GB2135300A - 4-Aminobutyric acid derivatives and processes for the preparation thereof - Google Patents
4-Aminobutyric acid derivatives and processes for the preparation thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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Abstract
4-Aminobutyric acid derivatives of the formula: <IMAGE> wherein R<1> is a cycloalkyl group having 3 to 7 carbon atoms which may be substituted by an alkyl group having 1 to 3 carbon atoms and R<2> is hydrogen atom or benzyl group, or a pharmaceutically acceptable salt thereof, are useful for the amelioration of cerebral metabolism and higher brain function disorder.
Description
SPECIFICATION 4-Aminobutyric acid derivatives and process for the preparation thereof
The present invention relates to novel 4-aminobutyric acid derivatives and to processes for the preparation thereof. More particularly, it relates to 4-aminobutyric acid derivatives of the formula:
wherein R' is a cycloalkyl group having 3 to 7 carbon atoms which may be substituted by an alkyl group having 1 to 3 carbon atoms and R2 is a hydrogen atom or benzyl group, and to processes for the preparation thereof.
It is known that calcium hopanthenate [chemical name: calcium D-( + )-(2,4-dihydroxy-3,3dimethylbutyramido)butyrate] relieves various symptoms such as for example, hyperactivity, short attention span, speech disorder or hypobulia which accompany with for example mild mental retardation, postencephalitic syndrome or cerebral palsy, and hence is useful as a remedy for the amelioration of cerebral metabolism and higher brain function disorder.
Based on the knowledge that when calcium hopanthenate is administered orally, it is present in vivo (e.g. in blood plasma and brain) in the form of free hopanthenic acid, we have investigated various analogous compounds. As a result, it has been found that the novel compounds of the above formula (I) when administered orally are well absorbed and show higher level of bioavailability or longer duration of action in blood and brain as compared with calcium hopenthenate. Hence, they can be useful as a medicine for amelioration of cerebral metabolism and higher brain function disorder.
Examples of compounds of the invention are the compounds of formula (I) wherein R' is a cycloalkyl group having 3 to 7 carbon atoms which may be substituted by a low alkyl group, e.g. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or 1-methylcyclohexyl and R2 is a hydrogen atom or a benzyl group. Preferred examples are the compounds of the formula (I) wherein R1 is a cyclopentyl or cyclohexyl group and R2 is a hydrogen atom. A particularly preferred compound is D-4-[N-(4-cyclohexylcarbonyloxy-3, 3-dimethyl-2-hydroxy-n-butyryl)ami- no]-n-butyric acid, which can advantageously be obtained in the crystalline form.
According to the present invention, the compounds of formula (I) can be prepared for example by reacting a 4-aminobutyric acid derivative of the formula:
wherein R2 is the same as defined above, with a reactive derivative of a carboxylic acid of the formula: R'COOH (III) wherein R1 is the same as defined above.
Alternatively, the compounds of formula (I) in which R2 is hydrogen may be prepared for example by subjecting a 4-aminobutyric acid ester derivative of the formula:
wherein R' us the same as defined above, to catalytic hydrogenation.
The processes of the present invention are explained in more detail below.
The reaction of the compound of formula (II) and a reactive derivative of the compound of formula (lli) can be carried out in a appropriate solvent in the presence or absence of a base.
When the compound of formula (II) in which R2 is hydrogen is employed, said compound may be used in the form of a salt thereof such as for example the calcium salt. Suitable examples of the reactive derivative of the compound of formula (III) are an acid halide or acid anhydride. The base may be, for example, an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate) or an organic tertiary amine (e.g.
triethylamine, pyridine, dimethylaniline, p-dimethylaminopyridine). The solvent may be, for example, tetrahydrofuran, dioxane, chloroform, methylene chloride, benzene, ethyl acetate, dimethylformamide, diethyl ether or water which may be used alone or in adminxture. The above reaction is usually carried out at a temperature of - 1 5 to 50"C, preferably 0 to 20"C.
