CA1219597A - 4-aminobutyric acid derivatives and process for the preparation thereof - Google Patents
4-aminobutyric acid derivatives and process for the preparation thereofInfo
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- CA1219597A CA1219597A CA000422240A CA422240A CA1219597A CA 1219597 A CA1219597 A CA 1219597A CA 000422240 A CA000422240 A CA 000422240A CA 422240 A CA422240 A CA 422240A CA 1219597 A CA1219597 A CA 1219597A
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- butyryl
- dimethyl
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Abstract
Abstract:
The invention provides novel 4-aminobutyric acid derivatives of the formula:
The invention provides novel 4-aminobutyric acid derivatives of the formula:
Description
4~Aminobutyric acid derivatives and Process for the ~reparation thereof The present invention relates to novel 4-aminobutyric acid derivatives and a process for the preparation thereof.
The invention thus provides 4-aminobutyric acid derivatives of the ~ormula:
RlCOOCH2-C - CH-CONH(cH2)3cOOH (I) wherein Rl is a straight or branched alkyl group having 1 to 8 carbon atoms, or a pharmaceutically acceptable salt theref.
It is known that calcium hopanthenate [chemical name:
calcium D-(~)-(2,4-dihydroxy-3,3-dimethylbutyramido) butyrate] relieves various s~mptoms such as hyperactivity, short attention span, speech disorders, hypobulia, etc.
which accompany mild mental retardation, postencephalitic syndrome, cerebral palsy, etc. and hence is useful as a reme~y for the amelioration of cerebral metabolism and higher brain unction 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, the present inventors have investigated various analogous compounds. As a result, it has been found that the novel compounds of the above formula (I~ when ~3LZ~97 administer~d orally are absorbed well and show higher levels of bioavailability or longer duration of action in th~ blood and brain than calcium hopanthenate. Hence, they are useful as medicines for the amelioration of cerebral metabolism and higher brain function disorders.
Specific examples of the compounds of the invention are the compounds of the formula (I) wherein Rl is a straiyht or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, sec.-pentyl, tert.-pentyl, 2,2-dimethylpropyl, l-ethyl-p~opyl, n-hexyl, n-heptyl, n-octyl, or the like. Suitable examples are the compounds of the formula (I) wherein Rl is a branched alkyl group having 3 to 5 carbon atoms, such as isopropyl, isobutyl, isopentyl, tert.-butyl, 2,2-di-methylpropyl, or l-ethylpropyl group. Particularly prefer-able compounds are D-4-[N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid and D-4-1N-(4-iso-valeroxyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyric acid. These compounds advantageously can be obtained in crystalline form.
The compounds (I) of the present invention can be prepared by the following processes:
A) subjecting a 4-aminobutyric acid ester of the formula:
RlCOOCH2-C - CH-CONH(CH2)3COOR2 (II) c~3 OH
. .. ~ ~, 1 . 3 wherein Rl is as defined above, and R2 is a group removable by a catalytic reduction (e.g. benzyl, p-methoxy-benzyl, p-chlorobenzyl, or p-nitrobenzyl group), to a catalytic reduction; or B) reacting a 4-aminobutyric acid derivative of the formula:
~H3 HOCH2-C - CH-CONH (CH2) 3COOH (III) wlth a reactive derivative of a carboxylic acid of the formula:
RlCOOH (IV) wherein Rl is as defined above.
The procedure of the above processes is explained in more detail below.
Process A
.
The startin~ compound (II) is catalytically reduced 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), tetra-hydrofuran, dioxane, or a mixture of these solvents with water. The above reaction is usually caried out at a temperature of 0 to 60C under 1 to 10 atm~, preferably at a temperature of 10 to 30C under 1 to 3 atm.
Process B
The starting compound ~III) and the reactive derivative of the compound (IV) are reacted in an appropriate solvent in the presence of a base. The compound (III) may be used in the form of ~ salt (e.g. the calcium salt thereof)~ The reactive derivative of the compound (IV) may be any conven-tional derivative, preferably an acid anhydride or acid halide thereof. The base may be, for example, an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydrox-ide~ an alkali metal carbonate (e.g. sodium carbonate, potassium ~arbonate3; an alkali metal bicarbonate (e~g.
sodium bicarbonate, pot~ssium bicarbonate), an organic ker-tiary amine (e.g. triethylamine, pyridine, dimethylaniline, p-dimethylaminopyridine~, or the like. The solvent may be9 for example, tetrahydrofuran, dioxane, chloroform, methyl-ene chloride, benzene7 ethyl acetate~ dimethylformamide, diethyl ether, water, or the like, which may be used alone or as a mixture thereofO The above reaction is usually carried out at a temperature of -15 to 50C, preferably 0 to 20C.
The compounds (I) of the present invention contain one asymmetric carbon within the molecule and hence include two optical isomers. The present invention includes these isomers individually as well as their racemic mixture. Of these isomers, the compounds wherein the asymmetric carbon has D-configuration are particularly preferable for medical use.
~Z19S~7 The starting compound (II) used in the above process is also novel and can be prepared by the following process.
A 4-aminobutyric acid ester of the formula:
l~3 HOC~-C - CH-CONH(CH2)3COOR2 ~V) wherein R2 is as defined above, is reacted with a reactive derivative of a carboxylic acid of the formula:
RlCOO~ (IV) wherein Rl is as deEined above.
The reaction of the compound (V) and the reactive derivatlve of a carboxylic acid (IV) is preferably carried out in an appropriate solvent (e.g. tetrahydrofuran, dioxane, chloroform, methylene chloride, benzene, ethyl acetate, dimethylformamide, diethyl ether, methyl ethyl ether, water, or a mixture thereof) in the presence or absence of a base (e.g. an organic tertiary amine such as triethylamine, pyridine, dimethylaniline, or p-dimethyl-aminopyridine; or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) at a temperature of -lS to 50C.
The compound (V) can be prepared by reacting a metal salt or organic amine salt of ~-[N-(2,4-di-hydroxy-3, 3-dimethyl-n-butyryl)amino]-n-butyric acid with a compound of the formula: R X (wherein R2 is as defined above, and X is a halogen atom, e.g. a chlorine, bromine or ~, iodine atom), or by reacting a 4-amino-n-butyric acid ester of the formula:
H2N~ 2)3CR2 (VI) wherein R2 is as defined above, with a Y-lactone of
The invention thus provides 4-aminobutyric acid derivatives of the ~ormula:
RlCOOCH2-C - CH-CONH(cH2)3cOOH (I) wherein Rl is a straight or branched alkyl group having 1 to 8 carbon atoms, or a pharmaceutically acceptable salt theref.
It is known that calcium hopanthenate [chemical name:
calcium D-(~)-(2,4-dihydroxy-3,3-dimethylbutyramido) butyrate] relieves various s~mptoms such as hyperactivity, short attention span, speech disorders, hypobulia, etc.
which accompany mild mental retardation, postencephalitic syndrome, cerebral palsy, etc. and hence is useful as a reme~y for the amelioration of cerebral metabolism and higher brain unction 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, the present inventors have investigated various analogous compounds. As a result, it has been found that the novel compounds of the above formula (I~ when ~3LZ~97 administer~d orally are absorbed well and show higher levels of bioavailability or longer duration of action in th~ blood and brain than calcium hopanthenate. Hence, they are useful as medicines for the amelioration of cerebral metabolism and higher brain function disorders.
Specific examples of the compounds of the invention are the compounds of the formula (I) wherein Rl is a straiyht or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, sec.-pentyl, tert.-pentyl, 2,2-dimethylpropyl, l-ethyl-p~opyl, n-hexyl, n-heptyl, n-octyl, or the like. Suitable examples are the compounds of the formula (I) wherein Rl is a branched alkyl group having 3 to 5 carbon atoms, such as isopropyl, isobutyl, isopentyl, tert.-butyl, 2,2-di-methylpropyl, or l-ethylpropyl group. Particularly prefer-able compounds are D-4-[N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid and D-4-1N-(4-iso-valeroxyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyric acid. These compounds advantageously can be obtained in crystalline form.
