JPH0587076B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention has a coronary vasodilating effect, a vertebral blood flow increasing effect,
A novel thienophenol that is useful as a medicine and has calmodillin inhibitory action, calcium/calmodillin-dependent phosphodiesterase inhibitory action, red blood cell deformability improving action, and/or platelet activating factor (hereinafter sometimes referred to as PAF) antagonistic action. (Triazolo)diazepine compounds and pharmaceutically acceptable salts thereof. [Prior art] Japanese Patent Publications No. 49-40000 and No. 49-40238 disclose that certain thieno[2,3-e]-1,4-diazepine derivatives have anti-anxiety and anticonvulsant effects on the central nervous system. It is also known from Japanese Patent Application Laid-Open No. 1986-
Publication No. 87623 discloses that a similar compound has PAF antagonistic activity. It has been reported, for example, by Arzneim. Forsch.
Res.) Volume 28 (), Page 1165, 1978. Furthermore, JP-A-61-87684 and the like disclose that similar compounds have PAF antagonistic activity. [Problems to be Solved by the Invention] By the way, several compounds specifically disclosed in the pharmacological experiment section of the above-mentioned Japanese Patent Application Laid-Open No. 61-87684 have excellent anxiolytic effects, and these compounds have an excellent anti-anxiety effect. Due to its pronounced effects on the central nervous system, it is not preferable to treat various diseases caused by PAF, and it is difficult to separate the effects from the central nervous system.
Enhancement of PAF antagonistic activity, expression of activity upon oral administration,
There is a desire to develop more useful compounds in terms of sustainability of action, etc. In addition, the recent increase in mortality rates from various cardiovascular diseases has led to the realization that research and development of effective drugs is an urgent issue. No direct beneficial effects on the circulatory system are known, other than antagonizing the effects of the drug. [Means for Solving the Problems] The present inventors have discovered a drug that does not act on the central nervous system, exhibits excellent PAF antagonistic activity, is effective even when administered orally, and has a sustained action. ,moreover,
As a result of intensive research aimed at obtaining compounds with other useful effects, surprisingly, the above-mentioned JP-A-61
- Certain thienotriazolodiazepine compounds, which are not specifically disclosed in Publication No. 87684, have strong coronary vasodilatory effects, vertebral blood flow increasing effects, calmodillin inhibitory effects, calcium/calmodillin-dependent phosphodiesterase inhibitory effects, It has been found that it has an effect of improving red blood cell deformability and is useful for heart failure, ischemic heart disease, cerebral circulation disorder, and various diseases based thereon. Furthermore, the present inventors have found that this group of compounds has superior properties compared to previous compounds.
Although it exhibits PAF antagonistic activity, it has been found that it does not substantially act on the central nervous system, is effective even when administered orally, and is persistent, leading to the completion of the present invention. The present invention relates to the following (1) and (2). (1) General formula

[Formula] (In the formula, Ar is phenyl or phenyl substituted with 1 to 3 halogens, lower alkyl or lower alkoxy, and R ¹ and R ³ are the same or different and hydrogen or alkyl having 1 to 4 carbon atoms. of,
R ² represents methyl, and R ⁴ represents a straight or branched alkyl having 6 to 18 carbon atoms. ) A thienotriazolodiazepine compound and a pharmaceutically acceptable salt thereof. (2) General formula

A thienodiazepine compound or a pharmaceutically acceptable salt thereof, represented by: (wherein Ar, R ¹ , R ² and R ⁴ have the same meanings as above). The compound of general formula () is also important as an intermediate for synthesizing the compound of general formula (). In the above formula, halogen in Ar means chlorine, bromine,
fluorine, etc., lower alkyl refers to alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc., lower alkoxy refers to methoxy, ethoxy,
It means alkoxy having 1 to 4 carbon atoms such as propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy. Examples of the alkyl having 1 to 4 carbon atoms represented by R ¹ and R ³ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
Class butyl is mentioned. The linear or branched alkyl having 6 to 18 carbon atoms represented by R ⁴ includes hexyl, heptyl, octyl, 2-ethylhexyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, and the like. Pharmaceutically acceptable salts of general formula () or compounds of general formula () include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, or salts with maleic acid, fumaric acid, malic acid, etc. , tartaric acid,
Examples include salts with organic acids such as succinic acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, and p-toluenesulfonic acid. Furthermore, when the compound of the present invention has an asymmetric carbon, the present invention also includes its optically active form, its diastereoisomer, or a mixture thereof. Furthermore, positional isomers are also included. The compound of the general formula () of the present invention can be obtained by reacting the compound of the general formula () with a thionating agent to obtain the compound of the general formula ().