The catalytic hydrogenation of the compound (I-a) can be carried out in an appropriate solvent in the presence of a catalyst while introducing hydrogen gas into the reaction system. The catalyst may be, for example, palladium black or palladium-carbon. The solvent may be, for example, a lower alkanol (e.g. methanol, ethanol, n-propanol, isopropanol), tetrahydrofuran, dioxane, or a mixture of any of these solvents with water. The above reaction is usually carried out at a temperature of O to 60"C under 1 to 10 atm., preferably at a temperature of 10 to 30"C under 1 to 3 atm.
The starting compound of formula (II) in which R2 is benzyl can be obtained readily, for example, by reacting a metal salt or an organic amine salt of 4-[N-(2,4-dihydrnxy-3,3-dimethyl n-butyryl)-amino]-n-butyric acid with a benzyl halide, or by reacting a benzyl 4-amino-n-butyrate with a y-lactone of 2,4-dihydroxy-3,3-dimethyl-n-butyric acid.
The compounds of formula (I) of the present invention contain one asymmetric carbon within the molecule and hence include two optical isomers. The present invention includes also these isomers. Among these isomers, the compounds wherein the asymmetric carbon has the Dconfiguration are particular preferable for medical use.
Where R2 in the resultant compounds of formula (I) is hydrogen they can be used as a medicine not only in the form of a free carboxylic acid but also in the form of a pharmaceutically acceptable salt thereof. Suitable examples of the salt are the calcium salt, sodium salt, potassium salt, lithium salt, magnesium salt, lysine salt, ornithine salt and the arginine salt.
The compounds of formula (I) or pharmaceutically acceptable salts thereof are preferably administered by the oral route (but may also be administered by the parenteral route) in a conventional preparation, for example, solid preparations e.g. tablets, pills, powders, capsules, or granules, and liquid preparations e.g. solutions, suspensions, or emulsions. Such preparations can be prepared in a conventional manner, for example, by admixing a compound of the formula (I), or a pharmaceutically acceptable salt thereof, with a conventional carrier or diluent, e.g. calcium carbonate, calcium phosphate, corn starch, potato starch, lactose, talc, or magnesium stearate.
Dose of the compounds of formula (I) or pharmaceutically acceptable salts thereof may vary in accordance with the kind of disease to be treated, the age and weight of the patients, the severity of the disease and the method of administration, but it usually in the range of 1 to 20 mg/kg/day, preferably 2 to 10 mg/kg/day, for oral administration.
When the compounds of formula (I) or pharmaceutically acceptable salts thereof are administered, they show a high level of blood and brain, which were confirmed by the following experiments in vivo.
Experiment 1
SD-male rats, weighing about 200 g 7 weeks old, having been fasted overnight (one group: 4 rats) were used. To each rat was orally administered a suspension (2 ml) of a test compound in a 0.5% carboxymethyl cellulose solution with a stomach sonde (dose of test compound: 389.4 IL mole/kg, corresponding to 100 mg.kg of calcium hopanthenate). One, two or three hours after the aministration, the rats were killed by cutting whole carotid arteries, and the blood was collected. The blood of each rat was centrifuged (2,800 r.p.m., 1 5 minutes) to separate blood plasma. Concentration of hopanthenic acid in the blood plasma (0.1 ml) was measured by gas chromatography and mass spectrometry. The results are shown in Table 1.
Table 1
Compound Level of hopanthenic acid in the blood plasma (Ibg/ml) (average + S.D.)
One hour after the Two hours after the Three hours after the
administration administration administration
A 31.7 + 8.3 13.7j1.5 9.0j1.7 Control 19.9 i 2.8 10.3 i 2.1 5.0 * 3.3 [Remarks]:
Compound A: D-4-[N-(4-Cyclohexylcarbonyloxy-3, 3-dimethyl-2-hydroxy-n-butyry- I)amino]-n-butyric acid
Calcium D-4-[N-(2,4-dihydroxy-3, 3-dimethyl-n-butyryl)amino]-n-bu Control: tyrate
Experiment 2
SD-male rats, weighing about 200 g, 7 weeks old, having been fasted overnight (one group: 5 rats) were used.To each rat was orally administered a suspension (2 ml) of a test compound in a 0.5% carboxymethyl cellulose solution with a stomach sonde (dose of test compound: 389.4 jbmole/kg, corresponding to 100 mg/kg of calcium hopanthenate). Two or three hours after the administration, the cerebrum was taken out and washed with physiological saline solution. To the cerebrum was added 9 times its volume of water, and the mixture was homogenated with a homogenizer for one minute under ice-cooling and then centrifuged at 10,000 r.p.m. at 4"C for one hour. Concentration of hopanthenic acid in the supernatant layer (1 ml, corresponding to 0.1 9 of the cerebrum) was measured by gas chromatography and mass spectrometry. The results are shown in Table 2. The test compounds were the same as used in
Experiment 1.
