JPH08291066A - Suppressant for transient ischemic attack - Google Patents

Abstract

PURPOSE: To obtain a suppressant having treating and preventing actions on transient ischemic attack by using a compound known as an inhibitor of thromboxane synthases. CONSTITUTION: This suppressant contains a compound of formula I R<1> is pyridyl; R<2> is a lower alkoxy, a lower alkyl, a halogen, trifluoromethyl, a (substituted)phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl; R<3> is H or a lower alkyl; Y is S, methylene or formula II [R<4> is H or acetyl; (m) is 0 or 1]; (l) is 0-6}, preferably formula III [(n) is 2-6], e.g. 7-phenyl-7-(3-pyridine)-6- heptenoic acid or its pharmacologically permissible salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a transient cerebral ischemic attack inhibitor having a therapeutic and preventive effect on transient cerebral ischemic attack (TIA).

[0002]

2. Description of the Related Art TIA is a symptom that precedes stroke and disappears in a short period of time, and is regarded as a precursor attack or a warning attack of ischemic brain disease. Generally, TIA
It is said that there is a high risk of gradually shifting to serious cerebrovascular disorders such as cerebral infarction, and conversely, by suppressing TIA, the onset and recurrence of serious cerebrovascular disorders can be suppressed. TI
NIH (National Institute of Health) diagnostic criteria for patients A [Classification of Celebrity Circular Diseases (Classification of
cerebrovascular disease) III (classification of cerebrovascular disease), Stroke (stroke) 21: 653-654, 19
90 years]: TIA is an attack in which a local disorder of brain function, which is considered to be due to ischemia, appears for a short time. It is usually confined to one vascular system (the left or right common carotid system, or the vertebral-basilar artery system), and no other cause is found.
Those with a seizure duration of less than 24 hours are customarily classified as TIA. The longer the seizure duration, the more the computed tomography (CT) or magnetic resonance imaging (MRI).
The frequency of cerebral infarction lesions increases above. The duration of TIA is usually acute in 2 to 15 minutes (peaks peak within 5 minutes, often 2 minutes). Extremely short seizures lasting only a few seconds are unlikely to be considered TIA. TIA does not leave persistent neurologic deficits, but attacks are often recurrent. There are some atypical cases that do not fit this definition. Kameyama et al., "Diagnostic Criteria, Disease Type Classification, and Severity Classification of Cerebrovascular Disease (Internal Medicine, 55 (6): 130
6, 1985) ”and the like, the symptoms of internal carotid TIA include one or more symptoms of motor dysfunction, loss of visual acuity, sensory deficits, and aphasia. In addition, vertebra / basilar artery system T
Similarly, as the symptoms observed in IA, movement disorders, neurological symptoms such as eye symptoms and dizziness, etc. appear individually or in combination. On the other hand, JP-B-63-47707 describes that the compound represented by the following formula (I) and a salt thereof used in the present invention have a thromboxane synthase inhibitory action.

[0003]

Although there are cerebral vasospasm theory, microinfarction theory, cerebral vascular insufficiency theory, etc. as the pathogenic mechanism of TIA, the latter two are considered to be influential. And prevention of TIA
Anticoagulation and antiplatelet therapy have been attempted for treatment, and some effects are observed. Examples of these include a therapeutic method using aspirin and ticlopidine, but clinically, a drug having less side effects, capable of withstanding long-term administration, and more highly effective is desired.

[0004]

Means for Solving the Problems As a result of intensive investigations by the present inventors to find a compound that suppresses TIA, a compound known as a thromboxane synthase inhibitor is T
It was first clinically confirmed to be effective for IA, and the present invention was completed based on this. The present invention is based on the formula (1)

[Chemical 4] [Wherein R ¹ is a pyridyl group, R ² is a lower alkoxy group,
A lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group and / or a phenyl, thienyl, freeyl, naphthyl, benzothienyl or pyridyl group which may be substituted with
³ is a hydrogen atom or a lower alkyl group, Y is a sulfur atom,
Methylene group or formula

Embedded image A transient cerebral ischemic attack (TIA) inhibitor containing the compound represented by the formula or a pharmacologically acceptable salt thereof, formula (2)

[Chemical 6] [In formula, n shows the integer of 2-6. ] The transient cerebral ischemic attack inhibitor according to the above (1), which comprises a compound represented by the following or a pharmacologically acceptable salt thereof, and (3) 7-
The present invention relates to the transient cerebral ischemic attack inhibitor and the like described in (1) above, which contains phenyl-7- (3-pyridyl) -6-heptenoic acid.

