EP0810862A2

EP0810862A2 - Use of vinyl carboxylic acid compounds for the treatment or prevention of transient ischaemic attacks

Info

Publication number: EP0810862A2
Application number: EP96903205A
Authority: EP
Inventors: Zen-Ichi Terashita; Kaneyoshi Kato; Takenobu Sohma
Original assignee: Takeda Chemical Industries Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 1995-02-22
Filing date: 1996-02-21
Publication date: 1997-12-10
Also published as: AU4730996A; CA2213507A1; WO1996025933A2; WO1996025933A3

Abstract

A pharmaceutical composition for treating a transient ischemic attack which comprises a compound of formula (I), wherein R1 is a pyridyl group, R2 is a phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl group, which may be substituted with a lower alkoxy group, a lower alkyl group, a halogen atom, trifluoromethyl group, a lower alkenyl group or/and methylenedioxy group, R3 is hydrogen atom or a lower alkyl group, and l is an integer of 0 to 6, Y is sulfur atom, methylene group or a group of formula (a), wherein R4 is hydrogen atom or acetyl group, and m is 0 or 1, or a pharmaceutically acceptable salt.

Description

DESCRIPTION

USE OF VINYL CARBOXYLIC ACID COMPOUNDS FOR THE TREATMENT OR PREVENTION OF TRANSIENT ISCHAEMIC ATTACKS

Technical Field

The present invention relates to a pharmaceutical composition for treating or preventing a transient ischemic attack exhibiting therapeutic and prophylactic activities against transient ischemic attack (TIA).

10

Background Art

TIA, a symptom that precedes cerebral stroke and disappears in short time, is positioned as a prodromal or alerting attack in ischemic cerebral disease. It is

-_e generally held that there is a high risk of gradual conversion of TIA to a severe cerebrovascular disorder, such as cerebral infarction, and that the onset and recurrence of severe cerebral disorder can be treated by treating TIA.

2 By NIH (National Institute of Health) Diagnostic Criteria for TIA Patients the Classification of Cerebrovascular Diseases, III, Stroke, Vol. 21:653-654, 1990), TIA is an attack characterized by short-term onset of local cerebral dysfunction attributable to ischemia. It

₂₅ is normally confined to a single vascular system (left or right common carotid arterial system, or vertebral vasilar system), involving no other causes. It is common practice to define TIA as an attack that lasts for no longer than 24 hours. The longer the attack, the more often cerebral

₃₀ infarction lesions are detected in computed tomography (CT) or magnetic resonance imaging (MRI). TIA normally lasts for 2 to 15 minutes, its onset being drastic (syndrome reaching peak within 5 minutes, mostly within 2 minutes). Very short attacks, that last for no longer than several

._jc seconds, are not viewed as TIA. Although TIA does not leave permanent nerve lesions, there are often relapses. As well, there are atypical cases to which the above definition does not apply.

By the "Diagnostic Criteria for Cerebrovascular Disorders—Classification by Pathologic Form and Severity" (Kameya a et al., Naika, 55(6):1306, 1985), TIA associated with the internal carotid arterial system is characterized by one or more symptoms of motor disorder, loss of vision, sensory disturbance and aphasia. Symptoms of TIA associated with the vertebral vasilar system also include nerve symptoms such as motor disorder, eye symptoms and vertigo, which develop singly or in combination.

On the other hand, EP-B-98690 describes that the compound of the formula (I) below and salts thereof possess thromboxane synthetase-inhibiting activity.

Disclosure of Invention

With regard to the mechanism of TIA onset, cerebral vasospasm, microembolization, cerebrovascular failure and other factors have been proposed as causative, the latter two being viewed as likely. To prevent and treat TIA, anticoagulation, antiplatelet and other therapies have been attempted, with some effect. Drugs used in such therapies include aspirin and ticlopidine; however, there is demand for a more effective drug that is clinically tolerable, with less severe adverse effects, in chronic administra¬ tion.