Table 2
Compound Level of hopanthenic acid in the cerebrum (g/g) (average + S.D.)
Two hours after the Three hours after the
administration administration
A 1.12+0.14 0.66+0.12 Control 0.59j0.04 0.28 + 0.11 As is clear from the above experimental results, when administered orally to rats in a dose of 389.4 y mole/ kg, D-4-[N-(4-Cyclohexylcarbonyloxy-3, 3-dimethyl-2-hydroxy-n-butyryl]-n-butyric acid showed a blood plasma level of hopanthenic acid about 1.3 to 1.8 times higher than the level when calcium hopanthenate is administered, and also showed a cerebrum level of hopanthenic acid about 1.9 to 2.4 times higher than the level when calcium hopanthenate is administered.
Moreover, the compounds of formula (I) of the present invention have low toxicity and hence have high safety. For instance, D-4-[N-(4-cyclohexylcarbonyloxy-3, 3-dimethyl-2-hydroxy-n-buty- ryl)amino]-n-butyric acid showed a maximum tolerance of above 1 ,000 mg/kg in mice (said maximum tolerance was measured by administering the test compound to mice and observing death of mice 48 hours after the administration; the maximum tolerance meaning the dose just smaller than the dose including the death of the mice).
Thus, the compounds of the present invention are converted into hopanthetic acid in vivo when administered and show higher level of hopanthenic acid in blood and brain in comparison with calcium hopanthenate with high safety, and hence, are useful as a medicine for the amelioration of cerebral metabolism and higher brain function disorder.
The present invention is illustrated by the following Examples but should not be construed to be limited thereto.
Example 1
Benzyl D-4-[N-2,4-dihydroxy-3, 3-dimethyl-n-butyryl)amino]-n-butyrate (4 g) is dissolved in tetrahydrofuran (30 ml), and thereto is added pyridine (2 ml). To the mixture is added dropwise with stirring a solution of cyclopentylcarbonyl chloride (2.0 9) in tetrahydrofuran (5 ml) under ice-cooling. The mixture is stirred at room temperature overnight and concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, and the solution is washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and saturated saline solution in that order. The ethyl acetate solution is dried and concentrated under reduced pressure to remove the solvent.The residue is purified by silica gel chromatography (solvent; chloroform: ethyl acetate = 4:1) to give benzyl D-4-[N-(4-cyclopentylcarbonyloxy-3,3-dimethyl-2- hydroxy-n-butyryl)amino]-n-butyrate (2.7 g, 52.0%) as a colorless crystals. M.p. 43-45 C, IR VnUaiol (cm-'): 3350, 3250, 1720, 1640, Mass (m/e): 419 (M +), [a12,5 + 26.1 (e = 1, ethanol)
Example 2
Benzyl D-4-[N-(4-cyclopentylcarbonyloxy-3, 3-d i methyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g) is dissolved in methanol (20 ml), and thereto is added palladium black (20 mg). The mixture is subjected to catalytic reduction at room temperature under atmospheric pressure.
