JPS59161343A - 4-aminobutyric acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is 3-7C cycloalkyl which may be substituted, e.g., with lower alkyl; R<2> is H, benzyl) or its salt. EXAMPLE:Benzyl D-4-[N-(4-cyclopentylcarbonyloxy-3, 3-dimethyl-2-hydroxy-n-butylyl)amino]-n-butyrate. USE:Improver of cerebral metabolism and higher cerebral functions: it has low toxicity and high safety. It is converted in a living body into hopantenic acid and its concentration in brain or serum is higher and more durative than when calcium hopantenate is administered. PREPARATION:The reaction between a compound of formula II and a reactive derivative of a carboxylic acid of the formula: R<1>COOH such as acid halide gives the compound of formula I . The reaction is effected in an appropriate solvent in the presence or absence of an acid acceptor such as triethylamine.

Description

[Detailed description of the invention]

The present invention relates to a 4-aminobutyric acid derivative and a method thereof, and its history in detail is expressed by the general formula % () (where nl is a carbon number that may have a lower alkyl group as an exchange group; 3 to 7 represents a cycloalkyl group of
R2 represents a hydrogen atom or a benzyl group. ] and its method A. Calcium bopanthenate (Chemistry 820-(+1-(2,
4-dihydroxy-3,3-J methylpunaramide (calcium salt of butyrate) -1 mild mental retardation, sequelae of encephalitis,
It is known to be a useful pharmaceutical compound as an agent for improving brain metabolism and higher brain function in order to alleviate symptoms such as hyperactivity, decreased attention, impaired speech, and decreased motivation associated with cerebral palsy. When the above-mentioned calcium hopanthenate was administered to the tongues of the present invention. Focusing on the fact that hopantenic acid exists as free hopantenic acid in the body (for example, in plasma or in the brain), we conducted extensive research and found that the above-mentioned compound CI) It is rapidly absorbed into the plasma and brain as phononthenic acid, exhibiting an extremely high concentration and long-lasting. For example, oral administration of each compound to rats (dose: 3
89.4 pmole/Kt) ) L, ・Administration 1,
When the concentration of hopantenic acid in plasma was measured after 2 and 3 hours - D-4-1 of the compound of the present invention: N-(4-cyclohexylcarbonyloxy-3,3-dimethyl-2-hydroxy-n-butyryl)amide ]-n-butyric acid showed a concentration of hopantenic acid about 1.3 to 1.8 times higher than that of lucium hopantenate. First, when each compound was orally administered to rats (dose: 389.4 μmole/YU) and the concentration of hopantenic acid in the brain was measured 2 or 3 hours after administration. D-4-CN of the compound of the present invention -(4-Cyclohexylcarbonyloxy-3゜3-dimethyl-2-hydroxy-11-butyryl)TminoJ-n-68rq2 has a hopantene content that is approximately 1.9 to 2.4 times higher than that of calcium hopanthenate. The acid concentration of D-4-CN-(4-cyclohequinyloxy-3) of the compound of the present invention is low in toxicity and ensures safety. , 3-dimethyl-2-hydroxy-n-butyryl)amino J-n-acetic acid. is 1.000 mFlyKqp. As mentioned above, the compound (I) of the present invention converts hopanthene MIc in vivo after administration, and the concentration of hopanthene in the brain [in the body and in the body] is higher than when hopantene calcium is administered. Better than 2 due to good sustainability
It is a useful medicinal compound as an agent for improving brain metabolism and higher-order stress levels 1 and 2. Examples of the compounds of the present invention include B
and R1 is a cycloalkyl group having 3 to 7 carbon atoms, which may contain a lower alkyl group (e.g., methyl group, ethyl group, propyl group) as a substituent.

