JPH0699301B2 - Thromboxane A ▲ Bottom 2 ▼ Antagonist - Google Patents

Description

TECHNICAL FIELD The present invention relates to an excellent thromboxane A ₂ antagonist.

(Prior Art) Thromboxane A ₂ (Thromboxan A ₂ , hereinafter referred to as TxA ₂ )
Is various animal organs (eg liver, kidney, lung, brain, etc.)
Arachidonic acid, which is widely present in
It is known that various thrombosis such as peripheral arterial thrombosis, pulmonary embolism, coronary artery occlusion, myocardial infarction, and transient cerebral ischemia are often caused due to the platelet aggregation action of TxA _2. ing. Therefore, 4- (2-benzenesulfonylaminoethyl) phenoxyacetic acid has been reported as a drug that suppresses platelet aggregation based on TxA ₂ [Thrombosis Research, Vol. 35, 37].
9-395 (1984)].

(Problems to be Solved by the Invention) The present invention provides a TxA ₂ antagonist superior to the above-mentioned known compounds.

(Means for Solving the Problems) The present invention provides the following general formula (I): (However, R ¹ is a phenyl group which may have a substituent, R ²
Is an optionally protected carboxyl group, Q is a lower alkylene group, and m is 0 or 1. ) A thromboxane A ₂ antagonist comprising an indanylglycine derivative or a salt thereof as an active ingredient.

Specific examples of the indanylglycine derivative, which is the active ingredient of the thromboxane A ₂ antagonist of the present invention, include general formula (I)
R ¹ is a phenyl group or a halogenophenyl group, R ²
Is a free carboxyl group, or is a carboxyl group protected by, for example, a lower alkyl group, a phenyl lower alkyl group, a lower alkoxy group-substituted phenyl lower alkyl group, a nitro group-substituted phenyl lower alkyl group or a benzhydryl group, Q Is a lower alkylene group and m is 0 or 1.

Among these, preferred compounds in terms of efficacy are compounds in which R ¹ is a phenyl group or a halogenophenyl group, R ² is a free carboxyl group or a lower alkoxycarbonyl group, Q is a lower alkylene group, and m is 0 or 1.

In the above specific examples, the lower alkyl group, the lower alkoxy group and the lower alkylene group mean an alkyl group having 1 to 3 carbon atoms, an alkoxy group and an alkylene group, respectively.

The indanylglycine derivative (I), which is the active ingredient of the present invention, can be used for medicinal use either in a free form or in the form of a pharmacologically acceptable salt thereof. The pharmacologically acceptable salts include salts with inorganic or organic bases, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, heavy metal salts such as zinc salt, Examples thereof include organic amine salts such as ammonium salts, triethylamine salts, pyridine salts, ethanolamine salts and basic amino acid salts, and also organic acid addition salts such as formate salts, oxalate salts, methanesulfonate salts and gruguronate salts. included.

The TxA ₂ antagonist of the present invention can be administered orally or parenterally, and can be used as an appropriate pharmaceutical preparation such as tablets, capsules, powders and injections by a conventional method. .

The dose of the indanylglycine derivative (I) or a salt thereof, which is the active ingredient of the present invention, depends on the administration method, the age of the patient,
Depending on body weight, condition and type of disease to be treated, it is usually about 0.01 to 50 mg / kg per day, especially 0.05 to 2
It is preferably 0 mg / kg.

The indanylglycine derivative (I) may have two optical isomers based on one asymmetric carbon atom, but the present invention includes both these isomers and a mixture thereof.

The compound (I) which is the active ingredient of the present invention has the general formula (Wherein R ¹ has the same meaning as described above) or a salt thereof and a general formula XCH ₂ (CONH-Q) _m R ²¹ (III) (wherein X is a reactive residue and R ²¹ is A carboxyl group which may be protected, Q and m have the same meanings as described above.) When R ²¹ is a protected carboxyl group, the protecting group is removed if desired. Can be manufactured. Alternatively, the compound (I) has the general formula (Wherein R ²¹ , Q and m have the same meanings as described above) and the general formula R ¹ SO ₃ H (V) (wherein R ¹ has the same meanings as described above). When R ²¹ is a protected carboxyl group by subjecting it to a condensation reaction with a sulfonic acid compound or a reactive derivative thereof, the protective group can be removed if desired for production.