In the above formula (I), R ¹ is substituted with a pyridyl group and R ² is substituted with a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group and / or a methylenedioxy group. Optionally represents a phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl group. In the formula (I), R ¹ ,
The pyridyl group represented by R ² may be any of 2-pyridyl, 3-pyridyl and 4-pyridyl, and the thienyl represented by R ² is 2-thienyl, 3-thienyl, furyl is 2-furyl, 3-furyl. , Naphthyl is α-naphthyl, β
-Naphthyl and benzothienyl are 2-benzothienyl, 3
It may be any of -benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl and 7-benzothienyl. Phenyl, thienyl, furyl, naphthyl, benzothienyl and pyridyl represented by R ² may be substituted, and examples of the lower alkoxy group as such a substituent include methoxy, ethoxy, n-propoxy and i-propoxy. , N-butoxy, i-butoxy, t
An alkoxy group having 1 to 4 carbon atoms such as butoxy,
Examples of the lower alkyl group include methyl, ethyl, n-
Propyl, i-propyl, n-butyl, s-butyl, i
An alkyl group having 1 to 5 carbon atoms such as -butyl, t-butyl, n-pentyl, i-pentyl, etc., as the halogen atom, for example, fluorine, chlorine, bromine, iodine, etc., and as the lower alkenyl group, for example: Examples thereof include alkenyl groups having 2 to 5 carbon atoms such as vinyl, allyl and pentenyl. When phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl represented by R ² has a substituent, these substituents can be substituted at 1 to 5 positions at any position on the ring. As R ¹ , 3-pyridyl and the like are preferable. R ² is preferably phenyl or the like. In the above formula (I), R ³ represents a hydrogen atom or a lower alkyl group. In the formula (I), the lower alkyl group represented by R ³ includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and the like having 1 carbon atom. To 4 alkyl groups and the like. R ³ is preferably a hydrogen atom. In the above formula (I), Y is a sulfur atom, a methylene group or a formula

[Chemical 7] (However, R ⁴ is a hydrogen atom or an acetyl group, and m is 0.
Or 1 is shown). Formula (III)
In, R ⁴ is a hydrogen atom or an acetyl group, and m is 0
Or 1 is shown. As Y, a methylene group is preferable.

[0006] In the above formula (II), n represents an integer of 2 to 6.
As the compound represented by the formula (II), a compound in which n is 4 is preferable. Among the compounds represented by the formula (I), a typical compound is 7-phenyl-7- (3-pyridyl)-
6-heptenoic acid and the like can be mentioned. The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be easily produced by the method described in the above Japanese Patent Publication No. 63-47707. Examples of the pharmaceutically acceptable salt of the compound represented by formula (I) include salts with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, malic acid, citric acid, Salts with organic acids such as succinic acid, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium,
Examples thereof include salts with basic amino acids such as arginine.
These salts can be easily produced by a conventional method, for example, by bringing the compound represented by the formula (I) into contact with an acid or an alkali. The preparation of the present invention containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof has low toxicity to various animals, high safety to humans, and prevention / treatment of TIA. Is effective for. The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may be used in the form of tablets, powders, capsules, fine granules, alone or together with a pharmaceutically acceptable carrier, by a known formulation technique. It can be formulated into a dosage form such as a granule, a sustained release preparation or an injection. The preparation of the present invention is usually administered to mammals including humans (eg, mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, etc.) by means such as oral, subcutaneous, intramuscular or intravenous injection. To be done. Among them, oral administration is preferable. The preparation of the present invention containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof varies depending on the symptoms, administration route and the like, but is, for example, TIA treatment for an adult (body weight 50 to 70 kg). When used for oral administration, it is usually administered in an amount of 20 to 200 mg / kg as a compound (I) or a pharmaceutically acceptable salt thereof per person by oral administration.
The daily dose is preferably 1 to 4 divided doses at a dose of 20 to 150 mg / day. The content of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof in the preparation of the present invention is usually 0.1 to 100% by weight, preferably 1 to 50% by weight of the whole preparation. .

