JPH04356459A - New benzylsuccinic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a new benzylsuccinic acid derivative useful as a treating agent for diabetes. CONSTITUTION:A benzylsuccinic acid derivative shown by formula I (A is bicyclic fused ring amino which may contain 1-2 unsaturated bonds in the ring; R is H, lower alkyl or aralkyl; C with * is in R configuration or S- configuration or C of mixture thereof) and a salt thereof such as (2S)-2- benzyl-3-(cis-hexahydro-2-isoindolylcarbonyl)propionic acid. The compound is produced by reacting a phenylbutyric acid derivative shown by formula II (R<3> in the formula is lower alkyl, aralkyl or another carboxyl protecting group) or a reactive functional derivative thereof with a compound shown by formula A-H (A is as shown above) and optionally eliminating a lower alkyl, aralkyl or protecting group.

Description

[Detailed description of the invention]

0001

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

More specifically, the present invention provides compounds of the general formula

00
03]

[Image Omitted] (In the formula, A is a bicyclic condensed amino group that may have 1 to 2 unsaturated bonds in the ring, and R is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or It is an aralkyl group having 7 to 10 carbon atoms, and C with * is a carbon atom in R configuration or S configuration, or a carbon atom in which these are mixed)
The present invention relates to a novel benzylsuccinic acid derivative represented by: and a salt thereof.

0004

[Prior Art] Regarding the benzylsuccinic acid derivatives of the present invention, the general formula

[0005]

Compounds and general formulas represented by [Chemical formula 8] (in the formula, R1 is a hydrogen atom, an ethyl group, or a benzyl group, and C appended with (R, RS) is a carbon atom in the R or RS configuration)

0
006]

embedded image (R2 in the formula is a hydrogen atom or a benzyl group, (R
) has been produced and used as an intermediate in the production of renin inhibitors, but there have been no reports on its pharmacological effects, etc. do not have. [Chemical Abstracts (
Chem. Abst. ) 108 volumes, 205097g (1
988), Volume 110, 135731z, 24298
u, 24311t, 39369s (1989), same 1
Volume 11, 7784c, 195417g, 214942t
(1989), Volume 112, 7934x, 77963
e, 178822p, 217541t, 217542u
(1990), Volume 113, 41323c, 5984
1e, 78956n (1990) vol. 114, 102
852u (1991)]

[0007]

OBJECTS OF THE INVENTION An object of the present invention is to provide a new benzylsuccinic acid derivative that has a hypoglycemic effect and is useful as a therapeutic agent for diabetes.

[0008]

[Means for Solving the Problems] As a result of extensive research, the present inventors have found that the benzylsuccinic acid derivative represented by the general formula (I) and its salts exhibit insulin secretion-promoting action and blood sugar-lowering action. This discovery led to the completion of the present invention.

In the compound of the general formula (I) of the present invention, the cyclic amino group which may have 1 to 2 unsaturated bonds in the ring refers to a cyclic amino group which may have 1 to 2 unsaturated bonds within the ring. It refers to a bicyclic condensed amino group in which a certain 5- to 6-membered cyclic hydrocarbon group and a 5- to 6-membered cyclic amino group are condensed, such as cis-hexahydro-1-indolinyl, trans-hexahydro- 1-indolinyl, 4,5,6,7
-tetrahydro-2-isoindolinyl, trans-3
a,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-pyriindine-2-
yl, trans-octahydro-2-pyriindine-2
-yl, cis-octahydro-1-pyridin-1-
yl, trans-octahydro-1-pyridine-1
-yl, cis-2-azabicyclo[3.3.0]octan-2-yl, trans-2-azabicyclo[3.3.
0] Octane-2-yl, cis-3-azabicyclo[3
．． 3.0] Octane-3-yl, 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,
Examples include 8-octahydro-1-quinolyl.

Among these amino groups, preferred are cis-hexahydro-2-isoindolinyl, cis-3a,4,7,7a-tetrahydro-2-isoindolinyl, trans-hexahydro-2-isoindolinyl, trans-hexahydro-2-isoindolinyl, and trans-hexahydro-2-isoindolinyl. Examples include -1-indolinyl and trans-decahydro-2-isoquinolyl.

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

That is, the general formula

[Chemical formula 10] (R3 in the formula is an alkyl group having 1 to 6 carbon atoms, 7 to 6 carbon atoms,
A phenylbutyric acid derivative or a reactive functional derivative thereof, which is a protecting group for the aralkyl group or other carboxyl group of 10, and C with * has the same meaning as above), and the general formula

AH

It can be produced by reacting a compound represented by (III) (in which A has the same meaning as above), and then removing a lower alkyl group, aralkyl group, or protective group as necessary.

