JP2686879B2 - Novel itaconic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to novel itaconic acid derivatives and salts thereof which are useful as pharmaceuticals.

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

[0003]

Embedded image

(In the formula, R is a hydrogen atom or has 1 to 6 carbon atoms.
A is a heterocyclic group, a 3- to 8-membered cycloalkyl group or a halogen atom as a substituent, a lower alkyl group having 1 to 6 carbon atoms or a lower alkoxy group having 1 to 6 carbon atoms. Is a phenyl group having 3 to 3 and B is a bicyclic condensed ring amino group which may have 1 to 2 unsaturated bonds in the ring), and a novel itaconic acid derivative and a salt thereof. It is a thing.

[0005]

The itaconic acid derivative of the present invention has a general formula

[0006]

Embedded image

A compound represented by the formula (R ² in the formula is a hydrogen atom or a methyl group) is used as an intermediate for the production of renin inhibitors, but its pharmacological action and the like have not been reported at all. Absent. [Journal of Medicinal Chemistry (J. Med. Chem.) 31
Vol. 2277-2288, 1988]

[0008]

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

[0009]

Means for Solving the Problems As a result of intensive studies by the present inventors, the itaconic acid derivative represented by the general formula (I) and a salt thereof have an insulin secretagogue promoting action,
The present invention has been completed by finding that it exhibits a suitable blood glucose lowering action.

In the compound of the general formula (I) of the present invention, examples of the heterocyclic group include a thienyl group, a furyl group and a pyridyl group. The bicyclic condensed ring amino group which may have 1 to 2 unsaturated bonds in the ring is a 5- to 6-membered cyclic hydrocarbon which may have 1 to 2 unsaturated bonds. Group means a bicyclic condensed ring amino group in which a 5- to 6-membered cyclic amino group is condensed, for example, cis-
Hexahydro-2-isoindolinyl, trans-hexahydro-2-isoindolinyl, 4,5,6,7-tetrahydro-2-isoindolinyl, trans-3a,
4,7,7a-tetrahydro-2-isoindolinyl,
Cis-3a, 4,7,7a-tetrahydro-2-isoindolinyl, 3a, 4,5,7a-tetrahydro-2-
Isoindolinyl, 3a, 7a-dihydro-2-isoindolinyl, trans-hexahydro-1-indolinyl, cis-hexahydro-1-indolinyl, trans-3a, 4,7,7a-tetrahydro-1-indolinyl, cis-3a, 4. 7,7a-Tetrahydro-1-indolinyl, 3a, 6,7,7a-tetrahydro-1-
Indolinyl, 3a, 7a-dihydro-1-indolinyl, cis-octahydro-2-pyrindin-2-yl,
Trans-octahydro-2-pyrindin-2-yl,
Cis-octahydro-1-pyrindin-1-yl, trans-octahydro-1-pyrindin-1-yl, cis-octahydro-1-cyclopenta [b] pyrrolyl, trans-octahydro-1-cyclopenta [b] pyrrolyl, cis- Octahydro-2-cyclopenta [c] pyrrolyl, 1,2,3,4,5,6,7,8-octahydro-2-isoquinolyl, cis-1,2,3,4,4a,
5,8,8a-octahydro-2-isoquinolyl, trans-1,2,3,4,4a, 5,8,8a-octahydro-2-isoquinolyl, trans-1,2,3,4
4a, 7,8,8a-octahydro-2-isoquinolyl, trans-1,2,3,4,4a, 5,6,8a-
Octahydro-2-isoquinolyl, cis-decahydro-
2-isoquinolyl, trans-decahydro-2-isoquinolyl, 1,2,3,4,5,8-hexahydro-2-
Isoquinolyl, trans-decahydro-1-quinolyl,
Cis-decahydro-1-quinolyl, cis-1,2,3
4,4a, 5,6,8a-octahydro-1-quinolyl, 1,2,3,4,5,6,7,8-octahydro-
1-quinolyl etc. can be mentioned.

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

That is, the general formula

Embedded image

An itaconic anhydride represented by the formula (A has the same meaning as described above)

It can be produced by reacting with a compound represented by B—H (III) (wherein B has the same meaning as described above), and esterifying if necessary.