The compounds (I) of the present invention can be prepared by the following processes:
A) subjecting a 4-aminobutyric acid ester of the formula:
RlCOOCH2-C - CH-CONH(CH2)3COOR2 (II) c~3 OH
. .. ~ ~, 1 . 3 wherein Rl is as defined above, and R2 is a group removable by a catalytic reduction (e.g. benzyl, p-methoxy-benzyl, p-chlorobenzyl, or p-nitrobenzyl group), to a catalytic reduction; or B) reacting a 4-aminobutyric acid derivative of the formula:
~H3 HOCH2-C - CH-CONH (CH2) 3COOH (III) wlth a reactive derivative of a carboxylic acid of the formula:
RlCOOH (IV) wherein Rl is as defined above.
The procedure of the above processes is explained in more detail below.
Process A
.
The startin~ compound (II) is catalytically reduced 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), tetra-hydrofuran, dioxane, or a mixture of these solvents with water. The above reaction is usually caried out at a temperature of 0 to 60C under 1 to 10 atm~, preferably at a temperature of 10 to 30C under 1 to 3 atm.
Process B
The starting compound ~III) and the reactive derivative of the compound (IV) are reacted in an appropriate solvent in the presence of a base. The compound (III) may be used in the form of ~ salt (e.g. the calcium salt thereof)~ The reactive derivative of the compound (IV) may be any conven-tional derivative, preferably an acid anhydride or acid halide thereof. The base may be, for example, an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydrox-ide~ an alkali metal carbonate (e.g. sodium carbonate, potassium ~arbonate3; an alkali metal bicarbonate (e~g.
sodium bicarbonate, pot~ssium bicarbonate), an organic ker-tiary amine (e.g. triethylamine, pyridine, dimethylaniline, p-dimethylaminopyridine~, or the like. The solvent may be9 for example, tetrahydrofuran, dioxane, chloroform, methyl-ene chloride, benzene7 ethyl acetate~ dimethylformamide, diethyl ether, water, or the like, which may be used alone or as a mixture thereofO The above reaction is usually carried out at a temperature of -15 to 50C, preferably 0 to 20C.
The compounds (I) of the present invention contain one asymmetric carbon within the molecule and hence include two optical isomers. The present invention includes these isomers individually as well as their racemic mixture. Of these isomers, the compounds wherein the asymmetric carbon has D-configuration are particularly preferable for medical use.
~Z19S~7 The starting compound (II) used in the above process is also novel and can be prepared by the following process.
A 4-aminobutyric acid ester of the formula:
l~3 HOC~-C - CH-CONH(CH2)3COOR2 ~V) wherein R2 is as defined above, is reacted with a reactive derivative of a carboxylic acid of the formula:
RlCOO~ (IV) wherein Rl is as deEined above.
The reaction of the compound (V) and the reactive derivatlve of a carboxylic acid (IV) is preferably carried out in an appropriate solvent (e.g. tetrahydrofuran, dioxane, chloroform, methylene chloride, benzene, ethyl acetate, dimethylformamide, diethyl ether, methyl ethyl ether, water, or a mixture thereof) in the presence or absence of a base (e.g. an organic tertiary amine such as triethylamine, pyridine, dimethylaniline, or p-dimethyl-aminopyridine; or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate) at a temperature of -lS to 50C.
The compound (V) can be prepared by reacting a metal salt or organic amine salt of ~-[N-(2,4-di-hydroxy-3, 3-dimethyl-n-butyryl)amino]-n-butyric acid with a compound of the formula: R X (wherein R2 is as defined above, and X is a halogen atom, e.g. a chlorine, bromine or ~, iodine atom), or by reacting a 4-amino-n-butyric acid ester of the formula:
H2N~ 2)3CR2 (VI) wherein R2 is as defined above, with a Y-lactone of
2,4-dihydroxy-3,3-dimethyl-n-butyric acid.
The compounds (I) of the present invention may be used in the form of a free acid or in the form of a pharma-ceutically acceptable salt thereof. Suitable examples of the salt are, for example, the calcium salt, sodium salt, potassium salt, lithium salt, magnesium salt, lysine salt, ornithine salt, or arginine salt.
The compounds (I) or a pharmaceutically acceptable salt thereof is preferably administered by the oral route (but may also be administered by the parenteral route) as a conventional preparation, for example, solid preparations such as tablets f pills ~ powders, capsules, or granules, and liquid preparations such as solutions, suspensions, or emulsions. Such preparations can be prepared in a conven-tional 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, and magnesium stearate.
The dose of the compound (I) or a pharmaceutically acceptable salt thereof may vary in accordance with the kind of disease to be treated, the age and weight of the patient, the severity of disease and the administration 5~37 routes, but is usually in the range of 1 to 20 mg/kg/day, preferably 2 to 10 mg/kg/day, for oral administration.
When the compound (I) or a pharmaceutically acceptable salt thereof of the present invention is administered, they can be detected in high levels in the blood and brain, as confirmed by the following in vivo experiments.
Experiment 1 5D-male rats, weighing about 200 g, 7 weeks of age, having been fasted overnight (one group: 4 rats) were used.
A suspension (2 ml) of a test compound in a 0.5 ~ carboxy-methyl cellulose solution was orally administered to each rat with a stomach sonde (dose of test compound: 389.4 llmole/kg, corresponding to 100 mg/kg of calcium hopanthen-ate). One or two hours after the administration, the rats were killed by cutting their carotid arteries, and the blood was collected. The blood of each rat was centrifuged (2,800 r.p~m., 15 minutes) to separate the blood plasma.
The 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 _ Level of hopanthenic acid in the Compound blood plasma (~g/ml) No. (average ~ S.D.) One hour after the Two hours after the administration administration 1 32.9 + 2.7 1~.4 + 3.5 2 37.3 + 1.8 21.3 + 1.8 Control 19.4 ~ 1~9 14.2 + 1.6 s~
[Remarks]:
Compound No. 1: D-4-[N-Isobutyryloxy-3,3~dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid Compound No. 2: D-4-[N-(4-Isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid Control: Calcium D-4-1N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate Experi_ent 2 SD-male rats, weighing about 200 g, 7 weeks of age, having been fasted overnight, (one group: 4 ra~s) were used. A suspension (2 ml) of a test compound in a 0.5 %
carboxymethyl cellulose solu~ion was orally administered to each rat with a stomach sonde (dose of test compound:
389.4 ~mole/kg, corresponding to 100 mg/kg of calcium hopanthenate). ~wo or three hours after the administra-tion, the ~erebrum was taken out and washed with physio-logical saline solution. To the cerebrum was added 9 times its volume of water, and the mixture wa~ homogen-ized with a homogenizer for one minute under ice-cooling and then centrifuged at lOrOOO r.p.m. at 4C for one hour.
The concentration of hopanthenic acid in the supernatant (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.
t L95~7 Table 2 . __ _____ _ ~
Level of hopanthenic acid in the Compound cerebrum (~g/g) No. (average ~ S.D.~
Two hours after the Three hours after the . ~ administration administration 1 1.57 ~ 0.25 0.63 ~ 0.13 2 1.42 ~ 0.32 0.56 ~ 0.07 Control 0.~ 0.]7 ~ 0,0~
It is clear from the above experimental results that, when administered orally to rats in a dose o~ 389.4 ~mole/
kg, the compounds of the present invention: D-4-~N-(4-iso-butyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl]-n-butyric acid and D-4-lN-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid showed a high blood plasma level of hopanthenic acid that is about 1.2 to 1.9 times higher than the level resulting from the administration of calcium hopanthenate, and also showed a high cerebrum level of hopanthenic acid that is about 1.5 to 2.2 times higher than the level obtained by administering calcium hopanthenate.
