JPH06107613A - New succinic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a new succinic acid derivative, capable of manifesting insulin secretion promoting and hypoglycemic actions and useful as a therapeutic agent for diabetes and its salt. CONSTITUTION:The objective new succinic acid derivative of formula I (R<1> is H, halogen or 1-4C alkyl; R<2> is H or 1-6C alkyl; R is H or two groups R are bound to form single bond; B is adamantyl, cycloalkyl or norbornyl) and its salt, especially succinic acid derivatives of formula II, III and IV and salts thereof, e.g. (E)-2-benzylidene-3-cyclohexylaminocarbonylpropionic acid. This compound of formula I, e.g. a compound of formula V is obtained by reacting a partially new benzylidenesuccinic anhydride of formula VI with primary amines of the formula B-NH2 and, as necessary, esterifying the resultant compound.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel succinic acid derivative and a salt thereof which are useful as a medicine.

More specifically, the present invention has a hypoglycemic action and is useful as a therapeutic agent for diabetes.

[0003]

[Chemical 5]

(In the formula, R ¹ is a hydrogen atom, a halogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R is a hydrogen atom. Or both are combined to form a single bond, and B is an adamantyl group, a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a lower alkyl group having 1 to 4 carbon atoms, or a norbornyl group). The present invention relates to a succinic acid derivative and a salt thereof.

[0005]

BACKGROUND OF THE INVENTION Regarding succinic acid derivatives such as the present invention,
formula

[0006]

[Chemical 6]

A compound or formula represented by

[0008]

[Chemical 7]

The compound represented by the formula (1) has been produced and used as an intermediate for the production of renin inhibitors, but none of its pharmacological actions has been reported. [Chemical Abstracts (Chem. Abst.) Volume 71,
22382u (1969), 99 volumes, 158866.
r (1983), 101, 211728k (19)
84), the same volume 105, 79373s (1986),
110, 232084y (1989), 111
Volume, 33474w, 214942t (1989), 112 volumes, 217541t (1990), 113
Volume, 59841e (1990), Volume 115, 136.
788p (1991), 116 volumes, 42060p
(1992)]

[0010]

An object of the present invention is to provide a novel succinic acid derivative having a blood glucose lowering action and useful as a therapeutic agent for diabetes.

[0011]

Means for Solving the Problems As a result of intensive studies by the present inventors, it was found that the succinic acid derivative represented by the general formula (I) and its salt exhibit insulin secretagogue action and hypoglycemic action. Heading out, the present invention has been accomplished.

In the compound of the general formula (I) of the present invention, the lower alkyl group means a linear or branched lower alkyl group, and the adamantyl group is a 1-adamantyl group or a 2-adamantyl group. Can be raised.

The succinic acid derivative represented by the general formula (I) of the present invention is a novel compound and can be produced as follows.

That is, of the succinic acid derivatives represented by the general formula (I) of the present invention, R is a general formula in which both are bonded to form a single bond.

[0015]

[Chemical 8]

The compound represented by the formula (wherein R ¹ , R ² and B have the same meanings as described above) has the general formula

[0017]

[Chemical 9]

Benzylidene succinic anhydride represented by the formula (R ¹ has the same meaning as described above) and the general formula B--NH ₂ (III)

It can be produced by reacting with a primary amine represented by (B in the formula has the same meaning as described above) and esterifying if necessary.

Among the succinic acid derivatives represented by the general formula (I) of the present invention, the general formula in which R is a hydrogen atom

[0021]

[Chemical 10]

The compound represented by the formula (wherein R ¹ , R ² and B have the same meanings as described above) is a compound represented by the general formula (Ia) above.
The succinic acid derivative represented by can be produced by reducing the double bond by catalytic hydrogenation or the like, and esterifying if necessary. Regarding stereoisomerism of the succinic acid moiety, a compound having S configuration or R configuration can be isolated by optical resolution or the like.