The benzylsuccinic acid derivative of the present invention represented by the general formula (I) in which A is a bicyclic condensed amino group having no unsaturated bond is a compound represented by the general formula

[0015]

It can also be produced by reducing the double bond of a benzylidene succinic acid derivative represented by the formula (in which A and R have the same meanings as above) by catalytic hydrogenation or the like.

The benzylsuccinic acid derivative represented by the general formula (I) of the present invention in which R is a lower alkyl group or an aralkyl group can also be produced by esterifying a compound in which R is a hydrogen atom by a conventional method. can do.

The phenylbutyric acid derivative of general formula (II) used as a starting material in this production method is a known compound and can be easily produced by methods described in literature. [Journal of Medicinal Chemistry (J.Med.Chem.), Volume 31, Page 2277 (1988)]

The amines represented by the general formula (III) are also known compounds, and can be purchased as commercial products or easily produced by methods described in literature. [Journal of Organic Chemistry (J, Org. Chem.), Volume 20, Page 1687 (1955)]

The benzylidene succinic acid derivative represented by the general formula (IV) used as a starting material in the second production method of the present invention is a new compound, and is represented by the formula

[0020]

Benzylidene succinic anhydride represented by the formula (I
It can be produced by reacting with the amines represented by II) and esterifying if necessary.

The compound of the general formula (I) of the present invention showed 0 in an in vivo blood glucose lowering test using mice.
．． Oral administration of about 1 to 10 mg/kg shows a clear blood sugar lowering effect.

The compound of the general formula (I) of the present invention has an asymmetric carbon in the succinic acid moiety, and compounds with R configuration and S configuration exist, and in the present invention, either of these may be used. Compounds in which the asymmetric carbon of the succinic acid moiety is in the S configuration exhibit suitable pharmacological effects in both secretion-promoting and hypoglycemic effects.

Further, in the compound of the general formula (I) of the present invention, R is preferably a hydrogen atom, and the amino group of A is preferably in the cis configuration.

Among the compounds of the general formula (I) of the present invention, (2S or 2RS)-2-benzyl-3-(cis-3a,4,7,7a-tetrahydro-
2-isoindolinylcarbonyl)propionic acid, (2
S or 2RS)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid, (2S or 2RS)-2-benzyl-3-(trans-decahydro-2-isoquinolylcarbonyl) Propionic acid, (2S or 2RS)-2-benzyl-3-
(trans-hexahydro-2-isoindolinylcarbonyl)propionic acid, (2S or 2RS)-2-benzyl-3-(trans-hexahydro-1-indolinylcarbonyl)propionic acid, and the most preferred compounds include is (2S)-2-benzyl-3
-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid.

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 of such substances include salts with inorganic bases such as sodium salts, potassium salts, and calcium salts, salts with organic amines such as morpholine, piperidine, and phenylalaninol, and salts with amino acids. Similar to carboxylic acids, these pharmacologically acceptable salts exhibit insulin secretion promoting and hypoglycemic effects, and are useful as antidiabetic agents.

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

The dosage is appropriately determined depending on the sex, age, weight, severity of symptoms, etc. of the target patient, but in the case of oral administration, it is approximately 10 to 1000 mg per day for an adult, and in the case of parenteral administration, it is approximately 100 mg per day for an adult. It is administered in the range of 1-100 mg per day.

[0028]

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

Reference Example 1 (E)-2-Benzylidene-3-(trans-decahydro-2-isoquinolylcarbonyl)propionic acid

00
30] (E)-Benzylidene succinic anhydride 0.94 g
1.49 ml of trans-decahydroisoquinoline was added dropwise to 20 ml of methylene chloride suspension at 0°C, and
Stir for hours. The reaction solution was washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, it was crystallized from ethyl acetate to give (E)-2-benzylidene-3-(trans-decahydro-2-isoquinolylcarbonyl)propionic acid 1.
．． 21 g was obtained.

[0031]

Reference Example 2 The following compound was produced in the same manner as in Reference Example 1, using trans-hexahydroisoindoline instead of trans-decahydroisoquinoline.

(E)-2-Benzylidene-3-(trans-hexahydro-2-isoindolinylcarbonyl)
propionic acid

[0034]

Reference Example 3 The following compound was produced in the same manner as in Reference Example 1, using trans-hexahydroindoline instead of trans-decahydroisoquinoline.

