• Abstract and Figures
• Public Full-text

Patentamt 0170 933 JEuropaischesEuropean Patent Office Publication number: B1 Office europeen des brevets EUROPEAN PATENT SPECIFICATION C 103/48, A 61 K 31/195 Date of publication of patent specification: 31.08.88 ). Int..ci.4: C 07 Application number: 85108744.5 Date of filing: 12.07.85 Gamma-aminobutyric acid derivatives, process for production thereof, and use thereof as medicaments. Priority: 13.07.84 JP 146553/84 Proprietor: KURARAY CO., LTD. 1621 Sakazu Kurashiki-City Okayama Prefecture (JP) Date of publication of application: 12.02.86 Bulletin 86/07 (72) Inventor: Kameyama, Tsutomu No. domil Nanzan 63, Takigawa-cho Publication of the grant of the patent: 702, 31.08.88 Bulletin 88/35 showa-ku Nagoya-City Aichi Pref. (JP) Inventor: Kitamura, Jiro Designated Contracting States: 1389-2, Sagiyama Nakasu CHDEFRGBITLINL Gifu City Gifu Pref. (JP) Inventor: Takigawa, Tetsuo References cited: 160-4, Bakuro-cho Kurashiki Okayama Pref. (JP) vol. 75, 1,5th July City CHEMICAL ABSTRACTS, no. Inventor: Mizuno, Masao 1746h, Columbus, Ohio, 1971, page 146, no. 335-18, Shimosho J. KITAMURA et al.: "Synthesis of N- US; Kurashiki City Okayama Pref. (JP) mevalonoyl-beta-alanine and its biological activities. V. Pantoic acid replacement activites of mevalonic acid on the growth of CD @ Representative: Kraus, Walter, Dr. et al Acetobacter suboxydans" Patentanwalte Kraus, Weisert & Partner Thomas-Wimmer-Ring 15 CO CHEMICAL ABSTRACTS, vol. 97, no. 1, 5th July D-8000Munchen22(DE) CO 1982, page 564, no. 5821f, Columbus, Ohio, US; o o CHEMICAL ABSTRACTS, vol. 93, no. 9, 1st September 1980, page 71, no. 88941m, Columbus, Ohio, US Note- Within nine months from the publication of the mention of the grant of the European patent, any person may Notice of shall give notice to the European Patent Office of opposition to the European patent granted. opposition deemed have been filed until the opposition fee has been CL be filed in a written reasoned statement. It shall not be to 99(1 ) European convention). 111 paid. (Art. patent Courier Press, Leamington Spa, England. 0 170 933 Description This invention relates to novel 4-aminobutanoic acid derivatives, a process for production thereof, and the use thereof as medicaments, particularly as medicaments for preventing or treating some kind of 5 cerebral dysfunction. It has already been known that gamma-aminobutyric acid (GABA) performs an important function as a chemical transmitter in the brain, and participates in the regulation of metabolism in the brain [G. B. Makara et al., Neuroendocrinology, 16, 178 (1975)]. With an eye on the participation of gamma- aminobutyric acid in the regulation of metabolism in the brain, a great deal of studies on the use of gamma- '0 aminobutyric acid as a medicine has been actively conducted in recent years. Since, however, gamma- aminobutyric acid itself hardly transmigrates through the blood brain barrier and is easily excreted into urine, the prior studies have been directed mainly to the chemical modification of gamma-aminobutyric acid into a form which can easily transmigrate through the blood brain barrier, namely to the discovery of a "prodrug" of gamma-aminobutyric acid which can easily transmigrate through the blood brain barrier. For is example, it has been proposed to use 4-[(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl)amino]butanoic acid (common name, "hoparitenic acid") or its pharmaceutically acceptable salts for the treatment of dementia attributed to head injuries, a surgical operation on the brain, or cerebrovascular impediments (Japanese Laid-Open Patent Publication No. 17329/1980). It has also been reported that intraperitoneal administration of nicotinoyl gamma-aminobutyric acid or isonicotinoyl gamma-aminobutyric acid to mice resulted in a 20 marked prolongation of the sleeping time and an appearance of mild anticonvulsive activity [Summaries of Paper Presented in the 104th Annual Meeting of the Pharmaceutical Society of Japan, page 666 (1984)]. Many compounds have been studied heretofore in order to develop prodrugs for gamma- aminobutyric acid and utilize its metabolism regulating effect in the brain, but except a few such as hopantenic acid or its salts, have proved to be unsatisfactory in regard to toxicity or the ability to 25 transmigrate through the brain barrier, and have not gained practical acceptance. It is an object of this invention to provide novel and useful gamma-aminobutyric acid derivatives, particularly gamma-aminobutyric acid derivatives, which easily transmigrate through the brain barrier and exhibit a useful pharmacological action, such as the activity of improving cerebral. Another object of this invention is to provide a process for producing the aforesaid novel gamma- 30 aminobutyric acid derivatives. Still another object of this invention is to provide an agent for improving cerebral function comprising the aforesaid gamma-aminobutyric acid derivatives as an active ingredient. Other objects and advantages of this invention will become apparent from the following detailed description. 