Further, the itaconic acid derivative represented by the general formula (I) of the present invention has the general formula

[0016]

Embedded image

(Wherein R ³ is a lower alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 10 carbon atoms or another carboxyl group-protecting group, and A has the same meaning as described above). The itaconic acid monoester compound or a reactive functional derivative thereof such as an active ester, an acid anhydride or a mixed acid anhydride thereof and a compound represented by the general formula (III) in the presence or absence of a condensing agent. Can also be produced by removing the alkyl group, aralkyl group or protecting group, if necessary.

The itaconic anhydride of the general formula (II) used as a starting material in the present production method contains a novel compound, and any of them is similar to the method for producing a known compound and is similar to the method described in the literature or similar thereto. It can be easily manufactured by the method.

Further, the amines represented by the general formula (III) are known compounds and can be purchased as a commercial product or can be easily produced by the method described in the literature.

The itaconic acid monoester compound of the general formula (IV) used as a starting material in the present production method can be easily produced by a method described in the literature or a method similar thereto.

The compound of the general formula (I) of the present invention was tested in an in vivo blood glucose lowering test using mice.
Oral administration of about 1 to 10 mg / kg shows a clear hypoglycemic effect.

The compound of the general formula (I) of the present invention has geometrical isomers of E-form and Z-form due to a double bond, and in the present invention, both of them are included. In the lowering action, the E form exerts a good pharmacological action and is suitable as a drug.

The compound of the general formula (I) of the present invention in which R is a hydrogen atom can be converted into a pharmacologically acceptable salt according to a conventional method. Examples thereof include salts with inorganic bases such as sodium salts and calcium salts, organic amines such as morpholine and piperidine, 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 itaconic acid derivative represented by the general formula (I) and its salt of the present invention are used for actual treatment, suitable pharmaceutical compositions such as tablets, powders, granules, capsules and injections are used. 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 depending on the sex, age, body weight, degree of symptoms, etc. of the subject patient. Oral administration is about 10 to 1000 mg per day for an adult, and parenteral administration is about 1 for an adult. It is administered within the range of 1 to 100 mg per day.

[0026]

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

Reference Example 1 (E) -2-Methylbenzylidene succinic anhydride potassium t-butoxide 8.5 g of t-butanol 10
A mixture of 6.0 g of 2-methylbenzaldehyde and 12.0 g of diethyl succinate was added dropwise to a 0 ml solution, and the mixture was heated under reflux for 3 hours. After the solvent was distilled off under reduced pressure, 100 ml of a 10% aqueous sodium hydroxide solution was added to the residue, and 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

Reference Example 2 The following compound was produced in the same manner as in Reference Example 1 using 3-methylbenzaldehyde instead of 2-methylbenzaldehyde.

(E) -3-Methylbenzylidenesuccinic anhydride Melting point: 117 to 118 ° C. NMR (CDCl ₃ , 270 MHz) δ: 2.42 (3H, s), 3.83 (2H, d, J =)
2.2 Hz), 7.2 to 7.45 (4 H, m), 7.7
6 (1H, t, J = 2.2Hz) IR (KBr): νCO 1830, 1760cm
^-1

Reference Example 3 The following compound was produced in the same manner as in Reference Example 1 using 2-isopropylbenzaldehyde instead of 2-methylbenzaldehyde.

(E) -2-Isopropylbenzylidene succinic anhydride Melting point: 110 to 111 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.27 (6H, d, J = 6.8 Hz), 3.2
3.35 (1H, m), 3.76 (2H, d, J = 2.
6 Hz), 7.25 to 7.5 (4 H, m), 8.17
(1H, t, J = 2.6 Hz) IR (KBr): νCO 1850, 1780 cm
^-1

Reference Example 4 The following compound was produced in the same manner as in Reference Example 1 using 2-fluorobenzaldehyde instead of 2-methylbenzaldehyde.

(E) -2-Fluorobenzylidene succinic anhydride Melting point: 154-155 ° C. NMR (CDCl ₃ , 270 MHz) δ: 3.92 (2H, d, J = 2.5 Hz), 7.15
~ 7.65 (4H, m), 7.89 (1H, t, J =
2.5 Hz) IR (KBr): νCO 1840, 1770 cm
^-1

Reference Example 5 The following compound was produced in the same manner as in Reference Example 1 using 2-ethoxybenzaldehyde instead of 2-methylbenzaldehyde.

