornstarch, 13 parts of crystalline cellulose
1 part and 9 parts of talc were thoroughly mixed and compressed into tablets,
Tablets each weighing 110 cm were obtained.

Preparation Example 21% Powder 1 part of the compound of the present invention (1) and milk I! 90 parts were mixed well and kneaded with an appropriate amount of a binder made from methylcellulose. Sieve this through a 16-mesh sieve and put it in the oven for 5 minutes.
Dry at 0°C. The dried granules were pressure sieved through a 32-mesh filter and thoroughly mixed with an appropriate amount of silicon dioxide to obtain a 1% septic.

Although the present invention has been fully described in the above specification and the examples contained therein, various changes and modifications may be made thereto without departing from the spirit and scope of the present invention.

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. phenyl having 1 to 3 atoms arbitrarily selected from 1 to 5 linear or branched alkoxy; A is alkylene having 1 to 8 carbon atoms or 1 to 8 carbon atoms;
- C1-C8 alkylene substituted with ~5 straight-chain or branched alkyl, R^1, R^2, R^3 are the same or different, hydrogen or C1-C5 alkylene R^4, R^5, R^6 are the same or different, hydrogen, halogen, hydroxyl group, straight chain or branched alkyl having 1 to 8 carbon atoms, , carbon number 1-8
straight-chain or branched alkoxy, phenyl, phenoxy, aralkyl, aralkyloxy, or halogen, hydroxyl group, straight-chain or branched alkyl having 1 to 5 carbon atoms, and straight chain or branched alkyl having 1 to 5 carbon atoms on the aromatic ring. represents phenyl, phenoxy, aralkyl or aralkyloxy having 1 to 3 substituents arbitrarily selected from linear or branched alkoxy. ) A therapeutic drug for circulatory system diseases, which contains a thienotriazolodiazepine derivative represented by the following formula and a pharmacologically acceptable acid addition salt thereof as an active ingredient. (2) The therapeutic agent for circulatory system diseases according to claim 1, which is a coronary vasodilator, a heart failure therapeutic, or a cerebral vasodilator.