After the reaction, the reaction mixture is filtered to remove undissolved substances, and the filtrate is concentrated under reduced pressure to give D-4-(N-(4-cyclopentylcarbonyloxy-3,3dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.45 g, 92.4%) as colorless viscous oil IR Umfllamx (cm-1): 3340, 1720, 1640, Mass (m/e): 329 (M+), [a]2D5 + 26.1 (e = 1, ethanol)
Example 3
In the same manner as described in Example 1 using benzyl D-4-[N-2,4-dihydroxy-3,3- dimethyl-butyryl)amino]-n-butyrate (4.0 g), tetrahydrofuran (35 ml), pyridine (2 ml) and cyclohexylcarbonyl chloride (2.2 g), there is obtained benzyl D-4-[N-(4-cyclohexylcarbonyloxy-3,3- dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (4.0 g, 74.6%).M.p. 67-69"C (recrystallized from ethyl acetate-n-hexane), IR VnUaiol (cm-l): 3350, 3300, 1720, 1640, Mass (m/e): 433 (M+), [a320 + 24.3 (c= 1, ethanol)
Example 4
In the same manner as described in Example 2 using benzyl D-4-[N-(4-cyclohexyl-carbonyloxy- 3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.0 g), methanol (30 ml) and palladium black (30 mg), the mixture is subjected to catalytic reduction. After the reaction, the reaction mixture is filtered to remove undissolved substances, and the filtrate is concentrated under reduced pressure.The residue is recrystallized from ethyl acetate-n-hexane to give D-4-[N-(4cyclohexylcarbonyloxy-3, 3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (2.2 g, 92.6%) as colorless crystals. M.p. 71-73 C, IR Vmax nujol (cm-1): 3400, 3320, 1735, 1720, 1620, Mass (m/e): 343 (M+), [a]20 + 30.4 (c= 1, ethanol)
Example 5
In the same manner as described in Example 1 using benzyl D-4-[N(2,4-dihydroxy-3,3dimethyl-n-butyryl)amino]-n-butyrate (5.0 g), tetrahydrofuran (40 ml), pyridine (2.5ml) and cyclopropylcarbonyl chloride (1.8 g), there is obtained benzyl D-4-[N-(4-cyclopropylcarbonyloxy3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.8 g, 62.8%) as a colorless viscous oil.IR Umfl(8m,(cml): 3350, 1730, 1650, Mass(m/e): 391 (M +) Example 6
In the same manner as described in Example 2 using benzyl D-4-[N-(4-cyclopropylcarbony loxy-3, 3-di methyl-2-hyd roxy-n-butyryl)aminoj-n-butyrate (3.6 g), methanol (40 ml) and palladium black (40 mg), there is obtained D-4-[N-(4-cyclopropylcarbonyloxy-3,3-dimethyl-2-hydroxy- n-butyryl)aminoj-n-butyric acid (2.5 g, 90.2%) as a colorless viscous oil.IR Umfiam, (cm-1): 3350, 1720, 1640, Mass (m/e): 301 (M+), [a]1D5 + 34.9 (e = 1, ethanol)
Example 7
In the same manner as described in Example 1 using benzyl D-4-[N-(2,4-dihydroxy-3,3dimethyl-n-butyryl)amino]-n-butyrate (5.0 g), tetrahydrofuran (40 ml), pyridine (2.5 ml) and cycloheptylcarbonyl chloride (3.0 g), there is obtained benzyl D-4-[N-(4-cycloheptylcarbonyloxy- 3, 3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (4.1 g, 59.2%) as colorless crystals. M.p.