(E) -2-Ethoxybenzylidene succinic anhydride Melting point: 137 to 139 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.48 (3H, t, J = 7.0 Hz), 3.77
(2H, d, J = 2.6 Hz), 4.14 (2H, q,
J = 7.0 Hz), 6.95 to 7.5 (4H, m),
8.24 (1H, t, J = 2.6Hz) IR (KBr): νCO 1840, 1770cm
^-1

Reference Example 6 The following compound was produced in the same manner as in Reference Example 1 using 2-propoxybenzaldehyde instead of 2-methylbenzaldehyde.

(E) -2-Propoxybenzylidene succinic anhydride Melting point: 108 to 109 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.0 to 1.15 (3 H, m), 1.8 to 1. 95
(2H, m), 3.77 (2H, d, J = 2.6H
z), 3.95 to 4.05 (2H, m), 6.9 to 7.
5 (4H, m), 8.25 (1H, t, J = 2.6H
z) IR (KBr): νCO 1830, 1770 cm
^-1

Reference Example 7 The following compound was produced in the same manner as in Reference Example 1 using 2,6-dimethylbenzaldehyde instead of 2-methylbenzaldehyde.

(Z) -2,6-Dimethylbenzylidenesuccinic anhydride Melting point: 159 to 161 ° C. NMR (CDCl ₃ , 400 MHz) δ: 2.21 (6 H, s), 3.79 (2 H, d, J =
2.3 Hz), 7.07 (2H, d, J = 7.6H
z), 7.18 (1H, t, J = 7.6 Hz), 7.2
9 (1H, t, J = 2.3 Hz) IR (KBr): νCO 1850, 1830, 17
00 cm ^-1

Reference Example 8 The following compound was produced in the same manner as in Reference Example 1 using 2,6-dichlorobenzaldehyde instead of 2-methylbenzaldehyde.

(E) -2,6-Dichlorobenzylidene succinic anhydride Colorless amorphous NMR (CDCl ₃ , 400 MHz) δ: 3.55 (2H, d, J = 2.8 Hz), 7.1-
7.45 (3H, m), 7.80 (1H, t, J = 2.
8 Hz) IR (KBr): νCO 1840, 1780 cm
^-1

Reference Example 9 The following compound was produced in the same manner as in Reference Example 1 using 2,6-dimethoxybenzaldehyde instead of 2-methylbenzaldehyde.

(E) -2,6-Dimethoxybenzylidenesuccinic anhydride Melting point: 167-168 ° C NMR (CDCl ₃ , 400 MHz) δ: 3.55 (2H, d, J = 2.7 Hz), 3. 88
(6H, s), 6.60 (2H, d, J = 8.4H
z), 7.39 (1H, t, J = 8.4 Hz), 7.9
9 (1H, t, J = 2.7Hz) IR (KBr): νCO 1840, 1770cm
^-1

Reference Example 10 The following compound was produced in the same manner as in Reference Example 1 using cyclohexanecarbaldehyde instead of 2-methylbenzaldehyde.

(E) -Cyclohexyl methylene succinic anhydride Melting point: 79 to 80 ° C. NMR (CDCl ₃ , 270 MHz) δ: 1.1 to 1.45 (5 H, m), 1.55 to 1.9
(5H, m), 2.1 to 2.3 (1H, m), 3.51
(2H, d, J = 2.7 Hz), 6.85 to 6.95
(1H, m) IR (KBr): νCO 1830, 1770 cm
^-1

Reference Example 11 (E) -3-Methoxycarbonyl-4- (3-methylphenyl) -3-butenoic acid 2.4 g of 3-methylbenzaldehyde and dimethyl succinate were added to a solution of 1.4 g of sodium methoxide in 20 ml of methanol. 3.5 g of the mixture was added dropwise, and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated under depressurization, 50 ml of water was added to the residue, and the mixture was washed with ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and a pale yellow viscous oil (E) -3-methoxycarbonyl-4- (3-methylphenyl) -3-butenoic acid 3.8 was obtained.
g was obtained.