Examples of the carrier which may be contained in the preparation of the present invention include excipients (eg calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, starches (corn starch etc.), crystalline cellulose (microcrystalline cellulose etc.). ), Talc, sucrose, porous substances, etc.), binders (eg dextrin, gums (eg gum arabic etc.), alcoholized starch, gelatin, hydroxypropyl cellulose,
Hydroxypropylmethylcellulose, pullulan, etc.),
Disintegrants (eg carboxymethylcellulose calcium, croscarmellose sodium, crospovidone,
Low-substituted hydroxypropyl cellulose, partially pregelatinized starch, etc., lubricants (eg magnesium stearate, calcium stearate, talc, starch, sodium benzoate etc.), colorants (eg tar pigments, caramel, ferric oxide, oxidation) Titanium, riboflavins etc.), corrigents (eg sweeteners, flavors etc.), stabilizers (eg sodium sulfite etc.) and preservatives (eg parabens, sorbic acid etc.) and the like are used in appropriate amounts as appropriate. Examples of the sustained release agent include fats and oils (eg triglyceride),
By using fatty acid esters such as polyglycerin, hydroxypropyl cellulose and the like, by means known per se,
It can be produced by coating tablets, granules, fine granules, capsules and the like. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion solution, sodium chloride, sodium hydroxide and the like are used. The preparation of the present invention containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is a cerebral circulation and blood flow improving agent, a cerebral metabolism improving agent, a hypertensive therapeutic agent, a diabetic therapeutic agent, an anti-diabetic agent. In addition to cerebral edema agents, thrombolytic agents, lipid metabolism improving agents, radical scavengers, anti-dementia agents, nitric oxide inhibitors, glutamate inhibitors, vascular hypertrophy inhibitors, etc. can be used together or with a time delay. . For example, as a cerebral circulation and blood flow improving agent that can be used in combination with the preparation of the present invention, kalan (trade name) (generic name: vinpocetine), and as a brain metabolism improving agent, avan (trade name) (generic name: idebenone) , As an antihypertensive agent, Adekat (trade name)
(Generic name: delapril hydrochloride), Calslot (trade name)
(Generic name: manidipine hydrochloride) and candesartan cilexetil, basin (trade name) (generic name: voglibose) and sulfonylurea agents as antidiabetic agents,
Glycerol is used as an anti-cerebral edema agent, tissue plasminogen activator and pro-urokinase is used as a thrombolytic agent, and mevalotene (trade name) (generic name: pravastatin) and amotril (trade name) (generic name: chlor) as lipid metabolism improving agents. Examples of fibrates) and radical scavengers include vitamins E and C.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION

EXAMPLES The present invention will now be specifically described with reference to Examples. Example 1

[Table 1] The above ingredients were mixed to give tablets.

Example 2

[Table 2] The tablets produced in Example 1 were coated with the above ingredients to give sugar-coated tablets.

Embodiment 3

[Table 3] The above ingredients were mixed and filled in a gelatin capsule to obtain a capsule.

Embodiment 4

[Table 4] The above components were mixed to give an injection.