Further, among the compounds (I), the compound of m = 1 has the general formula (Wherein R ¹ has the same meaning as described above) or a reactive derivative at the carboxyl group thereof and a general formula H ₂ N-Q-R ²¹ (VI) (wherein R ²¹ and Q are as described above). When R ²¹ is a protected carboxyl group, it can be produced by removing the protecting group, if desired, by subjecting R ²¹ to a protected carboxyl group.

The starting compound (II) of the present invention is, for example, a compound (V) obtained by nitrating 2-acetylaminoindane and then reducing it to remove the acetyl group of 2-acetylamino-5-aminoindane thus obtained. It can be produced by a condensation reaction. The starting compound (IV) can be produced by subjecting 2,5-diaminoindan and the compound (III) to a condensation reaction.

Experimental Example Arachidonic acid-induced pulmonary embolism inhibitory effect (in vivo) A carboxymethylcellulose solution as a test substance was orally administered (20 ml / kg) to an overnight fasted male ddy mouse.
After 3 hours, a arachidonic acid (125 mg / 10 ml / kg) solution was administered into the tail vein to induce pulmonary embolism. Time from arachidonic acid administration to recovery of walking movement (recovery time: minutes)
Was measured and compared with that of the sample non-administration group in which 0.25% CMC was administered instead of the sample. The arachidonic acid-induced pulmonary embolism inhibitory effect of the sample was expressed as a dose that reduced the recovery time by 15% or more as compared with the sample non-administration group. The results are shown in Table 1.

(Production Example) Production Example 1 5-amino-2- (4-chlorophenyl) sulfonylaminoindan 0.5 g was added to a hexamethylphosphoric triamide 5 ml solution at 5 to 10 ° C to obtain sodium hydrogencarbonate 0.2 g,
Add 0.25 g of methyl bromoacetate and stir at the same temperature for 4 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed, dried and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 7: 3), and further ethyl acetate-n
Recrystallization from a -hexane mixture gave 0.47 g of N- [2- (4-chlorophenyl) sulfonylaminoindan-5-yl] glycine methyl.

Mp130-132 ° C (decomposition) Production Examples 2 to 6 Corresponding raw material compounds were treated in the same manner as in Production Example 1 to give the following 2nd
The compounds listed are obtained.

Production Example 7 0.46 g of N- [2- (4-chlorophenyl) sulfonylaminoindan-5-yl] glycine methyl was dissolved in 20 ml of a mixed solution of methanol-tetrahydrofuran (1: 1), and 1N-aqueous sodium hydroxide solution 1.22 was added to the solution. Add ml, and stir at room temperature overnight and further at 60 ° C. for 3 hours. After the reaction, the solvent was distilled off, and the residue was recrystallized from an isopropyl alcohol-water mixed solution to give N- [2- (4-chlorophenyl) sulfonylaminoindan-5-yl] glycine sodium salt 0.37 g.
Is obtained as colorless crystals.

Mp239-242 ° C (decomposition) Free carboxylic acid: Mp137-139 ° C (decomposition) Production Examples 8 to 12 The corresponding starting material compounds were treated in the same manner as in Production Example 7, and the following third
The compounds listed are obtained.

Reference Example 1 (1) 20.5 g of 2-acetylaminoindan is gradually added to 200 ml of fuming nitric acid while cooling. After the reaction, mix the mixture with ice 100
Then, the solvent is distilled off from the chloroform extract and recrystallized from isopropyl alcohol to obtain 2-acetylamino-5-nitroindane (18.6 g).

Mp140-144 ° C (2) The ethanol solution of 3.98 g of this product is catalytically reduced in the presence of 0.4 g of 10% palladium-carbon at room temperature and atmospheric pressure. After the reaction, the catalyst is removed by filtration and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the crystals were collected by filtration to obtain 3.04 g of 2-acetylamino-5-aminoindane.

Mp154-156 ℃ (3) Add 9.27g of this product to 2N hydrochloric acid and reflux. After the reaction, the solvent was distilled off, and the residue was recrystallized from an isopropyl alcohol-water mixture to give 2,5-diaminoindan dihydrochloride.
Get 9.80g.