NMR (CDCl ₃ , 270 MHz) δ: 2.37 (3H, s), 3.59 (2H, s),
3, 84 (3H, s), 7.0-7.4 (4H, m),
7.90 (1H, s), 9.90 (1H, bs) IR (neat): νCO 1730,1710,1
650,1610 cm ^-1

Example 1 (E) -2- (4-Methylbenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionic acid (E) -4-methyl Benzylidene succinic anhydride 404
In a suspension of 30 mg of methylene chloride in cis-3a, 4,
500 mg of 7,7a-tetrahydroisoindoline was added dropwise, 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, the residue was crystallized from ethyl acetate to give (E) -2- (4-methylbenzylidene) -3-
420 mg of (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionic acid was obtained.

Melting point: 152-153 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.85 to 1.95 (2H, m), 2.2 to 2.5
(7H, m), 3.15 to 3.25 (1H, m), 3.
35 to 3.65 (5H, m), 5.6 to 5.75 (2
H, m), 7.15 to 7.3 (4H, m), 7.86
(1H, s) IR (KBr): νCO 1710,1650,16
00 cm ^-1

Example 2 (E) -4-Methylbenzylidenesuccinic anhydride was used in place of (E) -3-methylbenzylidenesuccinic anhydride, and the following compound was produced in the same manner as in Example 1. .

(E) -2- (3-methylbenzylidene)
-3- (cis-3a, 4,7,7a-tetrahydro-2
- isoindolinylcarbonyl) propionic acid Melting _{point: 141~143 ℃ NMR (CDCl 3,} 270MHz) δ: 1.8~2.0 (2H, m), 2.15~2.55
(7H, m), 3.05 to 3.25 (1H, m), 3.
3 to 3.65 (5H, m), 5.55 to 5.8 (2H,
m), 7.05 to 7.35 (4H, m), 7.84 (1
H, s) IR (KBr): νCO 1710, 1650, 16
30,1610 cm ^-1

Example 3 (E) -4-Methylbenzylidenesuccinic anhydride was used in place of (E) -4-methoxybenzylidenesuccinic anhydride, and the following compound was produced in the same manner as in Example 1. .

(E) -2- (4-Methoxybenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionic acid Melting point: 158-160 ° C NMR (DMSO −d ₆ , 270 MHz) δ: 1.75 to 1.95 (2H, m), 2.1 to 2.5
(4H, m), 3.1 to 3.45 (5H, m), 3.5
5 to 3.7 (1H, m), 3.78 (3H, s), 5.
6 to 5.75 (2H, m), 6.9 to 7.45 (4H,
m), 7.68 (1H, s), 12.36 (1H, b
s) IR (KBr): νCO 1710, 1610 cm
^-1

Example 4 Using cis-hexahydroisoindoline instead of cis-3a, 4,7,7a-tetrahydroisoindoline, the following compound was prepared in the same manner as in Example 1.

(E) -3- (cis-hexahydro-2-
Isoindolinylcarbonyl) -2- (4-methylbenzylidene) propionic acid Melting point: 173-175 ° C NMR (CDCl ₃ , 400 MHz) δ: 1.35-1.7 (8H, m), 2.2-2 .35
(2H, m), 2.37 (3H, s), 3.25-3.
35 (1H, m), 3.4 to 3.6 (5H, m), 7.
15-7.3 (4H, m), 7.87 (1H, s) IR (KBr): νCO 1710, 1650, 16
00 cm ^-1

Example 5 Instead of (E) -4-methylbenzylidenesuccinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2-methylbenzylidenesuccinic anhydride and cis- The following compound was produced in the same manner as in Example 1 using hexahydroisoindoline.

(E) -3- (cis-hexahydro-2-
Isoindolinylcarbonyl) -2- (2-methylbenzylidene) propionic acid Melting point: 154-156 ° C NMR (CDCl ₃ , 270 MHz) δ: 1.25-1.7 (8H, m), 2.1-2 .35
(5H, m), 2.9 to 3.55 (6H, m), 7.1
~ 7.35 (4H, m), 7.85 (1H, s) IR (KBr): νCO 1710, 1650, 16
00 cm ^-1

Example 6 Instead of (E) -4-methylbenzylidenesuccinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2-isopropylbenzylidenesuccinic anhydride and cis- With hexahydroisoindoline,
The following compounds were produced in the same manner as in Example 1.