35 According to one aspect of this invention, there are provided 4-[(3,5-dihydroxy-3-methyl-1-oxopentyl)- amino]butanoic acid, represented by the following formula, CH3 0 /*2\ /k s\ /CH2X /CH2X (I) HO CH2 OH CH2 NH CH2 COOH and its pharmaceutically acceptable salts and esters. 45 4-(3,5-Dihydroxy-3-methylpentylamide)butyric acid (to be abbreviated as "MV— GABA" for simplification) includes a DL-, a D-, and an L-form. Examples of suitable pharmaceutically acceptable salts of MV— GABA are alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium, magnesium and barium salts, an ammonium salt, and organic amine salts such as trimethylamine and triethylamine salts. Of these, the calcium salt is preferred. so The pharmaceutically acceptable esters of MV — GABA include those of the type which can be easily split off by the esterase existing in the human body, and specific examples are lower alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl and tert.-butyl esters. The term "lower", as used in the present specification, means that a group or compound qualified by this term has not more than 6, preferably not more than 4, carbon atoms. 55 According to another aspect of this invention, the MV— GABA or its salt or ester is produced by reacting a salt or ester of gamma-aminobutyric acid with tetrahydro-4-hydroxy-4-methyl-2H-pyran-2-one, and as required, converting the product in the form of a salt or ester to its free acid, i.e., MV— GABA, or as required, converting MV— GABA in the form of a free acid to its pharmaceutically acceptable salt or ester. - The reaction of the salt or ester of gamma-aminobutyric acid with beta-hydroxy-beta-methyl-delta- 60 valerolactone can be carried out usually in a suitable solvent at a temperature between about -30°C and about 100°C, preferably between room temperature and about 80°C. This reaction gives a salt or ester of MV — GABA. Examples of the solvent that can be used in this reaction are water, lower alkanols such as methanol, ethanol and isopropanol, ethylene glycol, 2-methoxyethanol, and 2-ethoxyethanol, and mixtures thereof. Water, ethanol, 2-methoxyethanol, 2-ethoxyethanol and mixtures thereof are advantageously 65 used. 0 170 933 The proportion of beta-hydroxy-beta-methyl-delta-valerolactone is not critical and can be varied within a wide range. For example, it is suitably used in a proportion of generally 0.5 to 5 moles, preferably 0.8 to 2 moles, per mole of the salt or ester of gamma-aminobutyric acid. More preferably, the salt or ester of gamma-aminobutyric acid and beta-hydroxy-beta-methyl-delta-valerolactone are used in a mole ratio of 5 1:1 and the reaction is carried out until it is fully completed, because this eases the purification of the product after the reaction. The salt of gamma-aminobutyric acid that can be used as a starting material in the above reaction includes, for example, alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium, magnesium and barium salts; an ammonium salt; and organic amine salts such as trimethyl- w amine and triethylamine salts. The esters of gamma-aminobutyric acid include lower alkyi esters such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl esters. It is particularly convenient to use calcium gamma-aminobutyrate as the starting material and react it with beta-hydroxy-beta-methyl-delta- valerolactone. As required, a salt or an ester of MV— GABA obtained by the above reaction can be converted to its free. is acid, i.e. MV— GABA by the methods known per se, for example, by treatment with a strong acid-type cation exchange resin or by hydrolysis respectively. The free acid may be further converted to a pharmaceutically acceptable salt or ester. The MV— GABA and its pharmaceutically acceptable salts or esters provided by this invention easily transmigrate through the blood brain barrier, and have marked effects on the regulation of metabolism in 20 the brain. The following animal experiments demonstrate that, for example, these compounds provided by this invention show an action of markedly decreasing locomotor activity, an antagonistic effect against the increase of motor activity induced by (S)-N,a-dimethylbenzeneethanamine, an action of markedly prolonging the time of sleeping induced by 5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione, an action of markedly inhibiting the increase of motor activity induced by 8-methyl-8-azabicyclo[3.2.1]oct-3-yl 25 a-(hydroxymethyl)benzeneacetate, and an effect of significantly improving the memories of a 4-[2-(3,5-di- methyl-2-oxocyclohexyl)-2-hydroxyethyl]-2,6-piperidinedione-induced amnesia model and an electric convulsive shock-induced amnesia model. The following pharmacological tests were conducted in order to demonstrate that the compounds provided by this invention have excellent pharmacological characteristics.

Load more

  14

Copy Link