The present inventors sought a compound that treats TIA, and clinically confirmed, for the first time, that a compound known as a thromboxane synthetase inhibitor is effective against TIA. The inventors investigated further based on this finding, and developed the present invention.

The present invention relates to (1) a pharmaceutical composition for treating a transient ischemic attack (TIA) which comprises a compound of the formula:

wherein Ri is a pyridyl group, R² is a phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl group, which may be substituted with a lower alkoxy group, a lower alkyl group, a halogen atom, trifluoromethyl group, a lower alkenyl group or/and methylenedioxy group, R3 is hydrogen atom or a lower alkyl group, and is an integer of 0 to 6, Y is sulfur atom, methylene group or a group of the formula:

wherein R* is hydrogen atom or acetyl group, and m is 0 or 1, or a pharmaceutically acceptable salt,

(2) a pharmaceutical composition as defined in (1) above, which comprises a compound of the formula:

wherein n is an integer of 2 to 6, or a pharmaceutically acceptable salt, and

(3) a pharmaceutical composition as defined in (1) above, wherein the compound is 7-phenyl-7-(3-pyridyl)-6-heptenic acid.

In the above formula (I), R¹ represents a pyridyl group, and R² represents a phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl group, which may be substituted with a lower alkoxy group, a lower alkyl group, a halogen atom, trifluoromethyl group, a lower alkenyl group or/and methylenedioxy group.

In the above formula (I), the pyridyl group of R¹ or R² is exemplified by 2-pyridyl, 3-pyridyl and 4-pyridyl, and, the thienyl, furyl, naphthyl and benzothienyl are exemplified by 2-thienyl and 3-thienyl; 2-furyl and 3- furyl; α-naphthyl and /3-naphthyl; 2-benzothienyl, 3- benzothienyl, 4-benzothienyl, 5-benzothienyl, 6- benzothienyl and 7-benzothienyl.

As the substituents of said phenyl, furyl, thienyl, naphtyl, benzothienyl and pyridyl of R² which may be substituted, mention is made of lower alkoxy groups (Cι_₄ alkoxy groups such as methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, i-butoxy, t-butoxy, etc.), lower alkyl c groups (C₁-₅ alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i- pentyl, etc.), halogen atoms (fluorine, chlorine, bromine, iodine, etc.) and lower alkenyl groups (C₂-₅ alkenyl groups such as vinyl, allyl, pentenyl, etc.). The phenyl, _Q thienyl, furyl, naphthyl, benzothienyl or pyridyl of R² optionally has 1 to 5 of these substituents at any substituable positions of the ring. Preferable example of Ri includes 3-pyridyl. Preferable example of R² includes phenyl. 5 In the above formula (I), R3 represents hydrogen atom or a lower alkyl group. As the lower alkyl of R3 in the above formula (I), mention is made of C₁- alkyl groups of such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, s-butyl, t-butyl, etc. Preferable example of R³ 0 includes hydrogen atom.

In the above formula (II), Y represents sulfur atom, methylene group or a group of the formula:

5 wherein R* is hydrogen atom or acetyl group, and m is 0 or 1. In the above formula (III), R4 represents hydrogen atom or acetyl group, and m represents 0 or 1. Preferable example of Y includes methylene group.

In the above formula (I), £ represents an integer 0 to

10 6. Preferable examples of e include an integer of 0 to 4, 2 is more preferably.

Preferable examples of the compound of the formula (I) include a compound, wherein Ri is 3-pyridyl, R² is phenyl, R3 is hydrogen atom, Y is methylene group and € is an

!5 integer of 0 to 4, namely a compound of the formula (II). In the above formula (II), n represents an integer 2 to 6. Preferable example of the compound of the formula (II) include a compound, wherein n is 4. Example of a representative compound represented by the formula (I) and

²⁰ (II) above includes 7-phenyl-7-(3-pyridyl)-6-heptenic acid. A compound of the formula (I) above or a pharmacologically acceptable salt thereof can easily be produced by the method described in the above-mentioned patent publication (EP-B-98690) .