The benzylidene succinic anhydride of the general formula (II) used as a starting material in the present production method contains a novel compound, and any of them can be easily prepared by the method described in the literature like the method of producing a known compound. It can be manufactured.

The amino compound represented by the general formula (III) is also a known compound and may be purchased as a commercial product or
It can be easily produced by a method described in the literature or a method similar thereto.

The compound of the above-mentioned general formula (I) of the present invention was tested in an in vivo blood glucose lowering test using mice.
Oral administration of about 5 to 10 mg / kg shows a clear hypoglycemic effect.

Among the compounds of the general formula (I) of the present invention, the compound of the general formula (Ia), in which R is a single bond, has E and Z geometric isomers due to a double bond. However, the E form exerts a favorable pharmacological action in insulin secretion action and blood glucose lowering action. Further, among the compounds of the general formula (I) of the present invention, the compound of the general formula (Ib) in which R is a hydrogen atom has an asymmetric carbon in the succinic acid moiety, and is a compound of the R configuration and the S configuration. In the present invention, the compounds having the S configuration exert a better pharmacological action in the action of suppressing insulin secretion and the action of lowering blood glucose.

Preferred compounds of the compound of the general formula (I) of the present invention include (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid, 2-benzyl-3-cyclohexylaminocarbonylpropionic acid and (S). 2-Benzyl-3-cyclohexylaminocarbonylpropionic acid can be mentioned.

In the compound of the general formula (I) of the present invention, R ²
The compound wherein is a hydrogen atom can be converted into a pharmaceutically acceptable salt according to a conventional method. As something like this,
Examples thereof include salts with inorganic bases such as sodium salts, potassium salts and calcium salts, organic amines such as morpholine, piperidine and phenylalaninol, or salts with amino acids. Similar to carboxylic acids, these pharmacologically acceptable salts also exhibit an insulin secretion promoting action and a blood glucose lowering action, and are useful as therapeutic agents for diabetes.

When the succinic acid derivative represented by the general formula (I) of the present invention and its salt are used for actual treatment, they are used as suitable pharmaceutical compositions such as tablets, powders, granules, capsules, injections and the like. It is administered orally or parenterally. These pharmaceutical compositions can be prepared by the pharmaceutical techniques performed in general preparations.

The dose is appropriately determined according to the sex, age, body weight, degree of symptoms, etc. of the target patient. Oral administration is about 10 to 1000 mg per day for adults, and parenteral administration is about for adults. It is administered within the range of 1 to 100 mg per day.

[0031]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference Example 1 (E) -2-Methylbenzylidene succinic anhydride

A mixture of 6.0 g of 2-methylbenzaldehyde and 12.0 g of diethyl succinate was added dropwise to a solution of 8.5 g of potassium t-butoxide in 100 ml of t-butanol, and the mixture was heated under reflux for 3 hours. After the solvent was distilled off under reduced pressure, 100 ml of 10% aqueous sodium hydroxide solution was added to the residue,
The mixture was heated under reflux for 5 hours. Concentrated hydrochloric acid was added to the reaction solution under ice cooling to make it acidic, and the precipitated crystals were collected by filtration to obtain (E) -2-methylbenzylidene succinic acid (3.6 g).

1.1 g of (E) -2-methylbenzylidene succinic acid was added to 20 ml of acetic anhydride, and the mixture was stirred at 60 ° C. for 2 hours. After the solvent was distilled off under reduced pressure, the residue was recrystallized from toluene-hexane (1: 5) to obtain 0.9 g of (E) -2-methylbenzylidene succinic anhydride.

Melting point: 112 to 113 ° C. NMR (CDCl ₃ , 400 MHz) δ: 2.43 (3H, s), 3.82 (2H, d, J =
2.6 Hz), 7.25 to 7.45 (4 H, m), 7.
77 (1H, t, J = 2.6Hz) IR (KBr): νCO 1840, 1780cm
^-1

Example 1 (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid

(E) -Benzylidene succinic anhydride 18
150 mg of cyclohexylamine was added dropwise to a suspension of 8 mg of methylene chloride in 10 ml, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 1N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
Crystallization from ethyl acetate gave (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid 1
86 mg was obtained.