[Example: EVA, cyclopropyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or 1-methylcyclohexyl group], and compounds in which R2 is a hydrogen atom or a benzyl group are mentioned. Among these, preferred compounds include the general formula (
In I), compounds in which R1 is a cyclopentyl group or a cyclo-\xyl group and R2 is a hydrogen atom are mentioned. A more preferable f compound is D-4-(N-
(4-cyclohexylcarbonyloxy-3,3-dimethyl-2-hydroxy-n-phthyryl)amino, 1-
n-Butyric acid is released, and the compound also has the advantage of being available in crystalline form. Note that the compound (f) of the present invention has an asymmetric carbon atom in the molecule. Among these isomers, when used as a medicine, the compound (I
) in which the asymmetric carbon atom is in the D configuration is particularly preferred. According to the present invention, compound (1) is a compound represented by the general formula eH3 (wherein R2 has the same meaning as above); ) can be produced by reacting with a reactive derivative of carboxylic acid shown in (). In addition, a compound in which 3 in the general formula (E) is a hydrogen atom can be produced by catalytic reduction of the compound (IV) represented by the general formula (wherein R1 has the same meaning as above). The reaction between compound (,11) and the reactive derivative of compound (lII) is carried out in the presence of a deoxidizing agent or in the absence of (()) in an appropriate solvent. The compound (phantom I/cE and R
When using a compound in which 2 is a hydrogen atom, it can also be used in the form of a salt (for example, calcium salt).As a reactive derivative of compound (H) used in this reaction, 1, for example, compound (I[) Acid halides or acid anhydrides are preferred. Examples of deoxidizing agents include ethylamine, pyridine, dimethylaniline, organic tertiary amines such as P-dimethylaminopyridine, sulfur hydroxide, water Inorganic salts such as alkali metal hydroxides such as potassium oxide (7), alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metals after heavy carbon such as sodium hydrogen carbonate and potassium hydrogen carbonate are preferably used. The solvent can be 5, for example, tetrahydrofuran, dioxane, chloroform, methylene chloride, benzene, ethyl acetate, dimethylformamide, and the reaction is preferably carried out at 0 to 20°C. It can be carried out in the presence of a catalyst in a solvent while passing hydrogen gas through it.As a catalyst, examples include palladium black, palladium-carbon, etc.As a solvent,
For example, lower alkaline alcohols (e.g., methanol, ethanol, n-propanol, impropanol, etc.), tetrahydrofuran, dioxane, or any of these
A mixed solvent of Ix't and water can be mentioned. This reaction is carried out at 1 to 10 atm: EF, 0 to 60°C, especially 1
Preferably, the reaction is carried out at 10 to 30°C under ~3 atmospheres. (If the group represented by R1 in compound (1) of the present invention is a hydrogen atom, then the compound CI)
When used as a medicine, it can be used in the form of the free carboxylic acid, but also in the form of its pharmacologically acceptable salt. Examples of such R2 salts include ``calcium salt, sodium salt, ``potassium salt, linium salt,
Preferably, magnesium salts, frunichi 7 AM, arginine salts, etc. are used. When the compound of the present invention (CI) or a pharmacologically acceptable salt thereof is used as a medicine, it can be administered orally (or parenterally). The compound of the present invention (II) may be used in the form of a solid preparation such as granules, etc., or a liquid preparation such as a solution, a liquid solution, or an emulsion. Such pharmaceutical carriers include, for example, calcium carbonate, calcium phosphate, corn starch, potato starch, sand, lactose, talc, magnesium stearate, etc. Compound (i) of the present invention or its pharmacological properties The permissible dosage of vine salt varies depending on the type of disease, age and weight of the patient, the degree of the disease, and the route of administration, etc. Especially for oral administration, the dosage is usually 1 to 20 n'j per day.
. Preferably, 2 to 10tIVK9 is suitable. In addition, one example of the starting compound (II) in which the group 3 and R2 in the general formula (II) is a benzyl group is 4-[N-(
7p, or 4-amino-n-, in which a metal salt or an organic amine salt of 2,4-dihydroxy-3,3-dimethyl-〇-butyryl J-amino/J butyryl is reacted with pencil halide.
Benzyl ester 2,4-dihydroxy-3,3
It can be easily cleaved by reacting -dumenal-n-butyric acid with γ-lactone. experiment! ;'l! 1 SD non-strain rat body weight fasted overnight: Approximately 2QOg,
7 weeks old, 1 group: 4 animals) were suspended with the test compound at 0.5'go carboxymethylcellulose m for 7 nights.