²⁵ The pharmacologically acceptable salt of a compound of the formula (I) is exemplified by salts with mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, malic acid, citric acid and

30 succinic acid, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and salts with basic amino acids such as arginine. These salts can easily be produced by bringing a compound of the formula (I) into contact with acid or

³⁵ alkali. The present composition comprising a compound of the formula (I) or a pharmacologically acceptable salt thereof has not significantly toxic to various animal species and very safe to humans. Therefore, the present composition is useful for treating or preventing TIA.

A compound of the formula (I) or a pharmacologically acceptable salt thereof can be prepared as it is or together with pharmaceutically acceptable carriers and/or additives into preparations in dosage form such as tablets,

10 powders, capsules, granules, fine granules, sustained- release preparations or injectable preparations, by known pharmaceutical production techniques, and is normally administered to mammals (e.g. mouse, rat, hamster, rabbit, cat, dog, caw, horse, sheep and monkey), including humans, -_c by oral, subcutaneous, intramuscular, intravenous or other methods. Oral administration is preferred. The present composition comprising a compound of the formula (I) or a pharmacologically acceptable salt thereof is administered normally at 20-200 mg/day, preferably 20-150 mg/day as a 2_Q compound of the formula (I) or a pharmacologically acceptable salt thereof per adult (weighting 50-70 kg) for oral administration, dividing 1 to 4 times, for treating TIA, depending on symptoms, route of administration etc. The content of a compound of the formula (I) or a _2c pharmacologically salt thereof in the pharmaceutical preparation of the present invention ranges usually from 0.1 to 100 weight %, preferably from 1 to 50 weight %, relative to the whole weight of the pharmaceutical preparation. ₃₀ The carriers which the present pharmaceutical preparations include adequately is selected from excipients (e.g. calcium carbonate, kaolin, sodium hydrogencarbonate, lactose, starch (e.g. corn starch), crystalline cellulose (e.g. microcrystallized cellulose), talc, saccharose and _3ς porous substance), binders (e.g. dextrin, gum (e.g. arabic gum), alcoholated starch, gelatin, hydroxypropyl cellulose. hydroxypropyl methyl cellulose and pullulane), disintegrants (e.g. carboxymethyl cellulose calcium, closcarmellose sodium, clospovidone, low-substituted hydroxypropyl cellulose and partial o-starch), lubricants (e.g. magnesium stearate, calcium stearate, talc, starch and sodium benzoate), colorants (e.g. tar pigment, caramel, iron sesquioxide, titanium oxide and riboflavins) , flavoring agents (e.g. sweeteners and perfume), stabilizers (e.g. sodium sulfite) and preservatives (e.g. parabens and

10 sorbic acid) in adequate amounts respectively. The sustained-release preparations can be produced by coating tablets, granules, fine granules or capsules with, for examples, oil and fat (e.g. triglyceride), ester of fatty acid of polyglycerine or hydroxypropyl cellulose, by per se

,5 known means. As the carriers for injectable preparations, use is made of, for examples, distilled water, physiological saline solution, glucose solution, an agent of infusion, sodium chloride and sodium hydroxide.

The present composition comprising a compound of the

2_Q formula (I) or a pharmacologically acceptable salt thereof can be used, at the same time or at intervals, in combination with antidementic agents, nitrogen monoxide inhibitors, glutamate inhibitors, vascular hypertrophy inhibitors etc., as well as with cerebral circulation and

25 blood flow-improving agents, cerebral metabolism-improving agents, hypertension remedies, diabetes mellitus remedies, anti-cerebral edema agents, thrombolytic agents, lipid metabolism-improving agents and radical scavengers.