60-61 C, Coilb8 + 24.8 (c = 1, ethanol)
Example 8
In the same manner as described in Example 2 using benzyl D-4-(N-(4-cycloheptylcarbony- loxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.5 g), methanol (40 ml) and palladium black (30 mg), there is obtained D-4-[N-(4-cycloheptylcarbonyloxy-3,3-dimethyl-2-hydroxy- n-butyryl)amino]-n-butyric acid (1.8 9, 90.0%) as a colorless viscous oil.IR Vmaxfilm (cm-1): 3350, 1720, 1640, Mass (m/e): 357 (M+), [a]1D8 + 22.5 (c (c= 1, ethanol)
Example 9
In the same manner as described in Example 1 using benzyl D-4-[N-2,4-dihydroxy-3,3dimethyl-n-butyryl)amino]-n-butyrate (5.0 9), tetrahydrofuran (40 ml), pyridine (2.5 ml) and 1methylcyclohexylcarbonyl chloride (2.8 9), there is obtained benzyl D-4-[N-(4-(1-methyl-cyclo hexylcarbonyl)oxy)-3, 3-d i methyl-2-hydroxy-n-butyryl)a mi no]-n-butyrate (3.7 g, 53.5%) as a colorless viscous oil.IR vfiam (cm-l): 3350, 1730, 1650, Mass (m/e): 447 (M+)
Example 10
In the same manner as described in Example 2 using benzyl D-4-[N-(4-(1 -methyl-cyclohexyl- carbonyl)-oxy)-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.5 g), methanol (40 ml) and palladium black (40 mg), there is obtained D-4-[N-(4-(1-methyl-cyclohexylcarbonyl)oxy-3,3 dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (2.6 9, 93.0%) as a colorless viscous oil.IR Uama (cam~'): 3350, 1720, 1640, Mass (m/e): 357, (M+), [a]1D8 + +29.0' (e = 1, ethanol) Example 11
Calcium D-4-[N-(2,4-dihydroxy-3,4-dimethyl-n-butyryl)amino]-n-butyrate hemihydrate (2.6 g) is dissolved in water (10 ml), and thereto are simultaneously added dropwise with stirring 1 N aqueous sodium hydroxide (20 ml) and cyclopentane carboxylic anhydride (4.0 g) under icecooling over a period of about 30 minutes, while keeping the pH of the mixture to 8-9. After the addition the mixture is stirred at the same temperature for 40 minutes. The reaction mixture is washed with ethyl acetate, and the aqueous layer is made acidic with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with water, dried and then concentrated under reduced pressure.The residue is purified by silica gel chromatography (solvent; chloroform: ethyl acetate = 4:1) to give D-4-[N-(4-cyclopentylcarbonyloxy-3,3-dimethyl- 2-hydroxy-n-butyryl)amino]-n-butyric acid (0.7 g, 21.0%) as colorless viscous oil.
The physicochemical properties of this product are identical with those of the product obtained in Example 2.
Reference Example
(1) Calcium D-4-[N-(2,4-dihydroxy-3, 3-dimethyl-n-butyryl)amino]-n-butyrate hemihydrate (100 g) is dissolved in water (500 ml), and the solution is passed through a column of an acidic type resin, followed by washing the column with water. The effluent and washing liquid are combined and thereto is added dicyclohexylamine (71 g). The mixture is washed with ether, and the aqueous layer is concentrated under reduced pressure. The residue is crystallized from ethyl acetate. The precipitated crystals are separated by filtration and washed with ether to give D-4 [N-(2,4-dihydroxy-3, 3-dimethyl-n-butyryl)amino]-n-butyric acid dicyclohexylamine salt (122 g, 75.6%) as colorless crystals.
(2) D-4-[N-(2,4-Dihydroxy-3, 3-dimethyl-n-butyryl)amino]-n-butyric acid dicyclohexylamine salt (121 9) is mixed with benzyl bromide (50 9) and dimethylformamide (700 ml), and the mixture is stirred at about 60"C for 6 hours. The reaction mixture is filtered to remove undissolved substances and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, and the solution is washed with dilute sulfuric acid, saline solution, aqueous sodium bicarbonate and saline solution in this order. The ethyl acetate layer is dried and evaporated to dryness under reduced pressure to give benzyl D-4-[N-(2,4-dihydroxy-3,3dimethyl-n-butyryl)amino]-n-butyrate (66 9, 69.9%) as a pale yellow oily substance. IR Umfilama (cm-'): 3350, 1725, 1650, Mass(m/e): 323, [a]2D0 + 32.0 (e = 1, ethanol)
Claims (11)
1. A compound of the general formula:
wherein R1 is a cycloalkyl group having 3 to 7 carbon atoms which may be substituted by an alkyl group having 1 to 3 carbon atoms and R2 is a hydrogen atom or a benzyl group.
2. A compound according to claim 1 wherein R1 is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or 1 -methyl-cyclohexyl.