[Chemical formula] (wherein, Ar, R ¹ , R ² , and R ⁴ have the same meanings as above) is obtained, and then a compound of this general formula () and a compound of the general formula R ³ CONHNH ₂ () ( (wherein, R ³ has the same meaning as above), or obtained by reacting the compound of general formula () with hydrazine or its hydrate. general formula

[Chemical formula] (wherein, Ar, R ¹ , R ² , and R ⁴ have the same meanings as above) is a compound represented by the general formula R ³ COOH () (wherein, R ³ has the same meanings as above). ) or a reactive derivative thereof, or a compound represented by the general formula R ³ C(OR ⁵ ) ₃ () (wherein R ⁵ is a lower group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc. (representing an alkyl group, and R ³ has the same meaning as above). In the above method, the thionating agent is phosphorus pentasulfide,
2,4-bis(4-methoxyphenyl)-1,3,
2,4-dithiadiphosphethane-2,4-disulfide (Lawesson's reagent), etc., and reactive derivatives of the compound of general formula () include carboxylic acid halides (carboxylic acid chloride, carboxylic acid bromide, etc.), carboxylic acid anhydrides, mixed acid anhydrides (lower alkyl carbonic acid mixed acid anhydrides, alkyl phosphoric acid mixed acid anhydrides, etc.), lower alkyl esters (methyl esters, ethyl esters, etc.),
Active esters (benzyl ester, p-nitrobenzyl ester, p-nitrophenyl ester,
p-chlorophenyl ester, etc.). The reaction between the compound of general formula () and the thionating agent is usually carried out in a solvent inert to the reaction (pyridine, dimethylaniline, benzene, toluene, xylene, tetrahydrofuran, dioxane, chloroform, etc., or a mixed solvent thereof) for 30 to 30 minutes. The process takes place at 100°C for 30 minutes to 5 hours. In addition, the reaction between the compound of general formula () and the compound of general formula () is usually carried out using a solvent inert to the reaction (benzene, toluene, xylene, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropyl alcohol, etc., or a mixture thereof). in the presence of organic acids (acetic acid, propionic acid, etc.), inorganic acids (hydrochloric acid, sulfuric acid, etc.) or silica gel in a solvent) from room temperature to the reflux temperature of the solvent used.
The process lasts from 30 minutes to 5 hours. Next, the reaction between the compound of general formula () and hydrazine or its hydrate is usually carried out using a solvent inert to the reaction (methanol, ethanol, propanol,
(isopropyl alcohol, butanol, etc.),
The process progresses at 0 to 40°C in about 5 minutes to 3 hours. Compounds of general formula () and compounds of general formula () or reactive derivatives thereof or general formula ()
The reaction with the compound is carried out in a solvent inert to the reaction (benzene, toluene, xylene, tetrahydrofuran, dioxane, etc., or a mixed solvent thereof).
In the presence of organic acids (acetic acid, propionic acid, etc.), inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or silica gel, from room temperature to the reflux temperature of the solvent used for 30 min.
progress in time. The compound of general formula () thus obtained can be separated and purified from the reaction mixture by methods known per se, such as recrystallization and chromatography. The compound of general formula () can be converted into the above-mentioned pharmaceutically acceptable salt by treating with an inorganic or organic acid in a conventional manner. Preferred compounds of the general formula () are 4-(2-chlorophenyl)-2-hexyl-
6,9-dimethyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Diazepine, 2-hexyl-4-(2-methoxyphenyl)-
6,9-dimethyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Diazepine, 2-hexyl-4-(2-methylphenyl)-
6,9-dimethyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Examples include diazepine. Further, the compound of the above general formula () is synthesized, for example, by the following method. That is, a compound represented by the general formula ArCOCH ₂ CN () (wherein Ar has the same meaning as above) and the general formula

[Formula] (In the formula, R ¹ and R ⁴ have the same meanings as above.) In the presence of sulfur, a compound represented by , using a base such as triethylamine, pyrrolidine, piperidine, or morpholine as a catalyst at room temperature or under heating to form the general formula

[Formula] (In the formula, Ar, R ¹ and R ⁴ have the same meanings as above.) A compound represented by the formula:

[Formula] (In the formula, Z ¹ and Z ² are the same or different and represent a halogen such as chlorine or bromine, and R ² has the same meaning as above.) A compound represented by the formula is reacted to form an N-haloacetyl compound. If necessary, potassium iodide, sodium iodide, etc. are further reacted to form the N-iodoacetyl form, and then ammonia is reacted to form the N-glycyl form. The reaction proceeds in a solvent such as acetone, tetrahydrofuran, dioxane, etc., under cooling, at room temperature, or under heating. The N-glycyl compound thus obtained is used in an inert solvent (ethanol, propanol, isopropyl alcohol, butanol, benzene,
Compound (2) is produced by subjecting it to a dehydration ring-closure reaction in toluene, dimethylformamide, dimethylacetamide, etc., preferably in the presence of a weak acid catalyst such as acetic acid, propionic acid, or silica gel, at room temperature or with heating. The compound of the general formula () is further defined by the general formula

[Formula] (In the formula, Ar, R ¹ , R ² and R ⁴ have the same meanings as above.) For the reaction, an inert solvent (ethanol, propanol, isopropyl alcohol, butanol, benzene, toluene, dimethylformamide, dimethylacetamide, etc.)
It can also be obtained by subjecting it to a dehydration ring closure reaction at room temperature or under heating, preferably in the presence of a weak acid catalyst such as acetic acid, propionic acid, or silica gel. Here, the compound of the general formula () is the compound of the general formula () and the compound of the general formula

[Formula] (In the formula, Z ³ represents a halogen such as chlorine or bromine, and W
represents an amine protected with a protecting group, and R ² has the same meaning as above. ) and the general formula obtained by reacting with the compound represented by

[Action and effect of the invention]

The compound of the present invention () and its pharmaceutically acceptable salts exhibit coronary vasodilatory action, vertebral blood flow increasing action, calmodillin inhibiting action, calcium/calmodillin dependent phosphodiesterase inhibiting action and/or red blood cell deformability improving action, and
It exhibits PAF antagonistic effects, has long-lasting effects, has low toxicity, and has virtually no central depressant effects such as sedation, or muscle relaxant effects. Therefore, the compound of the present invention () and its pharmaceutically acceptable salts can be used as coronary vasodilators and cerebral vasodilators to treat heart failure, ischemic heart disease (angina pectoris, myocardial infarction, etc.) or cerebral circulation disorders (cerebral infarction, etc.). , cerebral arteriosclerosis, cerebral hemorrhage, head disorders, etc.) or diseases based thereon (deterioration of spontaneity, depression, memory disorders, etc.)
as a treatment for cardiovascular diseases such as
Various diseases caused by PAF (inflammatory diseases,
allergic diseases, anaphylactic shots,
It is useful as a therapeutic agent for myocardial diseases, asthma, pulmonary edema, adult respiratory diseases, etc. Furthermore, the thienodiazepine compound represented by the general formula () is important as a synthetic intermediate for the thienotriazolodiazepine compound represented by the general formula (). Next, the pharmacological effects of the compounds of the present invention will be shown. Experimental Example 1 Effect on Coronary Blood Flow Pentobarbital Sodium 30 in Mongrel Adult Dogs
Anesthetize by administering mg/Kg intravenously. The left coronary artery was perfused and the blood flow rate was measured according to the method of Yago et al. described in Japanese Pharmacological Journal, Vol. 57, p. 380 (1961). 10-30μ of test compound is administered into the coronary artery. The effect of the test compound on coronary blood flow was determined by calculating the rate of increase in blood flow for each administration based on the amount of increase in blood flow when 3 μg of nifedipine was administered.