In the combination with the present composition,

-._Q cerebral circulation and blood flow-improving agents include Calan (trade name) (common name: vinpocetine) ; cerebral metabolism-improving agents including Avan (trade name) (common name: idebenone); hypertension remedies including Adecut (trade name) (common name: delapril

35 hydrochloride) , Calslot (trade name) (common name: manidipine hydrochloride) and Candesartan cilexetil; diabetes mellitus remedies including Basen (trade name) (common name: Voglibose) and sulfonyl urea agent; anti- cerebral edema agents including glycerol; thrombolytic agents including tissue plasminogen activator and prourokinase; lipid metabolism-improving agents including Mevalotin (trade name) (common name: pravastatin sodium) and Amotril (trade name) (common name: clofibrate); and radical scavengers including vitamins E and C.

Best Mode for Carrying out the Invention Working Example

The present invention is hereinafter described in more detail by means of the following example. Example 1

(Tablet)

100 mg

Ingredient 50 mg Tablet Tablet

(E)-7-(3-pyridyl)-7-pheny1-6- heptenic acid (test compound) 50.0 100.0

Lactose 21.4 42.8

Corn starch 15.65 31.3

Hydroxypropyl cellulose 2.6 5.2

Magnesium stearate 0.35 0.7

Total 1100.0 mg 180.0 mg

The above components were mixed to give tablet. Example 2

(Sugar coated tablet)

Ingredient the above lOOmg Tablet 180.0

Talc 30.0

Gum arabi 6.0

Saccharose 74.0

Total 290.0 mg

The tablet obtained in Example 1 was coated to give sugar coated tablet.

Example 3

(Capsule)

Ingredient

(E)-7-(3-pyridyl)-7-phenyl-6- heptenic acid 10.0

Crystallite cellulose 30.0

Loctose 57.0

Magnesium stearate 3.0

Total 100.0 mg

The above components were mixed and the gelatine capsule was filled to capsule. Example 4

(Injectable preparation)

The above components were mixed to give injectable preparation.

Test

Clinical effect on TIA

The protocol outline of, and the results from, the phase III clinical study of TIA are shown below.

Study design

This study was conducted in accordance with Good Clinical Practice (GCP).

Subjects and total number: The subjects of this study were patients who developed one or more TIA attacks associated with the internal carotid arterial system (NIH Diagnostic Criteria, 1990) during the 3-month period before initial administration (171 for efficacy and utility, 175 for safety) .

Investigational drug and method of administration: Tablets each containing 50 mg or 100 mg of the subject compound obtained in Example 1 were orally administered after breakfast once daily for 18 months. The study was conducted in double blind fashion. Contraindicated concomitant drugs: Concomitant use of ticlopidine, aspirin preparations, heparin, warfarin and ozagrel was prohibited. If in use, they were discontinued.

Items of observation and assessment, and time schedule:

Notes 2) CT (or MRI) examination

CT (or MRI) was conducted before initial administration and at 15 months to 18 months of administration. CT (or MRI) examination was 5 conducted before and after administration, in as similar a fashion as possible.

3) Cerebral angiography

Whenever possible, cerebral angiography was performed to assess the affected blood vessel ^_Q before study initiation.

4) ECG

ECG was performed before initial administration and at 18 months of administration.

5) Clinical signs of TIA

T_C TIA onset and the following items were examined at least every 3 months during the 3 months before initial administration and during the administration period. φ Date of onset 2_Q ® Diagnosis: TIA (internal carotid arterial system, vertebral vasilar system), @ Duration @ Syndromes: Sensory disturbance (numbness, anesthesia), motor disorder (site), 25 vision disorder (description), speech disorder (aphagia, alalia), others © Condition: Diurnal activity, just after at attack wakening, at rest, at sleep, others

30

6) Side effects, complications (cerebral, cardiac, peripheral vascular disorder onset and complications)

If any of the following cerebral, cardiac and 35 peripheral vascular disorders occurs (including complications) during the study period, its diagnosis, syndrome, course of disease, treatment etc. were recorded. φ Cerebral vascular: Cerebral infarction disorder (severity: mild, moderate and higher)

Note: "Mild" was defined as a state of disease in which the syndrome lasts for not less than 24 hours and not more than 3 weeks. Cerebral hemorrhage, subarachnoid hemorrhage

The following parameters were tested at initial administration and 3 months, 6 months, 1 year and 18 months of administration.