(E)-2-Benzylidene-3-(trans-hexahydro-1-indolinylcarbonyl)propionic acid

[0037]

Reference Example 4 Instead of trans-decahydroisoquinoline, cis-
The following compound was produced in the same manner as in Reference Example 1 using hexahydroisoindoline.

(E)-2-Benzylidene-3-(cis-
hexahydro-2-isoindolinylcarbonyl)propionic acid

[0040]

Example 1 2-benzyl-3-(trans-decahydro-2-isoquinolylcarbonyl)propionic acid

20 mg of 10% palladium on carbon was added to a suspension of 200 mg of (E)-2-benzylidene-3-(trans-decahydro-2-isoquinolylcarbonyl)propionic acid in 2 ml of ethanol, and the mixture was heated at room temperature under a hydrogen stream. Stirred at atmospheric pressure for 16 hours. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain 188 mg of 2-benzyl-3-(trans-decahydro-2-isoquinolylcarbonyl)propionic acid as a colorless viscous oil.

[0043]

Example 2 In place of (E)-2-benzylidene-3-(trans-decahydro-2-isoquinolylcarbonyl)propionic acid, (E)-2-benzylidene-3-(trans-hexahydro-2- The following compound was produced in the same manner as in Example 1 using isoindolinylcarbonyl)propionic acid.

2-Benzyl-3-(trans-hexahydro-2-isoindolinylcarbonyl)propionic acid

[0046]

Example 3 In place of (E)-2-benzylidene-3-(trans-decahydro-2-isoquinolylcarbonyl)propionic acid, (E)-2-benzylidene-3-(trans-hexahydro-1- The following compound was produced in the same manner as in Example 1 using indolinylcarbonyl)propionic acid.

2-Benzyl-3-(trans-hexahydro-1-indolinylcarbonyl)propionic acid

0
049]

Example 4 In place of (E)-2-benzylidene-3-(trans-decahydro-2-isoquinolylcarbonyl)propionic acid, (E)-2-benzylidene-3-(cis-hexahydro-2- The following compound was produced in the same manner as in Example 1 using isoindolinylcarbonyl)propionic acid.

2-Benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid

0
052]

Example 5 (2S)-2-benzyl-3-(cis-hexahydro-
Benzyl 2-isoindolinylcarbonyl)propionate

671 mg of (3S)-3-benzyloxycarbonyl-4-phenylbutyric acid was dissolved in 15 ml of anhydrous tetrahydrofuran, cooled to -20°C, and 0.5 ml of N-methylmorpholine and 0.38 ml of isobutyl chlorocarbonate were added with stirring. , after 20 minutes cis-hexahydroisoindoline 313 mg anhydrous tetrahydrofuran 5 m
l solution was added. After stirring at -10 to -20°C 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 0.5N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methylene chloride-hexane to give (2S)-2
-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate 772 mg
I got it.

[0055]

Example 6 (2S)-2-benzyl-3-(cis-hexahydro-
2-isoindolinylcarbonyl)propionic acid

00
57] Dissolve 400 mg of benzyl (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate in 3 ml of ethyl acetate, and add 10
Add 60 mg of % palladium on carbon, and leave at room temperature under a hydrogen stream.
Stirred at one atmosphere for 16 hours. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain 227 mg of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid as a colorless viscous oil.

[0058]

Example 7 The following procedure was carried out in the same manner as in Example 5, using (3R)-3-benzyloxycarbonyl-4-phenylbutyric acid in place of (3S)-3-benzyloxycarbonyl-4-phenylbutyric acid. A compound was prepared.

(2R)-Benzyl-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate

[0061]

Example 8 (2S)-2-benzyl-3-(cis-hexahydro-
The following procedure was carried out in the same manner as in Example 6, using benzyl (2R)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate instead of benzyl 2-isoindolinylcarbonyl)propionate. The compound was prepared.

(2R)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid

[0064]

Example 9 In place of (3S)-3-benzyloxycarbonyl-4-phenylbutyric acid and cis-hexahydroisoindoline, 3-propoxycarbonyl-4-phenylbutyric acid and cis-
The following compound was produced in the same manner as in Example 5 using 3a,4,7,7a-tetrahydroisoindoline.

2-benzyl-3-(cis-3a,4,7
, 7a-tetrahydro-2-isoindolinylcarbonyl)propyl propionate

[0067]

Example 10 2-benzyl-3-(cis-3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionic acid

2-benzyl-3-(cis-3a,4,7
, 198 mg of propyl (7a-tetrahydro-2-isoindolinylcarbonyl)propionate was added to 2 m of ethanol.
1 N sodium hydroxide aqueous solution (668 μl)
was added and stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in a small amount of water, and the neutral part was extracted and removed with ethyl acetate. The aqueous layer was made acidic with hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and crystallized from ether to give 2-benzyl-3-(cis-3a,
120 mg of 4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionic acid was obtained.