Mp> 270 ° C (4) Diazabicyclo [5.4.0] undec-7-ene 8.39 g is added to 4.0 g of a pyridine-methylene chloride solution. Then, a solution of 3.36 g of benzenesulfonyl chloride in methylene chloride was added dropwise with cooling, and the mixture was stirred. After the reaction, water is added, the organic layer is separated and the solvent is distilled off. The residue is crystallized from a mixed solution of ethanol-n-hexane, purified by silica gel column chromatography, and recrystallized from a mixed solution of ethyl acetate-n-hexane to give 2.98 g of 5-amino-2-benzenesulfonylaminoindane.

Mp105-107 ° C Reference Example 2 5-Amino-2- (4-chlorophenyl) sulfonyl was prepared by treating 2,5-diaminoindan dihydrochloride and 4-chlorophenylsulfonyl chloride in the same manner as in Reference Example 1- (4). Get Aminoindan.

Mp145-147 ° C (recrystallized from chloroform-n-hexane) (Effect of the invention) Among the known TxA ₂ antagonists, while they have TxA ₂ antagonistic action, they also show a transient TxA ₂ -like action. , Platelet aggregation,
Although some side effects such as bronchoconstrictor action and vasoconstrictor action may occur, the TxA ₂ antagonist of the present invention is characterized in that such side effects are not substantially associated with oral or parenteral administration. In addition, the glycine derivative (I), which is an active ingredient, has low toxicity, and for example, N- [2- (4-chlorophenyl) sulfonylaminoindan-5-yl] glycine sodium salt is orally administered at 1000 mg / kg, and 3 No deaths were observed even after observing for a day, and no inhibition of weight gain was observed.

Therefore, the TxA ₂ antagonist of the present invention can be used for the treatment of various diseases caused by TxA ₂ and the alleviation and prevention of symptoms based on its excellent antagonistic action. For example, the TxA _{2 of} the present invention
The antagonist is useful as a platelet aggregation inhibitor and is preferably used for treatment and prevention of various thrombosis such as cerebral thrombosis, coronary thrombosis, pulmonary thrombosis, peripheral vascular embolism, and thromboangiitis, and embolism. be able to. Further, the TxA ₂ antagonist of the present invention is a treatment for myocardial ischemia, unstable angina, coronary artery atrophy, cerebrovascular atrophy after subarachnoid hemorrhage, cerebral hemorrhage, asthma, nephritis, renal failure, shock, etc. -It can also be used effectively for mitigation and prevention. Further, it can be used for preventing thrombus during extracorporeal circulation and for organ (eg, kidney) transplantation.

Claims (8)

[Claims] 1. A general formula (However, R ¹ is a phenyl group which may have a substituent, R ²
Is an optionally protected carboxyl group, Q is a lower alkylene group, and m is 0 or 1. ) A thromboxane A ₂ antagonist comprising an indanylglycine derivative or a pharmacologically acceptable salt thereof as an active ingredient. _{2. The} thromboxane A ₂ antagonist according to claim 1, which comprises an indanylglycine derivative in which R ¹ is a phenyl group or a halogenophenyl group or a pharmacologically acceptable salt thereof as an active ingredient. 3. The thromboxane A ₂ antagonist according to claim 2, which comprises an indanylglycine derivative in which R ² is a free carboxyl group or a lower alkoxycarbonyl group, or a pharmacologically acceptable salt thereof as an active ingredient. 4. An indanylglycine derivative or a pharmaceutically acceptable salt thereof, wherein R ¹ is a chlorophenyl group and R ² is a free carboxyl group, as an active ingredient.
The described thromboxane A ₂ antagonist. 5. A platelet aggregation inhibitor, which is a platelet aggregation inhibitor.
Alternatively, the thromboxane A ₂ antagonist according to item 4. 6. The thromboxane A ₂ antagonist according to claim 1, which is a therapeutic or prophylactic agent for thrombosis or embolism. 7. A therapeutic or prophylactic agent for myocardial ischemia, unstable angina, coronary artery constriction, cerebral vasospasm after subarachnoid hemorrhage, cerebral hemorrhage, asthma, nephritis, renal failure, shock. The thromboxane A ₂ antagonist according to _2, 3, or 4. 8. The thromboxane according to claim 1, 2, 3 or 4, which is useful for preventing thrombus during extracorporeal circulation and for organ transplantation.
A ₂ antagonist.