2Q ~esides, the compounds (I) of the present invention have low toxicity and hence have high safety. For instance, the compounds o~ the present invention: D-4-[N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid and D-4-[N-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid showed a maximum ~.i 5~7 tolerance of above 2,000 mg/kg in mice (said maximum tolerance was measured by administer ing the test compound to mice and observing the deaths of the mice 48 hours after the administration; the maximum tolerance meaning the dose just less than the dose inducing death of the mice).
Thus, the compounds of ~he present invention are con-verted into hopanthenic acid _ vivo when administered and sbow higher levels of hopanthenic acid in the blood and brain in comparison with calcium hopanthenate with high safety, and hence, are useful as medicines for the amelior-ation of cerebral metabolism and higher brain function disorders.
The present invention is illus~rated by the following Examples but should not be construed to be limited thereto.
Example 1 (1) Benzyl D-4-[N-2,4-dihydroxy-3,3-dimethyl-n-butyryl) amino]-n-butyrate (5 g) is dissolved in tetrahydrofuran (50 ml~, and thereto is added pyridine (3 g). To the mixture is added dropwi~e with stirring a solution o~
isobutyryl chloride (1.8 9) in tetrahydrofuran (5 ml) at 0 - 5C. The mixture is stirred at room temperature overniqht and concentrated under reduced pressure. The resulting residue i5 dissolved in ethyl acetate, and the solution is washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution .~
~Z3L~S~7 and saturated saline solution in order. The ethyl acetate solution is dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel c~romatography (solvent; chloroform : ethyl acetate =
4 : 1) to give benzyl D-4-[N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.6 g, 59.2 %) as a colorless viscous oil.
IR ~ fllm (cm ): 3350, 1730, 1650, Mass (m/e): 393 (M ) (2) Benzyl D-4-[N-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.4 g) is dissolved in methanol (34 ml), and thereto is added palladium black (30 mg). The mixture is subjected to catalytic reduction at room temperature under atmospheric pressure. After the reaction, the reaction mixture is fil~ered to remove un-dissolved substances, and the filtrate is concentrated under reduced pressure. The resi~ue is recyrstallized from ethyl acetate-n-hexane to give D-4-[N-(4-isobutyry-loxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (2.0 g, 76.3 %) as colorless prisms. M.p. 73 - 75C, IR v nu~ol (cm 1): 3320, 1715, 1610, Mass (m/e): 303 (M ), [~ D6 ~37.2 (c=l, ethanol). Repeated recrys-tallization of this product from a mixture of ethyl acetate and isopropyl ether gives colorless prisms melting at 82 - 83.5C. [~]22 + 37 4O (c=l, ethanol).
The compounds (I) of the present invention may be used in the form of a free acid or in the form of a pharma-ceutically acceptable salt thereof. Suitable examples of the salt are, for example, the calcium salt, sodium salt, potassium salt, lithium salt, magnesium salt, lysine salt, ornithine salt, or arginine salt.
The compounds (I) or a pharmaceutically acceptable salt thereof is preferably administered by the oral route (but may also be administered by the parenteral route) as a conventional preparation, for example, solid preparations such as tablets f pills ~ powders, capsules, or granules, and liquid preparations such as solutions, suspensions, or emulsions. Such preparations can be prepared in a conven-tional 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, and magnesium stearate.
The dose of the compound (I) or a pharmaceutically acceptable salt thereof may vary in accordance with the kind of disease to be treated, the age and weight of the patient, the severity of disease and the administration 5~37 routes, but is usually in the range of 1 to 20 mg/kg/day, preferably 2 to 10 mg/kg/day, for oral administration.
When the compound (I) or a pharmaceutically acceptable salt thereof of the present invention is administered, they can be detected in high levels in the blood and brain, as confirmed by the following in vivo experiments.
Experiment 1 5D-male rats, weighing about 200 g, 7 weeks of age, having been fasted overnight (one group: 4 rats) were used.
A suspension (2 ml) of a test compound in a 0.5 ~ carboxy-methyl cellulose solution was orally administered to each rat with a stomach sonde (dose of test compound: 389.4 llmole/kg, corresponding to 100 mg/kg of calcium hopanthen-ate). One or two hours after the administration, the rats were killed by cutting their carotid arteries, and the blood was collected. The blood of each rat was centrifuged (2,800 r.p~m., 15 minutes) to separate the blood plasma.
The 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 _ Level of hopanthenic acid in the Compound blood plasma (~g/ml) No. (average ~ S.D.) One hour after the Two hours after the administration administration 1 32.9 + 2.7 1~.4 + 3.5 2 37.3 + 1.8 21.3 + 1.8 Control 19.4 ~ 1~9 14.2 + 1.6 s~
[Remarks]:
Compound No. 1: D-4-[N-Isobutyryloxy-3,3~dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid Compound No. 2: D-4-[N-(4-Isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid Control: Calcium D-4-1N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate Experi_ent 2 SD-male rats, weighing about 200 g, 7 weeks of age, having been fasted overnight, (one group: 4 ra~s) were used. A suspension (2 ml) of a test compound in a 0.5 %
carboxymethyl cellulose solu~ion was orally administered to each rat with a stomach sonde (dose of test compound:
389.4 ~mole/kg, corresponding to 100 mg/kg of calcium hopanthenate). ~wo or three hours after the administra-tion, the ~erebrum was taken out and washed with physio-logical saline solution. To the cerebrum was added 9 times its volume of water, and the mixture wa~ homogen-ized with a homogenizer for one minute under ice-cooling and then centrifuged at lOrOOO r.p.m. at 4C for one hour.
The concentration of hopanthenic acid in the supernatant (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.
t L95~7 Table 2 . __ _____ _ ~
Level of hopanthenic acid in the Compound cerebrum (~g/g) No. (average ~ S.D.~
Two hours after the Three hours after the . ~ administration administration 1 1.57 ~ 0.25 0.63 ~ 0.13 2 1.42 ~ 0.32 0.56 ~ 0.07 Control 0.~ 0.]7 ~ 0,0~
It is clear from the above experimental results that, when administered orally to rats in a dose o~ 389.4 ~mole/
kg, the compounds of the present invention: D-4-~N-(4-iso-butyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl]-n-butyric acid and D-4-lN-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid showed a high blood plasma level of hopanthenic acid that is about 1.2 to 1.9 times higher than the level resulting from the administration of calcium hopanthenate, and also showed a high cerebrum level of hopanthenic acid that is about 1.5 to 2.2 times higher than the level obtained by administering calcium hopanthenate.
2Q ~esides, the compounds (I) of the present invention have low toxicity and hence have high safety. For instance, the compounds o~ the present invention: D-4-[N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid and D-4-[N-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid showed a maximum ~.i 5~7 tolerance of above 2,000 mg/kg in mice (said maximum tolerance was measured by administer ing the test compound to mice and observing the deaths of the mice 48 hours after the administration; the maximum tolerance meaning the dose just less than the dose inducing death of the mice).
Thus, the compounds of ~he present invention are con-verted into hopanthenic acid _ vivo when administered and sbow higher levels of hopanthenic acid in the blood and brain in comparison with calcium hopanthenate with high safety, and hence, are useful as medicines for the amelior-ation of cerebral metabolism and higher brain function disorders.
The present invention is illus~rated by the following Examples but should not be construed to be limited thereto.
Example 1 (1) Benzyl D-4-[N-2,4-dihydroxy-3,3-dimethyl-n-butyryl) amino]-n-butyrate (5 g) is dissolved in tetrahydrofuran (50 ml~, and thereto is added pyridine (3 g). To the mixture is added dropwi~e with stirring a solution o~
isobutyryl chloride (1.8 9) in tetrahydrofuran (5 ml) at 0 - 5C. The mixture is stirred at room temperature overniqht and concentrated under reduced pressure. The resulting residue i5 dissolved in ethyl acetate, and the solution is washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution .~
~Z3L~S~7 and saturated saline solution in order. The ethyl acetate solution is dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel c~romatography (solvent; chloroform : ethyl acetate =
4 : 1) to give benzyl D-4-[N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.6 g, 59.2 %) as a colorless viscous oil.