(E) -3- (cis-hexahydro-2-
Isoindolinylcarbonyl) -2- (2-isopropylbenzylidene) propionic acid Melting point: 172 to 173 ° C NMR (CDCl ₃ , 270 MHz) δ: 1.1 to 1.7 (14H, m), 2.1 to 2 .3
(2H, m), 2.9 to 3.15 (3H, m), 3.2
~ 3.55 (4H, m), 7.05-7.4 (4H,
m), 7.95 (1H, s) IR (KBr): νCO 1680, 1640 cm
^-1

Example 7 Instead of (E) -4-methylbenzylidene succinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -4-chlorobenzylidene succinic anhydride and cis- The following compound was produced in the same manner as in Example 1 using hexahydroisoindoline.

(E) -2- (4-chlorobenzylidene)
-3- (cis-Hexahydro-2-isoindolinylcarbonyl) propionic acid Melting point: 172 to 174 ° C NMR (CDCl ₃ , 270 MHz) δ: 1.3 to 1.7 (8H, m), 2.15 2.4
(2H, m), 3.2-3.6 (6H, m), 7.25
~ 7.45 (4H, m), 7.85 (1H, s) IR (KBr): νCO 1710, 1650, 15
90 cm ^-1

Example 8 Instead of (E) -4-methylbenzylidenesuccinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2-chlorobenzylidenesuccinic anhydride and cis- The following compound was produced in the same manner as in Example 1 using hexahydroisoindoline.

(E) -2- (2-chlorobenzylidene)
3- (cis - hexahydro-2-isoindolinylcarbonyl) propionic acid Melting _{point: 180~181 ℃ NMR (DMSO-d} 6, 270MHz) δ: 1.15~1.65 (8H, m), 2. 05-2.
35 (2H, m), 3.05 to 3.55 (6H, m),
7.3 to 7.65 (4H, m), 7.74 (1H,
s), 12.73 (1H, bs) IR (KBr): νCO 1710, 1650, 16
00 cm ^-1

Example 9 Instead of (E) -4-methylbenzylidene succinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2-fluorobenzylidene succinic anhydride and cis- The following compound was produced in the same manner as in Example 1 using hexahydroisoindoline.

(E) -2- (2-Fluorobenzylidene) -3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid Melting point: 172-173 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1. 3 to 1.7 (8H, m), 2.15 to 2.35
(2H, m), 3.2-3.6 (6H, m), 7.05
~ 7.55 (4H, m), 7.86 (1H, s), 1
2.9 (1H, br) IR (KBr): νCO 1700, 1600 cm
^-1

Example 10 Instead of (E) -4-methylbenzylidenesuccinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2-methoxybenzylidenesuccinic anhydride and cis- The following compound was produced in the same manner as in Example 1 using hexahydroisoindoline.

(E) -3- (cis-hexahydro-2-
Isoindolinyl carbonyl) -2- (2-methoxybenzylidene) propionic acid Melting point: 148 to 149 ° C NMR (CDCl ₃ , 270 MHz) δ: 1.3 to 1.7 (8H, m), 2.15 to 2 .35
(2H, m), 3.15 to 3.55 (6H, m), 3.
83 (3H, s), 6.85-7.4 (4H, m),
7.97 (1H, s), 12.1 (1H, br) IR (KBr): νCO 1710, 1600 cm
^-1

Example 11 Instead of (E) -4-methylbenzylidene succinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2-ethoxybenzylidene succinic anhydride and cis- The following compounds were produced in the same manner as in Example 1 using hexahydroisoindoline.

(E) -2- (2-Ethoxybenzylidene) -3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid Melting point: 128-130 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1. 2 to 1.65 (11H, m), 2.1 to 2.2
5 (2H, m), 3.05 to 3.2 (1H, m), 3.
25-3.55 (5H, m), 4.02 (2H, q, J
= 7.0 Hz), 6.8 to 7.3 (4H, m), 7.8
8 (1H, s), 10.0 (1H, br) IR (KBr): νCO 1700, 1650, 16
10 cm ^-1

Example 12 Instead of (E) -4-methylbenzylidene succinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2-propoxybenzylidene succinic anhydride and cis- The following compound was produced in the same manner as in Example 1 using hexahydroisoindoline.