Melting point: 182 to 183 ° C. NMR (CDCl ₃ , 270 MHz) δ: 1.05 to 2.0 (10 H, m), 3.40 (2
H, s), 3.7 to 3.9 (1H, m), 6.05 (1
H, d, J = 7.4 Hz), 7.35 to 7.75 (5
H, m), 8.01 (1H, s) IR (KBr): νCO 1685, 1640 cm
^-1 νNH 3300cm ^-1

Example 2 The following compound was produced in the same manner as in Example 1 except that cyclopentylamine was used instead of cyclohexylamine.

(E) -2-benzylidene-3-cyclopentylaminocarbonylpropionic acid

Melting point: 168 to 169 ° C. NMR (CDCl ₃ , 270 MHz) δ: 1.2 to 2.1 (8H, m), 3.41 (2H,
s), 4.1 to 4.35 (1H, m), 6.17 (1
H, d, J = 6.9 Hz), 7.3 to 7.75 (5H,
m), 8.02 (1H, s), 9.6 (1H, br) IR (KBr): νCO 1675, 1650 cm
^-1 νNH 3300cm ^-1

Example 3 The following compound was produced in the same manner as in Example 1 except that exo-2-norbornylamine was used instead of cyclohexylamine.

(E) -2-Benzylidene-3- (exo-2-norbornylaminocarbonyl) propionic acid

Melting point: 175 to 177 ° C. NMR (DMSO-d ₆ , 400 MHz) δ: 1.0 to 1.7 (8 H, m), 2.0 to 2.3 (2
H, m), 3.1-3.6 (3H, m), 7.3-7.
55 (5H, m), 7.72 (1H, s), 7.80
(1H, d, J = 6.0 Hz), 12.52 (1H, b
s) IR (KBr): νCO 1700, 1635 cm
^-1 νNH 3360cm ^-1

Example 4 The following compound was produced in the same manner as in Example 1 except that 1-adamantylamine was used instead of cyclohexylamine.

(E) -3- (1-adamantylaminocarbonyl) -2-benzylidenepropionic acid

Melting point: 188 to 189 ° C. NMR (DMSO-d ₆ , 400 MHz) δ: 1.5 to 2.1 (15 H, m), 3.24 (2 H,
s), 7.3 to 7.55 (6H, m), 7.70 (1
H, s), 12.51 (1H, bs) IR (KBr): νCO 1700, 1645, 16
15 cm ⁻¹ νNH 3350 cm ⁻¹

Example 5 The following compound was produced in the same manner as in Example 1 except that 2-adamantylamine was used instead of cyclohexylamine.

(E) -3- (2-adamantylaminocarbonyl) -2-benzylidenepropionic acid Melting point: 202 to 204 ° C. NMR (DMSO-d ₆ , 400 MHz) δ: 1.4 to 2.1 (14H, m), 3.36 (2H,
s), 3.8 to 3.95 (1H, m), 7.3 to 7.6.
(5H, m), 7.72 (1H, s), 7.84 (1
H, d, J = 7.7 Hz), 12.61 (1H, bs) IR (KBr): νCO 1680, 1605 cm
^-1 νNH 3370cm ^-1

Example 6 Instead of (E) -benzylidene succinic anhydride (E)
Using 2-methylbenzylidene succinic anhydride, the following compound was produced in the same manner as in Example 1.

(E) -3-Cyclohexylaminocarbonyl-2- (2-methylbenzylidene) propionic acid

Melting point: 183 to 184 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.05 to 2.0 (10 H, m), 2.31 (3
H, s), 3.26 (2H, s), 3.7-3.85.
(1H, m), 5.82 (1H, d, J = 8.0H
z), 7.15 to 7.6 (4H, m), 8.06 (1
H, s) IR (KBr): νCO 1685, 1645 cm
^-1 νNH 3300cm ^-1

Example 7 Methyl (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionate

To a suspension of 100 mg of (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid in 10 ml of ether, 10 ml of an ether solution of diazomethane was added dropwise under stirring with ice cooling. After stirring at room temperature for 1 hour, acetic acid was added to decompose excess diazomethane, and the ether layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and crystallized from hexane to give (E) -2-
55 mg of methyl benzylidene-3-cyclohexylaminocarbonylpropionate was obtained.