Hematology and liver function also were tested at 2 weeks, 1 month, 2 months, 9 months and 15 months of administration.

Physical : Blood pressure, pulse rate examination

Hematology : Red blood cell count, hemoglobin content, hematocrit value, white blood cell count, platelet count, differential white blood cell count Blood bio- : (Liver function) chemistry Total protein, GOT, GPT, y-GTP, Al-P, LDH CK, total cholesterol, HDL-choles- terol, triglyceride (at hunger), BUN, creatinine, fasted blood glucose ϋrinalysis : Protein, sugar, urobilinogen, occult blood If an abnormal change (worsened from pre- administration value) is noted during the thera¬ peutic period, follow-up survey was performed to determine relation to the test drug. 8) Overall assessment

(1) Efficacy in suppressing TIA recurrence As regards conversion to cerebral infarction, temporal changes in TIA onset frequency, TIA symptoms and duration, etc., efficacy was rated at 0 6 months, 1 year and 18 months of administration, using a 5-grade rating system:

1. Effective

2. Slightly effective

3. Ineffective 5 4. Worsened

5. Indeterminable (Judgment criteria)

The attack frequency at time of rating (during therapeutic period) 1 year and 18 months after 0 initial administration served as an efficacy rating index. For rating at 6 months of adminis¬ tration and rating at less than 1 year due to discontinuation (adverse reactions etc.), rating was in regard to duration of administration

₂_ period, with reference to the following rating criteria.

Table 6 Rating Criteria for Efficacy in Suppressing TIA Recurrence (at 1 year and 18 months of __n administration)

35 Number of At¬ Number of Attacks during the Study Period tacks during 3 Months before Administration 0 1 2 3 or More

Effective

1 or Ineffec¬ Ineffective or slightly tive worsened effective

2 Effective Slightly Ineffective or effective worsened

Slightly Ineffec¬

3 Effective Effective effective tive or worsened

4 or more Effective Effective Effective *)

Duration of administration period was considered when rating at 6 months of administration and at less than 1 year due to discontinuation (adverse reactions etc.). Note 1) If a cerebral infarction attack is noted during the study period, the rating shall be "worsened." If myocardial infarction or peripheral and retinal arterial thrombotic disease is noted, the rating shall be "ineffective" or "worsened,". Note 2) If administration is discontinued due to onset of TIA attack during the study period, the rating shall be "ineffective." *) Not more than 50% of the number of pre-adminis- tration attacks: Effective

75-50% of the number of pre-administration attacks: Slightly effective

More than 75% of the number of pre-administration attacks: Ineffective or worsened

(2) Overall safety

Overall safety was rated on the basis of adverse reactions, complications, and presence or absence of abnormal changes in clinical laboratory parameters and their degrees, using a 5-grade rating system:

1. No problem

2. Slightly problematic

3. Considerably problematic

4. Very problematic

5. Indeterminable (3) Utility

On the basis of efficacy and overall safety ratings for suppression of TIA recurrence, utility was rated using a 5-grade rating system:

1. Useful

2. Slightly useful

3. Not useful

4. Undesirable

5. Indeterminable

However, if the overall safety rating was "considerably problematic" or "very problematic," the utility rating "useful."