IR ~ fllm (cm ): 3350, 1730, 1650, Mass (m/e): 393 (M ) (2) Benzyl D-4-[N-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.4 g) is dissolved in methanol (34 ml), and thereto is added palladium black (30 mg). The mixture is subjected to catalytic reduction at room temperature under atmospheric pressure. After the reaction, the reaction mixture is fil~ered to remove un-dissolved substances, and the filtrate is concentrated under reduced pressure. The resi~ue is recyrstallized from ethyl acetate-n-hexane to give D-4-[N-(4-isobutyry-loxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (2.0 g, 76.3 %) as colorless prisms. M.p. 73 - 75C, IR v nu~ol (cm 1): 3320, 1715, 1610, Mass (m/e): 303 (M ), [~ D6 ~37.2 (c=l, ethanol). Repeated recrys-tallization of this product from a mixture of ethyl acetate and isopropyl ether gives colorless prisms melting at 82 - 83.5C. [~]22 + 37 4O (c=l, ethanol).
(3) D-4-[N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid ~1.0 g) is dissolved in ethanol (20 ml) and thereto are added calcium hydroxide (0.15 g) and water (2 ml). The mixture ~LZ~5~7 is stirred at room tem~erature ~or about 40 minutes.
The reaction mixture is filtered to remove undissolved substances and the filtrate is concentrated under reduced pressure. The residue is treated with n-hexane to give calcium D-4- 1N- (4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (0.85 g, 80.0 %) as colorless powder. [~
+28.3 (c=l, ethanol) Exam~le 2 (1) In the same manner as described in Example 1 (1) using benzyl D-4-~N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (5.0 g), tetra-hydrofuran (55 ml), pyridine ~3 g) and isovaleryl chloride (2.1 g), there is obtained benzyl D-4-[N-(4-isovaleryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)-amir.o]-n-butyrate (4.0 g, 63.5 %) as a colorless viscous oil. IR vmax (cm ): 3350, 1730, 1650, ~ass (m/e): 407 (2) In the same manner as described in Exam~le 1 (2) using benzyl D-4-[N-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.8 g), methanol (38 ml) and palladium black (30 mg), there is obtained D-4-[N-(4-isovale~yloxy-3,3-dimethyl-2-hydroxv-n-butyryl)amino]-n-butyrate (2.1 g, 70.9 ~) as colorless prisms. M.p. 84 - 86C, IR Z'max (cm ):
3300, 1720, 1610, Mass (m/e): 317 (rl )~ [~]D +34.1 (c=l, ethanol) * Trade ~ark (3) In the same manner as described in Exam~le 1 (3) using D-4~[N-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.0 g), ethanol (20 ml), calcium hydroxide (0.13 g) and water (2 ml), there is obtained calcium D-4-[N-(4-isovaleryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (0.84 g, 79.2 %) as a colorless powder. ~C~21 +26.1 (c=l, ethanol) Exam~le 3 (1) In the same manner as described in Example 1 (1) using benzyl D-4-~N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (5.0 g), tetrahydrofuran (55 ml), pyridine (3 g) and iso-hexanoyl chloride (2.3 g), there is obtained benzyl D-4-[N-(4-isohexanoyloxy-3,3-dimethyl-2-hydroxy-n~butyryl)amino]-n-butyrate (4.~ g, 73.1 ~) as a colorless viscous oil. IRV nU~l*(Cm-l~
3350, 1730, 1650, Mass (m/e): 421 (M ) (2) In the same manner as described in Example 1 (2) using benzyl D-4-~N-(4-isohexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (4.0 g), methanol (40 ml) and palladium black (40 mg), there is obtained D-4-[N-(4-isohexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyr~l)amino]-n-butyric acid (2.9 g, 92.2 ~) as a colorless viscous oil. IR~JmaXm (cm 1):
3330, 1720, 1610, ~ass ~m/e): 331 (M ), [~]D6 +31.6 (c=l, ethanol) * Trade Mark ~. ~
9~
Example 4 (1) In the same manner as described in Example 1 (1) using benzyl D-4-~N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra~
hydrofuran (45 ml), pyridine (2.4 g) and pivaloyl chloride ~1.8 g), there is obtained benzyl D-4-[N-(4-pivaloyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.0 g, 47.6 %) as a colorless viscous oil.
IR vmaxm(cm 1): 3350, 1730, 1650, Mass (m/e): 407 (M ) (2) In the same manner as described in Example 1 (2) using benzyl D-4-[N-(4-pivaloyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.3 g), methanol (28 ml) and palladium black (30 mg~, there is ohtained D-4-[N-(4-pivaloyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.] g, 50.4 %) as colorless crystals. M.p. 79 - 82C recrystallized from a mixture of ethyl acetate and n-hexane, IR
(cm 1): 3350, 1730, 1710, 1610, Mass (m/e): 317 (M ) Example 5 (1) In the same manner as described in Example 1 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3 dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (45 ml), pyridine (2.4 g) and 3,3-dimethyl-n-butyryl chloride (2.0 g), there is obtained benzyl D-4-[N-(4-(3~3-dimethyl-n-butyryl)oxy-3~3-dimethyl-2 hydroxy-n-butyryl)amino]-n-butyrate (3.7 g, 71.0 ~) as a colorless sticky oily substance. IR ~maxm (cm ):
-~ * Trade Mar~
~5a59~
3350, 1730, 1650, Mass (m/e): 421 (M ) (2) In the same manner as described in Example 1 (2) using benzyl D-4-[N-(4-(3,3-dimethyl-n-butyryl)oxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.5 g), methanol (35 ml) and palladium black ( 40 mg ), there is obtained D-4-[N-(4-(3,3-dimethyl-n butyryl)oxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyric acid (2.2 g, 79.7 %) as colorless crystals. M.p. 102 - 104C, IR vmaU~l (cm 1): 3340, 10 1735, 1715, 1610, Mass (m/e): 331 (M+), [~]26 +32.0 (c=l, ethanol) Example 6 . _ (1) In the same manner as described in Example 1 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (45 ml), pyridine (2.4 g) and 2-ethyl-n-butyryl chloride (2.0 g), there is obtained benzyl D-4-[N-(4-(2-ethyl-n-butyryl)oxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.5 g, 47.9 %) as a colorless 20 viscous oil. IR vmaxm (cm 1): 3350, 1730, 1650, Mass (m/e): 421 (~ ) (2) In the same manner as described in Exam~le 1 (2) using benzyl D-4-[N-(4-(2-ethyl-n-butyryl)-oxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate 25 (2.4 g), methanol (24 ml) and palladium black ~30 mg), there is obtained D-4-[N-(4-(2-ethyl-n-butyryl)oxy-n-butyryl)amino]-n-butyric acid (1.7 g, 90.1 %) as * Trade Mark 9S~7 a colorless viscous oil. IRYmaX (cm ): 3350, 1730, 1710, 1645, Mass (m/e): 331 (M ), [~]19 +25.9 (c=l, ethanol) (3) In the same manner as described in 5 Example 1 (3) using D- 4- [N- ( 4 - ( 2-ethyl-n-butyryl)oxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.0 g), ethanol (20 ml), calcium hydroxide (130 mg) and water (2 ml), there is obtained calcium D-4-[N-(4-(2-ethyl-n-butyryl)oxy-3,3-dimethyl-2-10 hydroxy-n-butryl)amino]-n-butyrate (0.81 g, 76.6 %) as a colorless ~owder. [a]2l +24.7 (c=l, ethanol) Example 7 Calcium D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate hemihydrate (5.2 g) is dissolved in water (20 ml), and thereto are simul-taneously added dropwise with stirring lN aqueous sodium hydroxide (40 ml) and isobutyric anhydride (6.4 g) under ice-cooling over a period of about 30 minutes, while keeping a 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 recrystallized from ethyl acetate-n-hexane to give D-4-~N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (2.3 g, 37.4~) as colorless crystals.