Melting point: 135 to 136 ° C. NMR (CDCl ₃ , 270 MHz) δ: 1.05 to 2.0 (10 H, m), 3.40 (2
H, s), 3.7 to 3.8 (1H, m), 3.85 (3
H, s), 6.11 (1H, d, J = 6.9 Hz),
7.3 to 7.75 (5H, m), 7.91 (1H, s) IR (KBr): νCO 1720, 1640 cm
^-1 νNH 3300cm ^-1

Example 8 (E) -2-Benzylidene-3-cyclohexylaminocarbonyl sodium propionate

(E) -2-Benzylidene-3-cyclohexylaminocarbonylpropionic acid 60 mg was added to a solution of 2 ml of ethanol in 0.2 ml of 1N sodium hydroxide solution.
ml was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and colorless amorphous (E) -2-benzylidene-
64 mg of sodium 3-cyclohexylaminocarbonylpropionate was obtained.

NMR (DMSO-d ₆ , 400 MHz) δ: 1.05 to 1.8 (10 H, m), 3.14 (2
H, s), 3.45 to 3.6 (1H, m), 7.2 to
7.65 (6H, m), 9.52 (1H, d, J = 7.
1 Hz) IR (KBr): νCO 1640 cm ^-1 νNH 3420 cm ^-1

Example 9 2-Benzyl-3-cyclohexylaminocarbonylpropionic acid

(E) -2-Benzylidene-3-cyclohexylaminocarbonylpropionic acid 158 mg was added to a suspension of 10 ml of ethanol in 20 mg of 10% palladium carbon.
Was added, and the mixture was stirred under a hydrogen stream at room temperature and 1 atm for 15 hours. After removing the catalyst, the solvent was distilled off under reduced pressure and the residue was crystallized from ether to obtain 133 mg of 2-benzyl-3-cyclohexylaminocarbonylpropionic acid.

Melting point: 121 to 122 ° C. NMR (CDCl ₃ , 270 MHz) δ: 1.0 to 2.0 (10 H, m), 2.3 to 2.45
(2H, m), 2.7 to 2.9 (1H, m), 3.05
Up to 3.25 (2H, m), 3.65 to 3.85 (1H,
m), 5.49 (1H, d, J = 7.7 Hz), 7.1
~ 7.4 (5H, m) IR (KBr): νCO 1690, 1610 cm
^-1 νNH 3350cm ^-1

Example 10 (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid was replaced by (E) -2-benzylidene-3-cyclopentylaminocarbonylpropionic acid in the same manner as in Example 9. The following compounds were prepared.

2-benzyl-3-cyclopentylaminocarbonylpropionic acid

Melting point: 123 to 124 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.25 to 2.05 (8 H, m), 2.25 to 2.
5 (2H, m), 2.7-2.85 (1H, m), 3.
05 to 3.25 (2H, m), 4.05 to 4.25 (1
H, m), 5.68 (1H, d, J = 7.2 Hz),
7.1 to 7.35 (5H, m) IR (KBr): νCO 1720, 1630 cm
^-1 νNH 3330cm ^-1

Example 11 (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid was replaced with (E) -2-benzylidene-3- (exo-2-norbornylaminocarbonyl) propionic acid. The following compounds were produced in the same manner as in Example 9.