3. A compound according to claim 1 or 2 wherein R2 is a hydrogen atom.
4. A compound according to claim 3 being D-4-[N-(4-cyclohexylcarbonyloxy-3,3-dimethyl-2- hydroxy-n-butyryl)amino]-n-butyric acid.
5. A pharmaceutically acceptable salt of the compound claimed in claim 3 or 4.
6. Compounds of the formula given in claim 1 and, when R2 is a hydrogen atom pharmaceutically acceptable salts thereof, substantially as herein described with reference to and as illustrated in any of the Examples.
7. A pharmaceutical composition comprising an effective amount of a compound as claimed in any of claims 1 to 6 in admixture with a pharmaceutically acceptable carrier or diluent.
8. Compounds according to any of claims 1 to 6 for use in the amelioration of cerebral metabolism and higher brain function disorder.
9. A process for preparing a 4-aminobutyric acid derivative of the formula:
wherein R1 is a cycloalkyl group having 3 to 7 carbon atoms which may be substituted by a lower alkyl group and R2 is a hydrogen atom or a benzyl group, or a pharmaceutically acceptable salt thereof, which comprises reacting a 4-aminobutyric acid derivative of the formula:
wherein R2 is the same as defined above, with a reactive derivative of a carboxylic acid of the formula:
R1COOH wherein R' is the same as defined above, an optionally converting the product to a pharmaceutically acceptable salt thereof.
10. A process for preparing a 4-aminobutyric acid derivative of the formula:
wherein R1 is a cycloalkyl group having 3 to 7 carbon atoms which may be substituted by a lower alkyl group, or a pharmaceutically acceptable salt thereof, which comprises subjecting a 4aminobutyric acid derivative of the formula:
wherein R1 is the same as defined above, to a catalytic hydrogenation, and optionally converting the product to a pharmaceutically acceptable salt thereof.
11. Process for the preparation of a compound of the formula given in claim 1 and, when R2 is a hydrogen atom a pharmaceutically acceptable salt thereof, substantially as herein described with reference to and as illustrated in any of the Examples.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08304649A GB2135300A (en) | 1983-02-19 | 1983-02-19 | 4-Aminobutyric acid derivatives and processes for the preparation thereof |
| JP59027951A JPS59161343A (en) | 1983-02-19 | 1984-02-15 | 4-aminobutyric acid derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08304649A GB2135300A (en) | 1983-02-19 | 1983-02-19 | 4-Aminobutyric acid derivatives and processes for the preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8304649D0 GB8304649D0 (en) | 1983-03-23 |
| GB2135300A true GB2135300A (en) | 1984-08-30 |
Family
ID=10538272
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08304649A Withdrawn GB2135300A (en) | 1983-02-19 | 1983-02-19 | 4-Aminobutyric acid derivatives and processes for the preparation thereof |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS59161343A (en) |
| GB (1) | GB2135300A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995001169A1 (en) * | 1993-06-30 | 1995-01-12 | Nauchno-Proizvodstvennoe Obiedinenie 'vitaminy' | Neurotropic agent and process for producing it |
| WO1995023783A1 (en) * | 1994-03-02 | 1995-09-08 | Tovarischestvo S Ogranichennoi Otvetstvennostju 'pant' | Ketopanthenol with acetylating properties |
-
1983
- 1983-02-19 GB GB08304649A patent/GB2135300A/en not_active Withdrawn
-
1984
- 1984-02-15 JP JP59027951A patent/JPS59161343A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995001169A1 (en) * | 1993-06-30 | 1995-01-12 | Nauchno-Proizvodstvennoe Obiedinenie 'vitaminy' | Neurotropic agent and process for producing it |
| US5705687A (en) * | 1993-06-30 | 1998-01-06 | Nauchno-Proizvodstvennoe Obiedinenie "Vitaminy" | Neurotropic drug and method for preparation of same |
| WO1995023783A1 (en) * | 1994-03-02 | 1995-09-08 | Tovarischestvo S Ogranichennoi Otvetstvennostju 'pant' | Ketopanthenol with acetylating properties |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8304649D0 (en) | 1983-03-23 |
| JPS59161343A (en) | 1984-09-12 |
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