[Table] Experimental Example 2 Rabbit platelet aggregation inhibitory effect (in vitro test) Blood was collected from rabbits to which 1/10 volume of 3.8% sodium citrate solution was added, centrifuged at 200 x g for 10 minutes, and platelet-rich blood was collected. Plasma (PRP)
That's what it means. ) was prepared. Furthermore, the platelet-poor plasma (hereinafter referred to as
It's called PPP. ) was prepared. Aggregation ability was measured using a 6-channel NKK hematotracer 1 (PAT-6A) according to the BORN GVR turbidity measurement method described in J. Physiology, Vol. 168, p. 178 (1963). did. Light transmission was adjusted from 0 to 100% with PRP and PPP.
Add 3μ of the test compound solution or solvent to 0.3ml of PRP while stirring at 1000 rpm, hold at 37°C for 2 minutes, then add 3μ of synthetic platelet activating factor to a final concentration of 1.8 x 10 ^-7 M. Minute light transmission was recorded. The inhibition rate of platelet aggregation by the test compound was determined by the maximum light transmittance in the presence and absence of the test compound, as shown in the following formula. % inhibition = [1 - maximum aggregation in the presence of test compound/maximum aggregation in the absence of test compound] × 100 From this % inhibition versus dose curve, the IC ₅₀ value (μ
g/ml, 50% inhibitory concentration). Experimental Example 3 Rabbit platelet aggregation inhibitory effect (in vitro test) In the in vitro test of Experimental Example 2, instead of adding the test compound to PRP, 1 group 3
The test compound was orally administered to feathered rabbits, and citrated blood (9 volumes of blood in 1 volume of 3.8% sodium citrate) was collected over time. Thereafter, using this blood, the inhibitory effect was tested according to Experimental Example 2. Experimental Example 4 Effect on PAF-induced mouse shot death The experiment was carried out according to the method of Young et al. described in Prostaglandins, Vol. 30, p. 545 (1985).
Groups of 9 to 15 male ICR mice (Charles River) weighing 25 to 30 g were used. One hour after oral administration (0.1ml/10g) of the test compound, PAF (Serdary
Research Lab.) 80 μg/Kg was administered via the tail vein. After administering PAF, observation was made for 24 hours, and the results were
The table shows the number of surviving animals/number of animals used in the experiment and survival rate (%).