2-benzyl-3- (exo-2-norbornylaminocarbonyl) propionic acid

Melting point: 145 to 146 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.0 to 1.85 (8 H, m), 2.1 to 2.5
(4H, m), 2.7 to 2.9 (1H, m), 3.05
-3.3 (2H, m), 3.6-3.75 (1H,
m), 5.62 (1H, d, J = 3.7Hz), 7.1
5 to 7.4 (5H, m) IR (KBr): νCO 1690, 1605 cm
^{-1 νNH 3350cm -1}

Example 12 Instead of (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid, (E) -3- (1-
The following compound was produced in the same manner as in Example 9 using adamantylaminocarbonyl) -2-benzylidenepropionic acid.

3- (1-adamantylaminocarbonyl) -2-benzylpropionic acid

Melting point: 174 to 175 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.6 to 2.15 (15 H, m), 2.3 to 2.4
(2H, m), 2.7 to 2.85 (1H, m), 3.0
5 to 3.25 (2H, m), 5.25 (1H, s),
7.15 to 7.35 (5H, m), 11.5 (1H, b
r) IR (KBr): νCO 1705, 1615 cm
^-1 νNH 3360cm ^-1

Example 13 Instead of (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid, (E) -3- (2-
The following compound was produced in the same manner as in Example 9 using adamantylaminocarbonyl) -2-benzylidenepropionic acid.

3- (2-adamantylaminocarbonyl) -2-benzylpropionic acid

Melting point: 174 to 176 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.55 to 2.0 (14 H, m), 2.35 to 2.
55 (2H, m), 2.75 to 2.9 (1H, m),
3.1-3.3 (2H, m), 3.95-4.1 (1
H, m), 5.94 (1H, d, J = 7.9 Hz),
7.1-7.4 (5H, m) IR (KBr): νCO 1700, 1615 cm
^-1 νNH 3360cm ^-1

Example 14 (E) -2-Cyclohexylaminocarbonyl-2- (2-methylbenzylidene) propionic acid was used in place of (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid. The following compounds were produced in the same manner as in.

3-cyclohexylaminocarbonyl-2
-(2-Methylbenzyl) propionic acid

Melting point: 128 to 129 ° C. NMR (CDCl ₃ , 270 MHz) δ: 1.0 to 1.95 (10 H, m), 2.33 (3
H, s), 2.35 to 2.55 (2H, m), 2.65
~ 2.85 (1H, m), 3.05 to 3.25 (2H,
m), 3.65 to 3.8 (1H, m), 5.51 (1
H, d, J = 7.7 Hz), 7.05 to 7.2 (4H,
m) IR (KBr): νCO 1695, 1610 cm
^-1 νNH 3340cm ^-1

Example 15 (E) -2-benzylidene-3-cyclohexylaminocarbonyl 2-benzyl-3-instead of propionic acid
Using cyclohexylaminocarbonylpropionic acid,
The following compounds were produced in the same manner as in Example 7.

Methyl 2-benzyl-3-cyclohexylaminocarbonylpropionate

Melting point: 113 to 114 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.0 to 1.95 (10 H, m), 2.2 to 2.5
(2H, m), 2.75 to 3.05 (2H, m), 3.
15-3.25 (1H, m), 3.65 (3H, s),
3.65-3.8 (1H, m), 5.34 (1H, d,
J = 7.3 Hz), 7.1 to 7.35 (5 H, m) IR (KBr): νCO 1735, 1665, 16
40 cm ⁻¹ νNH 3260 cm ⁻¹

Example 16 (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid was replaced by 2-benzyl-3-
Using cyclohexylaminocarbonylpropionic acid,
The following compounds were produced in the same manner as in Example 8.

2-Benzyl-3-cyclohexylaminocarbonyl sodium propionate

Colorless amorphous NMR (DMSO-d ₆ , 400 MHz) δ: 1.0 to 1.75 (10 H, m), 1.9 to 2.0
5 (1H, m), 2.15 to 2.3 (1H, m), 2.
4-2.55 (2H, m), 2.9-3.05 (1H,
m), 3.4 to 3.55 (1H, m), 7.05 to 7.
25 (5H, m), 8.70 (1H, d, J = 7.6H
z)

Example 17 The following compound was produced in the same manner as in Example 1 except that 4-methylcyclohexylamine was used instead of cyclohexylamine.