Oral administration of 2 ml of the same wave using a gastric probe [Sample injection '4
, :11: 389.4-μmole/KL9. (
Calcium Hopantenate I Q Or'igu1KfiI
Old version equivalent to VRC] Administration 1 hour, 2 o'clock ft"5
Or 3 hours later, at 6:00: The carotid artery was cut, the animals were sacrificed, and blood was collected. Centrifuge the surface fluid of each rat'd9;(') (2
800 r-Plm, 715 minutes) The shite surface serum was collected, and 0.1-ml of it was used for measurement. Phonopoxic acid, A% i, in blood was determined by gas chromatography 7 mass spectrometry. The results are shown in Table 1 below. Compound 1 Table Compound A: D-4-[N-(4-cyclohexylcarbonyloxy-3,3-'/'methyl-2-hydroxy-n-butyryl)teriminoJ-n-butyric acid control compound: D- 4-CN-(2,4-dihydroxy-
3,3-dimethyl-n-butyryl]amino J-n-butyric acid calcium salt experimental example 2 SD male rats (body weight: approx. 200F,
, 7 weeks old, 1 group: 4 animals) were given 2 m of a suspension of the test compound in 0.5% carboxymethyl cellulose solution.
Orally administered using a gastric probe [sample dose meter: 389.
4 μmole /~, (calcium hopanthenate 100
m9/Yu corresponding to J). 2 hours after administration
After 81 hours, the tubes were removed and washed with saline. Add 9 times the amount of water to the cerebrum and homogenize with a homogenizer while cooling with water, then homogenize at 4°C.
Centrifuged for 1 hour at 10.00 Or, P, m. The supernatant was taken and 1 mt (corresponding to 0.1 g of brain) was used for measurement. The concentration of hopantenic acid in the supernatant was measured by gas chromatography/spectrometry. The results are shown in Table 2 below. The test compounds in Table 2 are the same compounds as in Experiment 1i71i 1. Implementation I D-4-CN-(2,4-dihydroxy-3,3-dimethyl-n-butyryl)amino J-n-FJ acid benzyl ester 4fj is dissolved in 30% of tetrahydrofuran, and then pyridine 2i is added.The mixture is diluted with 2.07% of cyclopentylcarbonyl chloride and 5% of tetrahydrofuran.
- Add the solution dropwise while stirring while cooling with ice water. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. Dissolve the residual culm in ethyl acetate, and wash the solution sequentially with dilute hydrochloric acid/water, aqueous sodium bicarbonate solution, and brine. After drying the ethyl acetate solution, concentrate under reduced pressure to remove the solvent.Residual culm FID-4-[
N-(4-cyclopentylcarbonyloxy-3,3
-') Methyl-2-hydroxy-〇-bunaryl]aminocone n-butyric acid benzyl ester 2.77 is obtained as colorless crystals. Yield: 52.0 Curse M, P, 43-45”
C r”J+uitfax (cm”n:
3350. 3250. 1720. 640 1JaSr; (Ill/Q): 4 19
(M+) [L3! Formula +26.1° [C=1. Ethanol〕Example? 2. 0!i!f Methanol 20 VC
Dissolve and then add teno<radium black 2 Q r:η. 1. The mixture is subjected to catalytic reduction at room temperature. After the reaction, the reaction mixture was filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure to obtain D-4-[N-(4-cycloguntylcarponyloxy-3,3-dumenal-2). -Hydroxy n-
Butyryl] Ami/”-n-drunkenness 1.45! V is colorless viscous 1
Obtained as a viscous oil. Yield: 92.4% IRν InaX ((full): 3
340.1720.164 (111ass (m/e
): 329 (M+) [α] Sweet 26.1° (C=
1, ethanoltumethyl-〇-butyryl]amino”-
n-benzyl ester 4.0! lZ, tetrahydrofuran 35-, pyridine 2In! And ``Cyclo dicarbonyl chloride'' 2.2! By treating I in the same manner as in Example 1, D-4-CN-(4-cyclohexylcarbonioquine-3,3-dumenal-2-hydeoxyn-)"tyryl)amino J-+1 - Acetic acid benzyl ester 4.07 is obtained. Yield near 4.6%1
．． 1. P, 67-69″C (recrystallized from vinegar-treated enal-γl-hexane mixture J I Rvnujol (2″): 3350,3300.