Embodiment 5

[Table 5] (100 mg tablet) (E) -7- (3-pyridyl) -7
-Phenyl-6-heptenoic acid 3,500 g, lactose 1,
After mixing 500 g and 910 g of corn starch in a fluidized granulation dryer, an aqueous solution in which 182 g of hydroxypropyl cellulose was dissolved was sprayed and granulated in the fluidized granulation dryer, and then dried in a fluidized granulation dryer. . The obtained granulated product was crushed using a power mill with a 1.5 mmφ punching screen to obtain a sized powder. This sized powder
Take 5,916g and corn starch 1
80.2 g and magnesium stearate 23.8 g were added and mixed with a tumbler mixer to give granules for tableting. The granules weigh 180 on a tablet machine using an 8.0 mmφ punch.
The tablets were tableted with mg to give about 34,000 tablets each containing 100 mg of (E) -7- (3-pyridyl) -7-phenyl-6-heptenoic acid. (50 mg tablet) (E) -7- (3-pyridyl) -7-
Phenyl-6-heptenoic acid 3,500 g, lactose 1,5
00 g and 910 g of corn starch were mixed in a fluidized granulation dryer, and then an aqueous solution in which 182 g of hydroxypropyl cellulose was dissolved was sprayed and granulated in the fluidized granulation dryer, and then dried in the fluidized granulation dryer. . The obtained granulated product was crushed using a power mill with a 1.5 mmφ punching screen to obtain a sized powder. This sized powder is 5,9
Take 16 g, and add corn starch 180.
2 g and magnesium stearate 23.8 g were added and mixed with a tumbler mixer to give granules for tableting. The granules were tabletted in a tableting machine with a 6.5 mmφ punch at a weight of 90 mg to give (E) -7- (3-pyridyl) -7-phenyl-
About 6 tablets containing 50 mg of 6-heptenoic acid per tablet
8,000 tablets were obtained.

Test Example Clinical effect on TIA The outline and results of the protocol of the phase III test on TIA are shown. Clinical trial method: This clinical trial was conducted in accordance with "Standards for Conducting Clinical Trials for Pharmaceutical Products (GCP)". Target patients and their total: TIA of the internal carotid system (NIH diagnostic criteria, 1990, more than once in 3 months before the start of drug administration)
Years (171 for efficacy and usefulness)
First name, safety was 175 people). Test drug and administration method: A tablet containing 50 mg or 100 mg of the test compound obtained in Example 1 was orally administered once a day after breakfast for 1 year and 6 months. The clinical trial was conducted in a double-blind method. Concomitant medications: Ticlopidine, aspirin preparations, heparin, warfarin, ozagrel were not co-administered, and withdrawal was discontinued if they were used before. Observation / evaluation items and implementation period:

[Table 6]

2) CT (or MRI) Examination Before the start of administration and 1 year 3 months to 1 year 6 months after administration, CT (or MRI) examination was performed. In addition, CT
(Or MRI) examination was made to match the examination method before and after administration as much as possible. 3) Cerebral angiography Whenever possible, cerebral angiography was performed before the start of the clinical trial to estimate the responsible blood vessel. 4) Electrocardiographic examination Electrocardiographic examination was performed before the start of administration and 1 year and 6 months after administration. 5) Clinical signs of TIA The presence or absence of TIA seizures and the following items were investigated 3 months before the start of administration and at least every 3 months during the clinical trial. Stroke date Diagnosis: TIA (internal carotid system, vertebral and basilar artery system) Duration Symptoms: sensory deficits (numbness, anesthesia), movement disorders (parts), visual impairment (content), language disorders (aphasia, Situation at the time of seizure: During daytime activities, immediately after waking up, at rest, during sleep, etc. 6) Side effects / complications (occurrence and complications of cerebral, cardiac, and peripheral vascular disorders) When the occurrence of brain, heart and peripheral vascular disorders and their complications were observed, the diagnosis name, symptom, course and treatment were examined. Cerebrovascular disease: Cerebral infarction (degree: mild, moderate or higher) (Note) “Mild” means that the symptoms last for 24 hours or more and within 3 weeks. Cerebral hemorrhage, subarachnoid hemorrhage Heart disease: Myocardial infarction, angina Peripheral and retinal arterial thrombosis disease 7) Clinical examination At the start of administration, 3 months, 6 months, 1 year, 1 year, 6 months later Was inspected. Further, a general blood test and a liver function test were performed 2 weeks, 1 month, 2 months, 9 months, 1 year and 3 months after administration. Physical examination: Blood pressure, pulse rate Blood general examination: Red blood cell count, hemoglobin amount, hematocrit level, white blood cell count, platelet count, leukocyte fraction Blood chemistry test: (liver function test) total protein, GOT, GPT, γ-G
TP, Al-P, LDHCK, total cholesterol, HDL-cholesterol, triglyceride (fasting), BUN, creatinine, fasting blood glucose urinalysis: protein, sugar, urobilinogen, occult blood Abnormal changes during treatment (compared to pre-dose values If it gets worse)
If any were observed, a follow-up study was conducted to determine the causal relationship with the investigational drug.