(E) -2-Benzylidene-3- (4-methylcyclohexylaminocarbonyl) propionic acid

Melting point: 187 to 189 ° C. NMR (CDCl ₃ , 270 MHz) δ: 0.8 to 2.05 (12 H, m), 3.38 (2
H, s), 3.6 to 4.1 (1H, m), 5.9 to 6.
4 (1H, m), 7.3 to 7.7 (5H, m), 8.0
0 (1H, s) IR (KBr): νCO 1680, 1650 cm
^-1 νNH 3300cm ^-1

Example 18 Example 9 was carried out by using (E) -2-benzylidene-3- (4-methylcyclohexylaminocarbonyl) propionic acid in place of (E) -2-benzylidene-3-cyclohexylaminocarbonylpropionic acid. The following compounds were produced in the same manner as in.

2-benzyl-3- (4-methylsillohexylaminocarbonyl) propionic acid

Melting point: 125 to 126 ° C. NMR (CDCl ₃ , 400 MHz) δ: 0.8 to 2.0 (12 H, m), 2.3 to 2.5
(2H, m), 2.7 to 2.85 (1H, m), 3.1
~ 3.25 (2H, m), 3.6-4.0 (1H,
m), 5.4 to 5.75 (1H, m), 7.15 to 7.
35 (5H, m) IR (KBr): νCO 1720, 1630 cm
^-1 νNH 3300cm ^-1

Example 19 Instead of (E) -benzylidene succinic anhydride, (E)
Using 4-chlorobenzylidene succinic anhydride, the following compound was produced in the same manner as in Example 1.

(E) -2- (4-chlorobenzylidene)
-3-Cyclohexylaminocarbonylpropionic acid

Melting point: 185 to 186 ° C. NMR (DMSO-d ₆ , 270 MHz) δ: 1.0 to 1.95 (10 H, m), 3.32 (1
H, s), 3.42 (1H, s), 3.5-3.75.
(1H, m), 7.45 to 7.7 (4H, m), 7.7
9 (1H, s), 7.92 (1H, d, J = 7.9H
z), 12.68 (1H, bs) IR (KBr): νCO 1685, 1645 cm
^-1 νNH 3290cm-1

Claims (4)

[Claims] 1. A general formula: (In the formula, R ¹ is a hydrogen atom, a halogen atom or a carbon number 1
Is a lower alkyl group having 4 to 4 carbon atoms, R ² is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, R is a hydrogen atom or both are bonded to form a single bond, B is an adamantyl group, and a carbon number. A succinic acid derivative represented by a C 3-8 cycloalkyl group or a norbornyl group which may be substituted with a 1-4 alkyl group and a salt thereof. 2. A general formula: (In the formula, R ¹ is a hydrogen atom, a halogen atom or a carbon number 1
Is a lower alkyl group having 4 to 4 carbon atoms, R is a hydrogen atom or both of them to form a single bond, B is an adamantyl group, and 3 to 4 carbon atoms optionally substituted with a lower alkyl group having 1 to 4 carbon atoms. 8 is a cycloalkyl group or a norbornyl group), and the succinic acid derivative and a salt thereof according to claim 1. 3. A general formula: (In the formula, R ¹ is a hydrogen atom, a halogen atom or a carbon number 1
Is a lower alkyl group having 4 to 4 and B is an adamantyl group, a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a lower alkyl group having 1 to 4 carbon atoms, or a norbornyl group). Item 2. A succinic acid derivative or a salt thereof according to item 2. 4. A general formula: (In the formula, R ¹ is a hydrogen atom, a halogen atom or a carbon number 1
Is a lower alkyl group having 4 to 4 and B is an adamantyl group, a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a lower alkyl group having 1 to 4 carbon atoms, or a norbornyl group). Item 2. A succinic acid derivative or a salt thereof according to item 2.