〔Example〕

The present invention will be specifically explained below with reference to Examples, but the present invention is not limited thereto. The compound included in the general formula () can be obtained as follows. Reference Example 1 31.8 g of 2-methylcyanoacetophenone and 6.7 g of sulfur were suspended in 50 ml of dimethylformamide,
Add 21 g of triethylamine while stirring on ice. Next, add 2.7 g of octylaldehyde to 15 ml of ethanol.
and stirred at 55-60°C for 3 hours.
The reaction solution was placed in ice water and extracted with 500ml of toluene.
After washing with water, dry with anhydrous magnesium sulfate. After filtering and concentrating under reduced pressure, 2-
50 g of amino-3-(2-methylbenzoyl)-5-hexylthiophene are obtained. Example 1 62 g of 2-amino-5-hexyl-3-(2-methylbenzoyl)-thiophene obtained in Reference Example 1
was dissolved in 200 ml of chloroform, 47.3 g of (DL)-N-phthalylalanyl chloride was added, and the mixture was dissolved under stirring.
Heat to reflux for an hour. After cooling, the mixture is washed with water and 5% sodium bicarbonate, and then dried over anhydrous magnesium sulfate. After filtration, it is concentrated under reduced pressure and crystallized from ethanol to give 5-
hexyl-3-(2-methylbenzoyl)-2-
(N-phthalylalanyl)amino-thiophene 65
get g. 30.2 g of the obtained compound was suspended in 300 ml of methanol, 8.3 g of methylhydrazine was added under ice cooling, and after stirring at room temperature for 30 minutes, 20 ml of concentrated hydrochloric acid was added, and
Heat to reflux for an hour. After concentration under reduced pressure, chloroform
Add 150ml and filter out the pyridazinone produced.
The chloroform layer was washed with 5% aqueous sodium bicarbonate and then dried over anhydrous magnesium sulfate. After filtration, it was concentrated under reduced pressure to obtain an oily crude product 2-(N
-alanyl)amino-5-hexyl-3-(2-
Methylbenzoyl)-thiophene was dissolved in 200 ml of isopropyl alcohol, 4.3 g of acetic acid was added, and the mixture was heated under reflux for 14 hours with stirring. After cooling, concentrate under reduced pressure.
When crystallized from isopropyl ether, the melting point
7-Hexyl-3- as colorless crystals at 173-175℃
11.6 g of methyl-5-(2-methylphenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2one are obtained. Similarly, the following compounds can be synthesized. (2) 7-hexyl-3-methyl-5-(2-methoxyphenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-
(3) 5-(2-chlorophenyl)-7-hexyl-
3-Methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting point 169-171°C (4) 7-hexyl-3,6-dimethyl-5 −(2
-methylphenyl)-1,3-dihydro-2H-
Thieno[2,3-e]-1,4-diazepine-
2-one (5) 7-hexyl-5-(3,4,5-trimethoxyphenyl)-3-methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4- Diazepin-2-one By using the compound obtained in the above example as a starting compound, a compound included in the following general formula () can be obtained. Example 6 7-hexyl-3-methyl-5-(2-methylphenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one
5.32 g and 2 g of phosphorus pentasulfide are suspended in 60 ml of toluene and stirred at 80-85°C for 3 hours. After vacuum concentration,
The residue was dissolved in 200 ml of chloroform, washed with 5% aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, it is concentrated under reduced pressure and crystallized from isopropyl ether to obtain 3.92 g of the thione compound. 3.92 g of this thione compound was suspended in 50 ml of methanol, 1.58 g of 100% hydrazine hydrate was added, and the mixture was stirred at room temperature for 1.5 hours. After concentration under reduced pressure, the residue is dissolved in 30 ml of toluene and dried over anhydrous magnesium sulfate. After filtration, add ethyl orthoacetate to the toluene solution.
Add 5.13g and heat under reflux for 2 hours. After cooling, 5%
Wash with aqueous sodium bicarbonate and brine, and dry with anhydrous magnesium sulfate. After filtration, it was concentrated under reduced pressure, and the oily residue was subjected to silica gel chromatography and crystallized from hexane-isopropyl ether to give 2-hexyl-4-(2-methylphenyl) as colorless crystals with a melting point of 83-85°C. )−
6,9-dimethyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Obtain 2.82 g of diazepine. The following compounds are produced in the same manner as in the above examples. (7) 4-(2-chlorophenyl)-2-hexyl-
6,9-dimethyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Diazepine, melting point 108-110℃ (8) 2-hexyl-4-(2-methoxyphenyl)
-6,9-dimethyl-6H-thieno[3,2-
f] [1,2,4] triazolo [4,3-a]
[1,4]Diazepine, melting point 92-95℃ (9) 2-hexyl-4-(2-methylphenyl)-
3,6,9-trimethyl-6H-thieno[3,
2-f] [1,2,4] triazolo[4,3-
a] [1,4] diazepine (10) 2-hexyl-4-(3,4,5-trimethoxyphenyl)-6,9-dimethyl-6H-thieno[3,2-f] [1,2 , 4] Triazolo[4,3-a][1,4]diazepine Next, an example of a pharmaceutical formulation when the compound of the present invention is used as a drug will be given. Formulation Example 1 Tablet 1 part of the compound (), 30 parts of lactose, 40 parts of crystalline cellulose, and 5 parts of corn starch were thoroughly mixed, and then thoroughly kneaded with a binder prepared from 2 parts of corn starch. This mixture was passed through a 16-mesh sieve,
After drying in an oven at 50°C, it was sieved through a 24-mesh sieve. The kneaded powder obtained here and 10 parts of cornstarch,
After thoroughly mixing 13 parts of crystalline cellulose and 9 parts of talc, the mixture was compressed into tablets to obtain tablets each weighing 110 mg. Formulation Example 2 1% Powder Mix 1 part of compound () and 90 parts of lactose thoroughly,
Thoroughly knead with an appropriate amount of a binder made from methylcellulose. This is passed through a 16 mesh sieve and dried in an oven at 50°C. The dried granules were sieved through a 32-mesh filter and thoroughly mixed with an appropriate amount of silicon dioxide to obtain a 1% powder. 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 (1)

[Claims] 1 General formula [Formula] (wherein, Ar is phenyl or phenyl substituted with 1 to 3 halogens, lower alkyl or lower alkoxy, and R ¹ and R ³ are the same or different and hydrogen or an alkyl having 1 to 4 carbon atoms, R ² is methyl, and R ⁴ is a straight or branched alkyl having 6 to 18 carbon atoms. A pharmaceutically acceptable salt thereof. 2 4-(2-chlorophenyl)-2-hexyl-
6,9-dimethyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Diazepine, 2-hexyl-4-(2-methoxyphenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3
-a][1,4]diazepine and 2-hexyl-4-(2-methylphenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3 The thienotriazolodiazepine compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from -a][1,4]diazepines. 3 General formula [Formula] (In the formula, Ar is phenyl or phenyl substituted with 1 to 3 halogens, lower alkyl or lower alkoxy, R ¹ is hydrogen or carbon number 1
~4 alkyl, ^R2 represents methyl, and ^R4 represents a straight or branched alkyl having 6 to 18 carbon atoms. ) or a pharmaceutically acceptable salt thereof.