(E) -3- (cis-hexahydro-2-
Isoindolinyl carbonyl) -2- (2-propoxybenzylidene) propionic acid Melting point: 138 to 139 ° C NMR (CDCl ₃ , 400 MHz) δ: 0.95 to 1.05 (3H, m), 1.2 to 1 .6
5 (8H, m), 1.7 to 1.85 (2H, m), 2.
05-2.25 (2H, m), 3.05-3.15 (1
H, m), 3.25 to 3.55 (5H, m), 3.85.
Up to 3.95 (2H, m), 6.8 to 7.35 (4H,
m), 7.89 (1H, s) IR (KBr): νCO 1700,1650,16
10 cm ^-1

Example 13 (E) -4-Methylbenzylidenesuccinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline were replaced by (Z) -2,6-dimethylbenzylidenesuccinic anhydride. With cis-hexahydroisoindoline,
The following compounds were produced in the same manner as in Example 1.

(Z) -2- (2,6-Dimethylbenzylidene) -3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid Melting point: 171 to 172 ° C. NMR (CDCl ₃ , 400 MHz) δ: 1.35 to 1.7 (8H, m), 2.24 (6H,
s), 2.25 to 2.4 (2H, m), 3.4 to 3.6.
5 (6H, m), 6.74 (1H, s), 6.95-
7.1 (3H, m) IR (KBr): νCO 1730, 1610 cm
^-1

EXAMPLE 14 Instead of (E) -4-methylbenzylidenesuccinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2,6-dichlorobenzylidenesuccinic anhydride was used. With cis-hexahydroisoindoline,
The following compounds were produced in the same manner as in Example 1.

(E) -2- (2,6-Dichlorobenzylidene) -3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid Melting point: 263-265 ° C. NMR (DMSO-d ₆ , 400 MHz) δ: 1.1 to 1.65 (8H, m), 2.0 to 2.35.
(2H, m), 3.0-3.5 (6H, m), 7.3-
7.65 (4H, m), 12.7 (1H, br) IR (KBr): νCO 1715, 1650, 16
00 cm ^-1

Example 15 Instead of (E) -4-methylbenzylidenesuccinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2,6-dimethoxybenzylidenesuccinic anhydride was used. The following compound was produced in the same manner as in Example 1 using cis-hexahydroisoindoline.

(E) -2- (2,6-Dimethoxybenzylidene) -3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid Melting point: 174 to 175 ° C. NMR (CDCl ₃ , 270 MHz) δ: 1.25-1.7 (8H, m), 2.1-2.3
(2H, m), 2.9 to 3.55 (6H, m), 3.7
5 (6H, s), 6.5-6.6 (2H, m), 7.2
~ 7.35 (1H, m), 7.51 (1H, s), 1
3.8 (1H, br) IR (KBr): νCO 1710, 1640, 15
90 cm ^-1

Example 16 Instead of (E) -4-methylbenzylidene succinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -2-tenylidene succinic anhydride and cis-hexahydro The following compounds were produced in the same manner as in Example 1 using isoindoline.

(E) -3- (cis-hexahydro-2-
Isoindolinylcarbonyl) -2- (2-tenylidene) propionic acid Melting point: 142-143 ° C NMR (CDCl ₃ , 270 MHz) ν: 1.3-1.75 (8H, m), 2.15-2. Four
5 (2H, m), 3.35-3.75 (6H, m),
6.9 (1H, br), 7.05 to 7.15 (1H,
m), 7.31 (1H, d, J = 3.3 Hz), 7.4
6 (1H, d, J = 4.9 Hz), 8.04 (1H,
s) IR (KBr): νCO 1710, 1650, 16
00 cm ^-1

Example 17 Instead of (E) -4-methylbenzylidene succinic anhydride and cis-3a, 4,7,7a-tetrahydroisoindoline, (E) -cyclohexyl methylene succinic anhydride and cis-hexahydro. The following compounds were produced in the same manner as in Example 1 using isoindoline.