Data analysis

With regard to the above rating items, data were analyzed using ITT (intent-to-treat analysis), with the utility rating in overall assessment at final administration (18 months after administration) as the major item. Results

The results of efficacy, overall safety and utility ratings of the test compound are shown in Tables 7 through ⁹'

The utility rates of the test compound in the 50 mg and 100 mg dose groups were 60.0 and 60.5%, respectively

(Table 9). The efficacy rates of the test compound at 50 mg and 100 mg were 64.7 and 66.3%, respectively (Table 7). The overall safety rates of the test compound at 50 and 100 mg were 86.0 and 79.8%, respectively (Table 8). In conclusion, the test compound is a useful drug for TIA patients.

Table 7 Efficacy (%)

Drug Effec¬ Slightly ¬ Number Effec¬ Inef¬ Inde (dose/day) tive termi¬ of tive fective Worsened nable Patients

Test compound 64.7 2.3 16.5 5.9 10.6 85 (50 mg)

Test compound 66.3 7.0 8.1 7.0 11.6 86 (100 mg)

Table 8 Overall Safety (%)

Consid¬

Drug Mo Slightly erably Very Inde¬ Number (dose/day) Problem Prob¬ termi¬ of lematic Prob¬ Prob¬ lematic lematic nable Patients

Test compound 86.0 8.1 1.2 0 4.7 86 (50 mg)

Test compound 79.8 13.5 1.1 2.2 3.4 89 (100 mg)

Table 9 Utility (%)

Number

Drug Useful Slightly Not Unde¬ Inde¬ (dose/day) Useful Useful sirable termi¬ of nable Patients

Test compound 60.0 5.9 23.5 5.9 4.7 85 (50 mg)

Test compound 60.5 10.5 16.3 9.3 3.5 86 (100 mg) Industrial Applicability

A compound of the formula (I) or a pharmacologically acceptable salt thereof treats or prevents transient ischemic attack.

Claims

1. A pharmaceutical composition for treating a transient ischemic attack which comprises a compound of the formula:

wherein R¹ is a pyridyl group, R² is a phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl group, which may be substituted with a lower alkoxy group, a lower alkyl group, a halogen atom, trifluoromethyl group, a lower alkenyl group or/and methylenedioxy group, R3 is hydrogen atom or a lower alkyl group, and £ is an integer of 0 to 6, Y is sulfur atom, methylene group or a group of the formula:

wherein R* is hydrogen atom or acetyl group, and m is 0 or

1, or a pharmaceutically acceptable salt.

2. A pharmaceutical composition according to claim 1, which comprises a compound of the formula:

wherein n is an integer of 2 to 6, or a pharmaceutically acceptable salt.

3. A pharmaceutical composition according to claim 1, wherein the compound is 7-phenyl-7-(3-pyridyl)-6-heptenic acid.

4. A method of treating a transient ischemic attack in a mammal which comprises administering to the mammal an effective amount of a compound of the formula:

wherein Ri is a pyridyl group, R2 is a phenyl, thienyl, furyl, naphthyl, benzothienyl or pyridyl group, which may

10 be substituted with a lower alkoxy group, a lower alkyl group, a halogen atom, trifluoromethyl group, a lower alkenyl group or/and methylenedioxy group, R3 is hydrogen atom or a lower alkyl group, and t is an integer of 0 to 6, Y is sulfur atom, methylene group or a group of the ^ formula:

20 wherein * is hydrogen atom or acetyl group, and m is 0 or

1, or a pharmaceutically acceptable salt.

5. Use of a compound of the formula:

30 be substituted with a lower alkoxy group, a lower alkyl group, a halogen atom, trifluoromethyl group, a lower alkenyl group or/and methylenedioxy group, R³ is hydrogen atom or a lower alkyl group, and i is an integer of 0 to 6, Y is sulfur atom, methylene group or a group of the ^ formula: wherein R* is hydrogen atom or acetyl group, and m is 0 or 1, or a pharmaceutically acceptable salt, for preparing a pharmaceutical composition for treating a transient ischemic attack.