1720°640 Mass (+++/e): 433 (M”-)
[α” snow +24.3° (C=1.ethanol) real,
1 [di) row 4 D-4-[N-(4-cyclohexylcarbonyl 30
A mixture of rnI and palladium black 3 Q rnq is catalytically reduced as in run flI2. After the reaction 9. The reaction mixture is filtered to remove insoluble matter, and the filtrate is concentrated under reduced pressure F. By recrystallizing the residual culm from a mixture of ethylene acetate and n-hexynane, D-4-[N-(4-cyclohexycarbonyloxy:3,:1-dime]=ru:cyhydroxy-
2.2 〇-butyryl)amino/''-n-butyric acid is obtained as colorless crystals. Yield p: 92.6%M,P,
71-73 °C I RVnW'(C7+1"), 113400.332
0.1735-1720.1620 tAass (m/e] : 3 4 3(
rA) CO13 + 30,4° (C=1, ethanol) Example 5 D-4-1:N-(2,4-dihydroxy-3,:)-
dimethyl-〇-butyryl)amino J n-W benzyl ester s, oy, tetrahydrofuran 40-, pyridine 2.51 nl and cyclopropyl luponibonyloxy-3,3-dumenal-2-hydroxy 62.8 y F '-V z (cm"): 3350-17
30.1650Mass (m/e) :391 (
M+3 Example 6 D-4-(N-(4-cyclopylcarbonyloxy-3,3-dimethyl-?-hydroxy-n-bunaryl)
D-4-[N-(4-cyclopropylic acid) was prepared by treating 3.6 ml of amino'-n-butyric acid benzyl ester, 40 ml of methanol, and 40 d of palladium black as in Example 2. 3-dumenal-2-hydroxy-n-butyric acid 2.5]
As a colorless viscous curved shape, we get the answer ↓. Yield: 90.2% f'i1m
-i・IRνmax (cm), 3350.1720
, 1640Mass (m/e): 301 (M”
) [fl! J"5 +34.9' (C=1, ff
! /-R) Example 7 D-4-[N-(2,4-dihydroxy-3,3-dimethyl-n-butyryl]amino J-n-butyric acid benzyl ester 5.0 g, tetrahydrofuran 40 +nlrpyridine 2.5rn1 . and cyclohepnaryl chloride 3.07 J:
4.1 g of RiD-4-[N=(4-cyclohebutylcarbonyloxy-3,3-dumenal-2-hydroxy-〇-butyryl]amino J-n-butyric acid benzyl ester)
is obtained as colorless crystals. Yield: 59°2M, P, 60-61°C [olJH+ 24.8° (C=1.ethanol] Example 8 D-4-1: N-(4-cyclohebutylcarbonyloxy-3, D-4-CN-( 4-cyclohebutylcarbonyloxy-3,3-dumenal-2-hydroxy-n-bunari/l/) ymi/J-n-butyric acid 1.
8 g are obtained as a colorless viscous oil. yield:! No 0.