(E) -2-Cyclohexylmethylene-3
- (cis - hexahydro-2-isoindolinylcarbonyl) propionic acid Melting _{point: 168~169 ℃ NMR (CDCl 3,} 400MHz) δ: 1.1~1.9 (18H, m), 2.15~2. Four
(3H, m), 3.2 to 3.65 (6H, m), 6.7
9 (1H, d, J = 10.0Hz), 10.8 (1H,
br) IR (KBr): νCO 1715 1600 cm
^-1

Example 18 Methyl (E) -2- (3-methylbenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionate (E) -3- Methoxycarbonyl-4- (3-methylphenyl) -3-butenoic acid (1.05 g) was dissolved in anhydrous tetrahydrofuran (20 ml), cooled to -20 ° C, and stirred under N 2 atmosphere.
-Methylmorpholine 0.74 ml and isobutyl chlorocarbonate 0.75 ml were added and stirred for 20 minutes. -20 ° C
A solution of 773 mg of cis-3a, 4,7,7a-tetrahydroisoindoline in 2 ml of anhydrous tetrahydrofuran was added to the mixture under cooling and stirring, the mixture was stirred for 1 hour, the precipitate was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give a colorless viscous oil (E) -2- (3
-Methylbenzylidene) -3- (cis-3a, 4,7,
There was obtained 446 mg of methyl 7a-tetrahydro-2-isoindolinylcarbonyl) propionate.

NMR (CDCl ₃ , 270 MHz) δ: 1.85 to 2.05 (2H, m), 2.2 to 2.5
5 (7H, m), 3.25 to 3.65 (6H, m),
3.81 (3H, s), 5.55 to 5.75 (2H,
m), 7.1 to 7.35 (4H, m), 7.88 (1
H, s) IR (neat): νCO 1720, 1650 cm
^-1

Example 19 Methyl (E) -2- (4-methoxybenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionate (E) -2- (4-Methoxybenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionic acid (50 mg) was added to an ether (5 ml) suspension under ice-cooling while stirring, and 2 ml of diazomethane ether solution was added. Dropped. 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 water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent:
(E) -2- (4-methoxybenzylidene) -3- in the form of a colorless viscous oil, which was purified by hexane / ethyl acetate = 4/1).
(Cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) methyl propionate 51 mg
I got

NMR (CDCl ₃ , 270 MHz) δ: 1.85 to 2.05 (2H, m), 2.2 to 2.5
5 (4H, m), 3.25 to 3.7 (6H, m), 3.
79 (3H, s), 3.82 (3H, s), 5.6-
5.75 (2H, m), 6.85-7.5 (4H,
m), 7.87 (1H, s) IR (neat): νCO 1720,1650,1
610 cm ^-1

Example 20 Instead of (E) -2- (4-methoxybenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionic acid, (E)-
The following compound was produced in the same manner as in Example 19 using 3- (cis-hexahydro-2-isoindolinylcarbonyl) -2- (2-methylbenzylidene) propionic acid.

(E) -3- (cis-hexahydro-2-
Methyl isoindolinylcarbonyl) -2- (2-methylbenzylidene) propionate Colorless viscous oil NMR (CDCl ₃ , 270 MHz) δ: 1.3 to 1.7 (8H, m), 2.1 to 2.4 ( 5
H, m), 3.25 to 3.55 (6H, m), 3.82.
(3H, s), 7.1 to 7.45 (4H, m), 7.9
2 (1H, s) IR (neat): νCO 1720, 1650 cm
^-1

Example 21 Instead of (E) -2- (4-methoxybenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionic acid, (E)-
2- (4-chlorobenzylidene) -3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid was used to produce the following compound in the same manner as in Example 19.