8) Comprehensive evaluation (1) Efficacy for suppressing TIA recurrence Considering the transition to cerebral infarction, the change in the number of TIA attacks, its symptoms and duration, and comparing it with the condition for 3 months before the start of administration. Then, 6 months after administration, 1 year later and 1 year 6 months later, the following 5 categories were judged. 1. Effective 2. Somewhat effective 3. Invalid 4. Totally invalid (worse) 5. Undecidable (Judgment Criteria) The number of seizures at the time of judgment (during the treatment period) 1 year and 1 year and 6 months after administration was used as a guideline for judging the efficacy. Judgment and discontinuation 6 months after administration (side effect etc.)
For the determination in less than 1 year, the determination period was taken into consideration with reference to the following determination criteria.

[Table 7] (2) Overall safety level The following 5 categories were judged based on the presence or absence of side effects, complications, and abnormal changes in clinical laboratory values and their extent. 1. No problem 2. Some problems 3. There are considerable problems 4. Very problematic 5. Undecidable (3) Usefulness Considering both efficacy for TIA recurrence suppression and general safety, it was classified into 5 categories. 1. Useful 2. Somewhat useful 3. Not useful 4. Not desirable 5. However, it was not judged to be “useful” if the overall safety level was “very problematic” or “very problematic”.

Data analysis: With respect to the above-mentioned evaluation items, the usefulness of comprehensive judgment at the final point of administration (1 year and 6 months after administration) is the main evaluation item, and ITT (intent-to-treat analys
is) was used for analysis. Results: The results of the efficacy, general safety and usefulness of the test compounds are summarized in [Table 8] to [Table 10]. The usefulness of the test compound in the 50 and 100 mg administration groups was 60.0 and 60.5%, respectively (Table 10). Further, the efficacy of 50 and 100 mg of the test compound was 64.7 and 66.3%, respectively (Table 8). Furthermore, the overall safety level of 50 and 100 mg of the test compound is
They were 86.0 and 79.8%, respectively [Table 9]. Thus, it is clear that the test compound is a useful drug for patients with TIA.

[0017]

[Table 8]

[0018]

[Table 9]

[0019]

[Table 10]

[0020]

The preparation of the present invention containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof exhibits an action of suppressing transient cerebral ischemic attack.

Claims (3)

[Claims] (1) Formula (1) [Wherein R ¹ is a pyridyl group, R ² is a lower alkoxy group,
A lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group and / or a phenyl, thienyl, freeyl, naphthyl, benzothienyl or pyridyl group which may be substituted with
³ is a hydrogen atom or a lower alkyl group, Y is a sulfur atom,
Methylene group or formula A transient cerebral ischemic attack inhibitor containing a compound represented by: or a pharmacologically acceptable salt thereof. 2. The formula: [In formula, n shows the integer of 2-6. ] The transient cerebral ischemic attack inhibitor according to claim 1, which comprises a compound represented by the formula or a pharmaceutically acceptable salt thereof. 3. 7-Phenyl-7- (3-pyridyl) -6
-The transient cerebral ischemic attack inhibitor according to claim 1, which comprises heptenoic acid.