0% I RJ' max (cX) -3350,1720
,1640Mass (m/e'): 357 (
:A+I[α]1B+'22.5'(C=1,
Example 9 D-4-CN-(2,4-dihydroxy-3,3-dimenal-n-butyryl)amino J-n-66 benzyl ester 5, og, tetrahydrofuran 40ml, pyridine 2.5, D-4-[N-(4-[1-menal-cyclohexylcarbonyloxyj-3, co3-dimenal-2 -Hydroxy-n-7'tyryl]amino J-n-butyric acid benzyl ester 3.75 i' is obtained as a light-colored viscous oil. Yield: 53.5% IRL'','','#: (ci''
)': 3350-1730.1650Mass (+
n/e): 447 (IJ+3 implementation% 10 D-4-[injection-(4-(1-methylcyclohexylcarbonyloxyl-3, 1-dumenal-2-hydroxy-〇-butyryl)amino J-n- D-4-1: N -(4-(1-methyl-cyclohexylcarbonyloxy) -3,:(-di/chill-2-
Hydroxy-n-butyryl)amino J-n-butyric acid 2.6
! iZ is obtained as a colorless, viscous, chalky substance. Yield: 93.0% IR, fR, m + tyil): 3350-17
20, 16401Jass (m/e): 35
7 (M+)[αj廿+29.0°(C=l,ethanol)]Example 11 o-4-(N-(2,4-dihy10xy3,4-dimethyl-n-bunaryl)amino J-n - Dissolve 2.67 liters of calcium salt l/2 hydrate in water and press down with water cooling. p+
Add dropwise over about 30 minutes while maintaining the concentration of 1 to 8-9. After the dropwise addition, the mixture is stirred at the same temperature for 40 minutes. The reaction mixture was washed with ethyl acetate, the aqueous layer was made acidic with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure. The residual culm was subjected to silica gel chromatography (m medium: chloroform: ethyl acetate = 4
D-4-[N-(4
50.79 of -cyclodibutylcarbonyloxy-3,3-dimenal-2-hydroxy-n-butyryl)amino J-n-butyryl is obtained as a colorless viscous oil. Yield 221
．． 0E2; The silicochemical properties of the main island are consistent with the specimen obtained in Example 2. Reference examples are) D-4-[:N-(2,4-dihydrokinube,
3-dimethyl-n-butyryl)amino J-n-6g acid calcium salt l/2 hydrate 1007 in water 500ml 1°K
Dissolve and pass the solution through the acid form resin, then wash the resin with water. Combine the effluent and washing liquid and add 71v of dicyclohexylamine. The IU compound f is washed with ether, and the aqueous layer is concentrated under reduced pressure. The remaining culm is delivered with ethyl acetate, the precipitated product is filtered, and then washed with ether to obtain D-4.
-[N-(2,4-dihydroxy-3,3-dimethyl-
n-butyl)amino J-n-r+8e dicyclohexylamine salt 122 is obtained as #if color crystals.
Yield near 5-6% +21 0-4-(N-'(2,4-dihydroxy-3
゜3-dimethyl-n-phthyryl)amino J-n-butyric acid.
Dicyclohexylamine salt 121 is mixed with 507 Febenzyl bromide and 700 rnl of dimenalformamide and the mixture is stirred at 60° C. for 6 hours. The reaction mixture is filtered, the waste material is distilled off, and the filtrate is concentrated under reduced pressure. Dissolve the residual culm in ethyl acetate, and add 1 part of the G solution to dilute sulfuric acid.
Wash sequentially with a saline solution and an aqueous solution of sodium bicarbonate. The ethyl acetate layer was dried and the solvent was distilled off under pressure.
-4-Crq -(2゜4-dihydroxy-3,3-
Dimethyl-n-zotyryl)ami/J-n-ff15 acid benzyl ester 66y- is obtained as a pale yellow oil.
Yield: 69.9%. I Rν""(cm'): 335Q, 1725. i
650 MaBS (m/θ]: 323

Claims (1)

[Claims] 1. General formula % Formula % (where R1 represents a cycloalkyl group having carbons a3 to 7 which may have a lower alkyl group as a substituent)
R2 represents a hydrogen atom or a benzyl group. ) or a pharmacologically acceptable salt thereof. 2. The compound represented by the general formula % formula % (11 (2 [(However, R2 represents a hydrogen atom or a benzyl group)] is a one-step formula % formula % (However, R1 is a lower alkyl group as a substituent. (wherein R1 and R2 have the same meanings as above) 3. A method of using a 4-amylbutyric acid derivative or a pharmacologically acceptable salt thereof represented by the formula (wherein R1 has 3 to 7 carbon atoms, which may have a lower alkyl group as a substituent) The cycloalkyl group of formula % is characterized in that the compound represented by n is catalytically reduced, and if necessary, the product is converted into its pharmacologically acceptable salt (wherein R1 has the same meaning as above.] A method for producing a 4-aminobutyric acid derivative or a pharmacological VC8F-compatible salt thereof.