The physicochemical properties of this product are identical with those of the product obtained in Example 1 (2).
Example 8 In the same manner as described in Example 7 using calcium D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino-n-butyrate hemihydrate (5.2 g), iso-valeric anhydride (7.4 g) and lN aqueous sodiumhydroxide (30 ml~, there is obtained D-4-[N-(4-iso-valeryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.9 g, 29.6 %) as colorless crystals.
The physicochemical properties of this product are identical with those cf the product ob-tained in Example 2 (2).
Exam~le 9 . .
(1) Benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g) is dissolved in tetrahydrofuran (30 ml) and thereto is added pyridine (2 ml). To the mixture is added dropwise a solution of acetyl chloride (1.2 g) in tetrahydrofuran (5 ml) under ice-cooling. The mixture is stirred at room temperature overnight and then concentra-ted under reduced pressure. The residue - is dissolved in ethyl acetate, and the solution is washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and saline solution in order. The ethyl acetate layer is dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography (solvent; chloroform : ethyl acetate = 4 : 1) to give benzyl D-4-[N-(4-acetoxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.3 g, 50.9 %) as a colorless viscous oil. IR vmax (cm ): 3350, 1730, 1650, Mass (m/e): 365 (M ) (2) Benzyl D-4-[N-(4-acetoxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g) is dis-solved in methanol (20 ml) and thereto is added palladium black (20 mg). I'he mixture is subjecte~ to catalytic reduction at room temperature under atmospheric ~ressure.
After the reaction, the reaction mix-ture is filtered to remove undissolved substances, and the filtrate is concentrated under reduced pressure to give D-4-[N-(4-acetoxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.38 g, 91.6 ~) as a colorless viscous oil.~ IR ~max (cm ): 3350, 1720, 1640, Mass (m/e): 275 (M ), [~]D0 +33.1 (c=l, ethanol) Exam~le 10 (1) In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml~, pyridine (2 ml) and propionylchloride (1.4 g), there is obtained benzyl D-4-[N-(4-propionyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.2 g, 46.9 %) as a colorless viscous oil. IR vmaxm (cm )o 3350, 1730, 1650, r~ass (m/e): 379 (M ) (2) In the same manner as described in Example 9 (2) using benzyl D-4-[N-(4-propionyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g), methanol (20 ml) and palladium black (20 mg), there is obtained D-4-[N-~4-propionyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.46 g, 95.7 %) as a colorless viscous oil. IR ymaxm (cm ):
3350, 1720, 1640, Mass (m/e): 289 (M ), [~X]D +30.0 (c=l, ethanol) Example 11 (I) In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetrahydrofuran (35 ml), pyridine (2 ml) and n-butyryl chloride (1.6 g), there is obtained benzyl D-4-[N-(4-n-butyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyrate (2.9 g, 59.6 %) as a colorless viscous oil. IR vmaxm (cm ): 3370, 1730, 1650, Mass (m/e): 393 (M )~ [~]D ~27.6 (c=l, ethanol) (2) In the same manner as described in Example 9 (2) using benzyl D-4-[N-(4-n-butyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g), methanol (20 ml) and palladium black (20 mg), there is ob-tained D-4-[N-(4-n-butyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino~-n-butyric acid (1.48 g, 96.0 ~) as a colorless viscous oil. IRv film (cm 1): 3350, 1720, 1640, Mass (m/e): 303 ~M )~
[~]D0 +30.2 (c=l, ethanol) Example 12 (1) In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml~, pyridine (2 ml) and n-valeryl-chloride (1.8 g), there is obtained benzyl D-4-[N-(4-n-valeryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyrate (3.0 g, 59.5 %) as a colorless crystals. M.p. 34 - 35C. IR ~mUaxol(cm 1): 3370, 1730, 1650, Mass (m/e): 407 (M ) (2) In the same manner as described in ~xample 9 ~2) using benzyl D-4-[N-(4-valeryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.6 g), methanol (30 ml) and palladium black (30 mg), there is obtained D-4-[N-(4-n-valeryloxy -3,3-dimethyl-20 2-hydroxy-n-butyryl)amino]-n-butyric acid (1.9 g, 93.8 %) as a colorless viscous oil. IR ~max (cm ):
3350, 1720, 1640, Mass (m/e): 317 (M ), [~]D0 +31.8 (c=l, ethanol) (3) D-4-[N-(4-Valeryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (0.9 g) is dissolved in methanol (10 ml), and thereto is added L-lysine (0.41 g). The mixture is stirred at room * Trade Mark ~Z~95~3~
,~
temperature for 30 minutes. ~he reaction mixture is concentrated under reduced pressure to remove the solvent. The residue is treated with n-hexane, and the resulting powder is collecte~ by filtration to give D-4-[N-(4-valeryloXy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid L-lysine salt (1.13 g, 86.3 %) as a colorless powder. ~.p. 130 - 133C, ~]D +25.5 (c=l, ethanol~
The reaction mixture is filtered to remove undissolved substances and the filtrate is concentrated under reduced pressure. The residue is treated with n-hexane to give calcium D-4- 1N- (4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (0.85 g, 80.0 %) as colorless powder. [~
+28.3 (c=l, ethanol) Exam~le 2 (1) In the same manner as described in Example 1 (1) using benzyl D-4-~N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (5.0 g), tetra-hydrofuran (55 ml), pyridine ~3 g) and isovaleryl chloride (2.1 g), there is obtained benzyl D-4-[N-(4-isovaleryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)-amir.o]-n-butyrate (4.0 g, 63.5 %) as a colorless viscous oil. IR vmax (cm ): 3350, 1730, 1650, ~ass (m/e): 407 (2) In the same manner as described in Exam~le 1 (2) using benzyl D-4-[N-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.8 g), methanol (38 ml) and palladium black (30 mg), there is obtained D-4-[N-(4-isovale~yloxy-3,3-dimethyl-2-hydroxv-n-butyryl)amino]-n-butyrate (2.1 g, 70.9 ~) as colorless prisms. M.p. 84 - 86C, IR Z'max (cm ):
3300, 1720, 1610, Mass (m/e): 317 (rl )~ [~]D +34.1 (c=l, ethanol) * Trade ~ark (3) In the same manner as described in Exam~le 1 (3) using D-4~[N-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.0 g), ethanol (20 ml), calcium hydroxide (0.13 g) and water (2 ml), there is obtained calcium D-4-[N-(4-isovaleryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (0.84 g, 79.2 %) as a colorless powder. ~C~21 +26.1 (c=l, ethanol) Exam~le 3 (1) In the same manner as described in Example 1 (1) using benzyl D-4-~N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (5.0 g), tetrahydrofuran (55 ml), pyridine (3 g) and iso-hexanoyl chloride (2.3 g), there is obtained benzyl D-4-[N-(4-isohexanoyloxy-3,3-dimethyl-2-hydroxy-n~butyryl)amino]-n-butyrate (4.~ g, 73.1 ~) as a colorless viscous oil. IRV nU~l*(Cm-l~
3350, 1730, 1650, Mass (m/e): 421 (M ) (2) In the same manner as described in Example 1 (2) using benzyl D-4-~N-(4-isohexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (4.0 g), methanol (40 ml) and palladium black (40 mg), there is obtained D-4-[N-(4-isohexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyr~l)amino]-n-butyric acid (2.9 g, 92.2 ~) as a colorless viscous oil. IR~JmaXm (cm 1):
3330, 1720, 1610, ~ass ~m/e): 331 (M ), [~]D6 +31.6 (c=l, ethanol) * Trade Mark ~. ~
9~
Example 4 (1) In the same manner as described in Example 1 (1) using benzyl D-4-~N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra~
hydrofuran (45 ml), pyridine (2.4 g) and pivaloyl chloride ~1.8 g), there is obtained benzyl D-4-[N-(4-pivaloyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.0 g, 47.6 %) as a colorless viscous oil.