(E) -2- (4-chlorobenzylidene)
Methyl 3- (cis-hexahydro-2-isoindolinylcarbonyl) propionate Colorless viscous oil NMR (CDCl ₃ , 270 MHz) δ: 1.3-1.75 (8H, m), 2.15-2.4
(2H, m), 3.35-3.6 (6H, m), 3.8
1 (3H, s), 7.3 to 7.45 (4H, m), 7.
86 (1H, s) IR (neat): νCO 1720, 1650 cm
^-1

Example 22 Propyl (E) -2- (E) -2- (4-methylbenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionate (4-Methylbenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionic acid 310 mg of N, N-
To 20 ml of dimethylformamide solution, 105 mg of triethylamine and 125 mg of propyl bromide were added, and the mixture was stirred at room temperature for 15 hours. 50 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to give (E) -2- (4-methylbenzylidene)-as a colorless viscous oil.
3- (cis-3a, 4,7,7a-tetrahydro-2-
Isoindolinylcarbonyl) propyl propionate 1
Obtained 65 mg.

NMR (CDCl ₃ , 270 MHz) δ: 0.95 to 1.05 (3H, m), 1.65 to 1.
8 (2H, m), 1.85 to 2.05 (2H, m),
2.15 to 2.55 (7H, m), 3.25, to 3.
7 (6H, m), 4.05 to 4.25 (2H, m),
5.6 to 5.75 (2H, m), 7.1 to 7.4 (4
H, m), 7.89 (1H, s) IR (neat): νCO 1710, 1650 cm
^-1

Example 23 Instead of (E) -2- (4-methylbenzylidene) -3- (cis-3a, 4,7,7a-tetrahydro-2-isoindolinylcarbonyl) propionic acid, (E)- Two
The following compound was produced in the same manner as in Example 22 by using-(2-chlorobenzylidene) -3- (cis-hexahydro-2-isoindolinylcarbonyl) propionic acid.

(E) -2- (2-chlorobenzylidene)
Propionate-3- (cis-hexahydro-2-isoindolinylcarbonyl) propionate colorless viscous oil NMR (CDCl ₃ , 270 MHz) δ: 1.00 (3H, t, J = 7.4Hz), 1.25
~ 1.85 (10H, m), 2.1-2.4 (2H,
m), 3.25 to 3.6 (6H, m), 4.18 (2
H, t, J = 6.4 Hz), 7.2 to 7.75 (4H,
m), 7.96 (1H, s) IR (neat): νCO 1720, 1650 cm
■ -1

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location C07D 403/06 C07D 403/06 (72) Inventor Toyohiro Kobayashi 3152 Nakagawate, Meishina-cho, Higashichikuma-gun, Nagano Prefecture Address Examiner Yasushi Tominaga

Claims (8)

(57) [Claims] 1. A compound of the general formula (Wherein R is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, A is a heterocyclic group, a cycloalkyl group having 3 to 8 membered ring or a halogen atom as a substituent, a lower alkyl group having 1 to 6 carbon atoms) It is a phenyl group having 1 to 3 alkyl groups or 1 to 6 lower alkoxy groups having 1 to 6 carbon atoms, and B is 1 to 2 in the ring.
Itaconic acid derivative represented by a bicyclic condensed ring amino group which may have one unsaturated bond) and a salt thereof. 2. A compound of the general formula The itaconic acid derivative and a salt thereof according to claim 1, which are represented by the formula (R, A and B in the formula have the same meanings as described above). 3. A compound of the general formula (In the formula, R ¹ is a halogen atom, a lower alkyl group having 1 to 6 carbon atoms or a lower alkoxy group having 1 to 6 carbon atoms,
n is an integer of 1 to 3 and R and B have the same meanings as described above), and the itaconic acid derivative and a salt thereof according to claim 2. 4. A compound of the general formula (Z in the formula is an ethylene group or a vinylene group, R,
R ¹ and n have the same meanings as described above), and the itaconic acid derivative and the salt thereof according to claim 3. 5. A general formula: The itaconic acid derivative and its salt according to claim 4, which are represented by the formula (Z, R ¹ and n in the formula have the same meanings as described above). 6. A general formula: The itaconic acid derivative and a salt thereof according to claim 5, wherein X is a halogen atom and Z and n have the same meanings as described above. 7. A general formula: The itaconic acid derivative and a salt thereof according to claim 5, wherein Z and n in the formula have the same meanings as described above. 8. A compound of the general formula The itaconic acid derivative and a salt thereof according to claim 5, wherein Z and n in the formula have the same meanings as described above.