[0070]

Example 11 Methyl 2-benzyl-3-(cis-hexahydro-2-isoindolinyl)propionate

3 to 100 mg of 2-benzyl-3-(cis-hexahydro-2-isoindolinyl)propionic acid.
% hydrogen chloride methanol solution was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride and washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine. After treatment with activated carbon, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 91 mg of methyl 2-benzyl-3-(cis-hexahydro-2-isoindolinyl)propionate as a colorless viscous oil.
I got it.

[0073]

Example 12 Propyl 2-benzyl-3-(cis-hexahydro-2-isoindolinyl)propionate

2 ml of propanol was added to 100 mg of 2-benzyl-3-(cis-hexahydro-2-isoindolinyl)propionic acid, and while stirring, 12 μl of boron trifluoride diethyl ether complex was added, and after stirring at room temperature for 24 hours, the solvent was dissolved. was distilled off under reduced pressure. The residue was dissolved in methylene chloride, 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 to obtain 106 mg of propyl 2-benzyl-3-(cis-hexahydro-2-isoindolinyl)propionate as a colorless viscous oil.

[0076]

Example 13 (2S)-2-benzyl-3-(cis-hexahydro-
Sodium 2-isoindolinylcarbonyl)propionate monohydrate

To a solution of 1.38 g of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid in 5 ml of ethanol was added 2.19 ml of a 2N aqueous sodium hydroxide solution. After distilling off the solvent under reduced pressure, it was crystallized from ethyl acetate to give (2S)-2
1.44 g of sodium -benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate monohydrate was obtained.

[0079]

Example 14 The following compound was produced in the same manner as in Example 13, using a 1N aqueous potassium hydroxide solution instead of a 2N aqueous sodium hydroxide solution.

(2S)-2-Benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate potassium monohydrate

[0082]

Example 15 (2S)-2-benzyl-3-(cis-hexahydro-
Calcium 2-isoindolinylcarbonyl)propionate dihydrate

To a suspension of 133 mg of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid in 4 ml of water was added 0.2 ml of 25% aqueous ammonia and dissolved, and 111 mg of calcium chloride was dissolved.
2 ml of water solution was added, and the precipitated crystals were collected by filtration. After drying, it was recrystallized from isopropanol to give (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)calcium propionate dihydrate 117.
mg was obtained.

[0085]

Example 16 (2S)-2-benzyl-3-(cis-hexahydro-
2-isoindolinylcarbonyl)propionic acid L-arginine salt

A solution of 47.7 mg of L-arginine in 3 ml of water was added to a solution of 86.4 mg of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid in 5 ml of ethanol, and the mixture was heated to room temperature. de1
Stir for hours. The solvent was distilled off under reduced pressure and crystallized from ethanol-ether to give (2S)-2-benzyl-3-
130 mg of (cis-hexahydro-2-isoindolinylcarbonyl)propionic acid L-arginine salt was obtained.

[0088]

Example 17 The following compound was produced in the same manner as in Example 16 using D-phenylalaninol in place of L-arginine.

(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid D-phenylalaninol salt

[0091]

Claims (6)

[Claims] Claim 1: General formula [Formula 1] (In the formula, A is a bicyclic condensed amino group that may have 1 to 2 unsaturated bonds in the ring, and R is a hydrogen atom or a carbon number It is an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and the C marked with * is a carbon atom in the R configuration or S configuration, or a carbon atom in which these are mixed)
Benzylsuccinic acid derivatives and salts thereof. 2. The benzylsuccinic acid derivative and its salt according to claim 1, which is represented by the general formula: [Image Omitted] (A and C with * in the formula have the same meanings as above). [Claim 3] General formula [Chemical formula 3] (C with (S) in the formula is a carbon atom in the S configuration,
The benzylsuccinic acid derivative and its salt according to claim 2, wherein A has the same meaning as above. 4. 2-benzyl-3-(cis-3a,4,7,7a-
Tetrahydro-2-isoindolinylcarbonyl)propionic acid and its salts. [Claim 5] 2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propion represented by the formula [Chemical formula 5] (C in the formula has the same meaning as above) Acids and their salts. [Claim 6] (2S)-2-benzyl-3-(cis-hexahydro-2- isoindolinylcarbonyl)propionic acid and its salts.