IR vmaxm(cm 1): 3350, 1730, 1650, Mass (m/e): 407 (M ) (2) In the same manner as described in Example 1 (2) using benzyl D-4-[N-(4-pivaloyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.3 g), methanol (28 ml) and palladium black (30 mg~, there is ohtained D-4-[N-(4-pivaloyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.] g, 50.4 %) as colorless crystals. M.p. 79 - 82C recrystallized from a mixture of ethyl acetate and n-hexane, IR
(cm 1): 3350, 1730, 1710, 1610, Mass (m/e): 317 (M ) Example 5 (1) In the same manner as described in Example 1 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3 dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (45 ml), pyridine (2.4 g) and 3,3-dimethyl-n-butyryl chloride (2.0 g), there is obtained benzyl D-4-[N-(4-(3~3-dimethyl-n-butyryl)oxy-3~3-dimethyl-2 hydroxy-n-butyryl)amino]-n-butyrate (3.7 g, 71.0 ~) as a colorless sticky oily substance. IR ~maxm (cm ):
-~ * Trade Mar~
~5a59~
3350, 1730, 1650, Mass (m/e): 421 (M ) (2) In the same manner as described in Example 1 (2) using benzyl D-4-[N-(4-(3,3-dimethyl-n-butyryl)oxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.5 g), methanol (35 ml) and palladium black ( 40 mg ), there is obtained D-4-[N-(4-(3,3-dimethyl-n butyryl)oxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyric acid (2.2 g, 79.7 %) as colorless crystals. M.p. 102 - 104C, IR vmaU~l (cm 1): 3340, 10 1735, 1715, 1610, Mass (m/e): 331 (M+), [~]26 +32.0 (c=l, ethanol) Example 6 . _ (1) In the same manner as described in Example 1 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (45 ml), pyridine (2.4 g) and 2-ethyl-n-butyryl chloride (2.0 g), there is obtained benzyl D-4-[N-(4-(2-ethyl-n-butyryl)oxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.5 g, 47.9 %) as a colorless 20 viscous oil. IR vmaxm (cm 1): 3350, 1730, 1650, Mass (m/e): 421 (~ ) (2) In the same manner as described in Exam~le 1 (2) using benzyl D-4-[N-(4-(2-ethyl-n-butyryl)-oxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate 25 (2.4 g), methanol (24 ml) and palladium black ~30 mg), there is obtained D-4-[N-(4-(2-ethyl-n-butyryl)oxy-n-butyryl)amino]-n-butyric acid (1.7 g, 90.1 %) as * Trade Mark 9S~7 a colorless viscous oil. IRYmaX (cm ): 3350, 1730, 1710, 1645, Mass (m/e): 331 (M ), [~]19 +25.9 (c=l, ethanol) (3) In the same manner as described in 5 Example 1 (3) using D- 4- [N- ( 4 - ( 2-ethyl-n-butyryl)oxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.0 g), ethanol (20 ml), calcium hydroxide (130 mg) and water (2 ml), there is obtained calcium D-4-[N-(4-(2-ethyl-n-butyryl)oxy-3,3-dimethyl-2-10 hydroxy-n-butryl)amino]-n-butyrate (0.81 g, 76.6 %) as a colorless ~owder. [a]2l +24.7 (c=l, ethanol) Example 7 Calcium D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate hemihydrate (5.2 g) is dissolved in water (20 ml), and thereto are simul-taneously added dropwise with stirring lN aqueous sodium hydroxide (40 ml) and isobutyric anhydride (6.4 g) under ice-cooling over a period of about 30 minutes, while keeping a 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 recrystallized from ethyl acetate-n-hexane to give D-4-~N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (2.3 g, 37.4~) as colorless crystals.
The physicochemical properties of this product are identical with those of the product obtained in Example 1 (2).
Example 8 In the same manner as described in Example 7 using calcium D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino-n-butyrate hemihydrate (5.2 g), iso-valeric anhydride (7.4 g) and lN aqueous sodiumhydroxide (30 ml~, there is obtained D-4-[N-(4-iso-valeryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.9 g, 29.6 %) as colorless crystals.
The physicochemical properties of this product are identical with those cf the product ob-tained in Example 2 (2).
Exam~le 9 . .
(1) Benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g) is dissolved in tetrahydrofuran (30 ml) and thereto is added pyridine (2 ml). To the mixture is added dropwise a solution of acetyl chloride (1.2 g) in tetrahydrofuran (5 ml) under ice-cooling. The mixture is stirred at room temperature overnight and then concentra-ted under reduced pressure. The residue - is dissolved in ethyl acetate, and the solution is washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and saline solution in order. The ethyl acetate layer is dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography (solvent; chloroform : ethyl acetate = 4 : 1) to give benzyl D-4-[N-(4-acetoxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.3 g, 50.9 %) as a colorless viscous oil. IR vmax (cm ): 3350, 1730, 1650, Mass (m/e): 365 (M ) (2) Benzyl D-4-[N-(4-acetoxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g) is dis-solved in methanol (20 ml) and thereto is added palladium black (20 mg). I'he mixture is subjecte~ to catalytic reduction at room temperature under atmospheric ~ressure.
After the reaction, the reaction mix-ture is filtered to remove undissolved substances, and the filtrate is concentrated under reduced pressure to give D-4-[N-(4-acetoxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.38 g, 91.6 ~) as a colorless viscous oil.~ IR ~max (cm ): 3350, 1720, 1640, Mass (m/e): 275 (M ), [~]D0 +33.1 (c=l, ethanol) Exam~le 10 (1) In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml~, pyridine (2 ml) and propionylchloride (1.4 g), there is obtained benzyl D-4-[N-(4-propionyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.2 g, 46.9 %) as a colorless viscous oil. IR vmaxm (cm )o 3350, 1730, 1650, r~ass (m/e): 379 (M ) (2) In the same manner as described in Example 9 (2) using benzyl D-4-[N-(4-propionyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g), methanol (20 ml) and palladium black (20 mg), there is obtained D-4-[N-~4-propionyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.46 g, 95.7 %) as a colorless viscous oil. IR ymaxm (cm ):
3350, 1720, 1640, Mass (m/e): 289 (M ), [~X]D +30.0 (c=l, ethanol) Example 11 (I) In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetrahydrofuran (35 ml), pyridine (2 ml) and n-butyryl chloride (1.6 g), there is obtained benzyl D-4-[N-(4-n-butyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyrate (2.9 g, 59.6 %) as a colorless viscous oil. IR vmaxm (cm ): 3370, 1730, 1650, Mass (m/e): 393 (M )~ [~]D ~27.6 (c=l, ethanol) (2) In the same manner as described in Example 9 (2) using benzyl D-4-[N-(4-n-butyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g), methanol (20 ml) and palladium black (20 mg), there is ob-tained D-4-[N-(4-n-butyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino~-n-butyric acid (1.48 g, 96.0 ~) as a colorless viscous oil. IRv film (cm 1): 3350, 1720, 1640, Mass (m/e): 303 ~M )~
[~]D0 +30.2 (c=l, ethanol) Example 12 (1) In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml~, pyridine (2 ml) and n-valeryl-chloride (1.8 g), there is obtained benzyl D-4-[N-(4-n-valeryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyrate (3.0 g, 59.5 %) as a colorless crystals. M.p. 34 - 35C. IR ~mUaxol(cm 1): 3370, 1730, 1650, Mass (m/e): 407 (M ) (2) In the same manner as described in ~xample 9 ~2) using benzyl D-4-[N-(4-valeryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.6 g), methanol (30 ml) and palladium black (30 mg), there is obtained D-4-[N-(4-n-valeryloxy -3,3-dimethyl-20 2-hydroxy-n-butyryl)amino]-n-butyric acid (1.9 g, 93.8 %) as a colorless viscous oil. IR ~max (cm ):
3350, 1720, 1640, Mass (m/e): 317 (M ), [~]D0 +31.8 (c=l, ethanol) (3) D-4-[N-(4-Valeryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (0.9 g) is dissolved in methanol (10 ml), and thereto is added L-lysine (0.41 g). The mixture is stirred at room * Trade Mark ~Z~95~3~
,~
temperature for 30 minutes. ~he reaction mixture is concentrated under reduced pressure to remove the solvent. The residue is treated with n-hexane, and the resulting powder is collecte~ by filtration to give D-4-[N-(4-valeryloXy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid L-lysine salt (1.13 g, 86.3 %) as a colorless powder. ~.p. 130 - 133C, ~]D +25.5 (c=l, ethanol~
(4) D-4-[N-(4-n-Valeryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.0 g) is dissolved in methanol (10 ml), and thereto are added calcium hydroxide (0.12 g) and water (5 ml). The mixture is stirred at room temperature and then con-centrated under reduced pressure. To the residue is added ethanol, and the mixture is concentrated to dryness under reduced pressure to give calcium D-4-[N-(4-n-valeryloxy -3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyrate (1.0 g, 94.3 %) as a colorless powder.
ExamPle 13 (1) In the same manner as described in Example 9 (1) using benzyl D-4-[N-~2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetrahydrofuran (35 ml), pyridine (2 ml) and n-hexanoyl chloride (2.0 g), there is obtained benzyl D-4-[N-(4-n-hexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.2 g, 61.4 %) as a colorless viscous oil. IR7~maX (cm 1): 3370, 1730, 1650, Mass (m/e): 421 (M ) (2) In the same manner as described in Example 9 (2) using benzyl D-4- LN- (4-n-hexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate
ExamPle 13 (1) In the same manner as described in Example 9 (1) using benzyl D-4-[N-~2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetrahydrofuran (35 ml), pyridine (2 ml) and n-hexanoyl chloride (2.0 g), there is obtained benzyl D-4-[N-(4-n-hexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.2 g, 61.4 %) as a colorless viscous oil. IR7~maX (cm 1): 3370, 1730, 1650, Mass (m/e): 421 (M ) (2) In the same manner as described in Example 9 (2) using benzyl D-4- LN- (4-n-hexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate
5 (2.0 g), methanol (20 ml) and palladium black (20 mg), there is obtained D-4-[N-(4-hexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (lo 35 g, ~5.9 %) as a colorless viscous oil. IR film (cm 1): 3350, 1720, 1640, Mass (m/e): 331 (M ), [~]D0 ~27.6 (c=l, ethanol) (3) In the same manner as described in Example 12 (3) using D-4-[N-(4-n-hexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.0 g), L-lysine (0.44 g) and methanol (10 ml), there 15 is obtained D-4-[N-(4-n-hexanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid L-lysine salt (1.3 g, 90.2 %) as a colorless powder. M.p. 131 -134C, [~]D +25.1 (c=0.5, ethanol) Example 14 (1~ In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml), pyridine (2 ml) and n-heptanoyl chloride (2.2 g), there is obtained benzyl D-4-[N-(4-n-heptanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyrate (2.5 g, 46.4 %) as a colorless viscous oil. IR~JmaXm (cm 1): 3370, 1730, 1650, ~ L9~i~37 ~.2 ~
r~
Mass (m/e): 435 (M ) (2) In the same manner as described in Example 9 (2) using benzyl D-4-[N-(4-n-heptanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (1.8 g), methanol (20 ml) and palladium black (20 mg), there is obtained D-4-[N-(4-n-heptanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino] n-butyric acid (1.3 g, 91.1 %) as a colorless viscous oil. ~max 3330, 1720, 1640, Mass (m/e): 345 (M )~ [~D3 -~30.2 (c=l, ethanol) Example 15 (1) In the same manner as described in Example 9 (1) using benzyl 4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml), pyridine (2 ml) and n-octanoyl chloride (2.4 g), there is obtained benzyl D-4-[N-(4-n-octanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyrate (2.2 g, 39.6 %) as a colorless viscous oil. IR ~'max (cm ): 3370, 1730, 1~50, Mass (m/e): 449 (M ) (2) In the same manner as described in Exam~le 9 (2) using benzyl D-4-[N-(4-n-octanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-bu-tyrate (1.4 g), methanol (20 ml) and ~alladium black (15 mg), there is obtained D-4-[N-(4-n-octanoyloxy-3,3,-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.05 g, 93.8 %) as a colorless viscous oil. IR~'max (cm ):
5~7 3340, 1710, 1640, Mass (m/e): 359 (M )~ [~]D +27.4 (c=0.5, ethanol) Example 16 (1) In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dime-thyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml), pyridine (2 ml) and n-nonanoyl chloride (2.6 y), there is obtained benzyl D-4-[N-(4-n-nonanoyloxy~3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.9 g, 68.0 %) as a colorless viscous oil. IR~maX (cm ): 3370, 1735, 1650, Mass (m/e): 463 (M ) (2) In the same manner as described in Example 9 (2) using benzyl D-4-[M-(4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g), methanol (20 ml) and palladium black (20 mg), there is obtained D-4-[N-(4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.4 g, 86.9 ~) as a colorless viscous oil. IR ~'max (cm 1):
20 3330, 1720, 1640, Mass (m/e): 373 (M )~ [~]D +26.2 (c=l, ethanol) (3) In the same manner as described in Example 12 (3) using D-4-[N-(4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (0.9 g), methanol (10 ml) and L-lysine (0.35 g), there is obtained D-4-[N-(4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyric acid L-lysine salt (1.15 g, 91.8 ~) ~J~
as a colorless powder. M.p. 158 - 161C, [~]18 +22.9 (c=0.5, ethanol) J Reference Exam~le (1) Calcium D-4-[N-(2,4-dihydroxy-3,3-5 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 ion-exchange resin, followed by washing the column with water. The effluent and washing liquid are eombined and thereto 10 is added dicycl~hexylamine (71 g). The mixture is washed with ether, and the aqueous layer is concent rated under reduced pressure. The residue is crystal-lized from ethyl acetate. The precipitates 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 g) is mixed with benzyl bromide (50 g) and dimethyl-formamide (700 ml), and the mixture is stirred at about 60C for 6 hours. The reaction mixture is filtered to remove undissolved substances and the filtrate is con-centrated under reduced pressure. The residue is dis-solved 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 5~
acetate layer is dried and evaporated to dryness under reduced pressure to give benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (66 g, 69.9 ~) as a pale yellow oil. IR Vmax (cm ):
3350, 1725, 1650, Mass (m/e): 323, [~]D +32.0 (c=l, ethanol)
r~
Mass (m/e): 435 (M ) (2) In the same manner as described in Example 9 (2) using benzyl D-4-[N-(4-n-heptanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (1.8 g), methanol (20 ml) and palladium black (20 mg), there is obtained D-4-[N-(4-n-heptanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino] n-butyric acid (1.3 g, 91.1 %) as a colorless viscous oil. ~max 3330, 1720, 1640, Mass (m/e): 345 (M )~ [~D3 -~30.2 (c=l, ethanol) Example 15 (1) In the same manner as described in Example 9 (1) using benzyl 4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml), pyridine (2 ml) and n-octanoyl chloride (2.4 g), there is obtained benzyl D-4-[N-(4-n-octanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyrate (2.2 g, 39.6 %) as a colorless viscous oil. IR ~'max (cm ): 3370, 1730, 1~50, Mass (m/e): 449 (M ) (2) In the same manner as described in Exam~le 9 (2) using benzyl D-4-[N-(4-n-octanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-bu-tyrate (1.4 g), methanol (20 ml) and ~alladium black (15 mg), there is obtained D-4-[N-(4-n-octanoyloxy-3,3,-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.05 g, 93.8 %) as a colorless viscous oil. IR~'max (cm ):
5~7 3340, 1710, 1640, Mass (m/e): 359 (M )~ [~]D +27.4 (c=0.5, ethanol) Example 16 (1) In the same manner as described in Example 9 (1) using benzyl D-4-[N-(2,4-dihydroxy-3,3-dime-thyl-n-butyryl)amino]-n-butyrate (4.0 g), tetra-hydrofuran (35 ml), pyridine (2 ml) and n-nonanoyl chloride (2.6 y), there is obtained benzyl D-4-[N-(4-n-nonanoyloxy~3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (3.9 g, 68.0 %) as a colorless viscous oil. IR~maX (cm ): 3370, 1735, 1650, Mass (m/e): 463 (M ) (2) In the same manner as described in Example 9 (2) using benzyl D-4-[M-(4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyrate (2.0 g), methanol (20 ml) and palladium black (20 mg), there is obtained D-4-[N-(4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (1.4 g, 86.9 ~) as a colorless viscous oil. IR ~'max (cm 1):
20 3330, 1720, 1640, Mass (m/e): 373 (M )~ [~]D +26.2 (c=l, ethanol) (3) In the same manner as described in Example 12 (3) using D-4-[N-(4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid (0.9 g), methanol (10 ml) and L-lysine (0.35 g), there is obtained D-4-[N-(4-n-nonanoyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)-amino]-n-butyric acid L-lysine salt (1.15 g, 91.8 ~) ~J~
as a colorless powder. M.p. 158 - 161C, [~]18 +22.9 (c=0.5, ethanol) J Reference Exam~le (1) Calcium D-4-[N-(2,4-dihydroxy-3,3-5 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 ion-exchange resin, followed by washing the column with water. The effluent and washing liquid are eombined and thereto 10 is added dicycl~hexylamine (71 g). The mixture is washed with ether, and the aqueous layer is concent rated under reduced pressure. The residue is crystal-lized from ethyl acetate. The precipitates 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 g) is mixed with benzyl bromide (50 g) and dimethyl-formamide (700 ml), and the mixture is stirred at about 60C for 6 hours. The reaction mixture is filtered to remove undissolved substances and the filtrate is con-centrated under reduced pressure. The residue is dis-solved 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 5~
acetate layer is dried and evaporated to dryness under reduced pressure to give benzyl D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino]-n-butyrate (66 g, 69.9 ~) as a pale yellow oil. IR Vmax (cm ):
3350, 1725, 1650, Mass (m/e): 323, [~]D +32.0 (c=l, ethanol)
Claims (12)
1. A process for preparing a 4-aminobutyric acid derivative of the formula:
( I) wherein R1 is a straight or branched alkyl group having 1 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof; which method comprises:
(A) subjecting a 4-aminobutyric acid derivative of the formula:
(II) wherein R1 is as defined above, and R2 is a group removable by catalytic reduction, to catalytic reduction, and optionally converting the product to a pharmaceutically acceptable salt thereof; or (B) reacting a 4-aminobutyric acid derivative of the formula:
( III) with a reactive derivative of a carboxylic acid of the formula:
R1COOH (IV) wherein R1 is as defined above, and optionally convert-ing the product into a pharmaceutically acceptable salt thereof.
( I) wherein R1 is a straight or branched alkyl group having 1 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof; which method comprises:
(A) subjecting a 4-aminobutyric acid derivative of the formula:
(II) wherein R1 is as defined above, and R2 is a group removable by catalytic reduction, to catalytic reduction, and optionally converting the product to a pharmaceutically acceptable salt thereof; or (B) reacting a 4-aminobutyric acid derivative of the formula:
( III) with a reactive derivative of a carboxylic acid of the formula:
R1COOH (IV) wherein R1 is as defined above, and optionally convert-ing the product into a pharmaceutically acceptable salt thereof.
2. A process according to claim 1 which comprises carrying out reaction (A) or reaction (B) employing a starting material (I) or (IV) respectively in which R1 is a straight chain alkyl group having 1 to 8 carbon atoms.
3. A process according to claim 1 which comprises carry-ing out reaction (A) or reaction (B) employing a starting material (I) or (IV) respectively in which R1 is a branched chain alkyl group having 1 to 8 carbon atoms.
4. A process according to claim 1 which comprises carry-ing out reaction (A) or reaction (B) employing a starting material (I) or (IV) respectively in which R1 is a member selected from the group consisting of isopropyl, isobutyl, isovaleryl, tert-butyl, 2,2-dimethylpropyl and 1-ethyl-propyl.
5. A process according to claim 1 which comprises either:
(A) subjecting a compound of formula (II) of D-configuration in which R1 is isobutyl to catalytic reduction, and optionally converting the product to a pharmaceutically acceptable salt thereof; or (B) reacting a compound of formula (III) of D-configuration with a compound of formula (IV) in which R1 is isobutyl, and optionally converting the product into a pharmaceutically acceptable salt thereof.
(A) subjecting a compound of formula (II) of D-configuration in which R1 is isobutyl to catalytic reduction, and optionally converting the product to a pharmaceutically acceptable salt thereof; or (B) reacting a compound of formula (III) of D-configuration with a compound of formula (IV) in which R1 is isobutyl, and optionally converting the product into a pharmaceutically acceptable salt thereof.
6. A process according to claim 1 which comprises either:
(A) subjecting a compound of formula (II) of D-configuration in which R1 is isovaleryl to catalytic reduction, and optionally converting the product to a pharmaceutically acceptable salt thereof; or (B) reacting a compound of formula (III) of D-configuration with a compound of formula (IV) in which R1 is isovaleryl, and optionally converting the product into a pharmaceutically acceptable salt.
(A) subjecting a compound of formula (II) of D-configuration in which R1 is isovaleryl to catalytic reduction, and optionally converting the product to a pharmaceutically acceptable salt thereof; or (B) reacting a compound of formula (III) of D-configuration with a compound of formula (IV) in which R1 is isovaleryl, and optionally converting the product into a pharmaceutically acceptable salt.
7. A 4-aminobutyric acid derivative of the formula:
(I) wherein R1 is a straight or branched alkyl group having 1 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof; whenever prepared by the process of claim 1 or an obvious chemical equivalent.
(I) wherein R1 is a straight or branched alkyl group having 1 to 8 carbon atoms, or a pharmaceutically acceptable salt thereof; whenever prepared by the process of claim 1 or an obvious chemical equivalent.
8. A compound according to claim 7, wherein R1 is a straight chain alkyl group having 1 to 8 carbon atoms;
whenever prepared by the process of claim 2 or an obvious chemical equivalent.
whenever prepared by the process of claim 2 or an obvious chemical equivalent.
9. A compound according to claim 7, wherein R1 is a branched chain alkyl group having 1 to 8 carbon atoms;
whenever prepared by the process of claim 3 or an obvious chemical equivalent.
whenever prepared by the process of claim 3 or an obvious chemical equivalent.
10. A compound according to claim 7, wherein R1 is a member selected from the group consisting of isopropyl, isobutyl, isovaleryl, tert-butyl, 2,2-dimethylpropyl and 1-ethylpropyl; whenever prepared by the process of claim 4 or an obvious chemical equivalent.
11. A compound according to claim 7, which is D-4-[N-(4-isobutyryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid or a pharmaceutically acceptable salt thereof;
whenever prepared by the process of claim 5 or an obvious chemical equivalent.
whenever prepared by the process of claim 5 or an obvious chemical equivalent.
12. A compound according to claim 7, which is D-4-[N-(4-isovaleryloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amino]-n-butyric acid or a pharmaceutically acceptable salt thereof;
whenever prepared by the process of claim 6 or an obvious chemical equivalent.
whenever prepared by the process of claim 6 or an obvious chemical equivalent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000422240A CA1219597A (en) | 1983-02-23 | 1983-02-23 | 4-aminobutyric acid derivatives and process for the preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000422240A CA1219597A (en) | 1983-02-23 | 1983-02-23 | 4-aminobutyric acid derivatives and process for the preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1219597A true CA1219597A (en) | 1987-03-24 |
Family
ID=4124625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000422240A Expired CA1219597A (en) | 1983-02-23 | 1983-02-23 | 4-aminobutyric acid derivatives and process for the preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1219597A (en) |
-
1983
- 1983-02-23 CA CA000422240A patent/CA1219597A/en not_active Expired
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