JPH0112746B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel and pharmaceutically useful compounds of the general formula (In the formula, X is a halogen atom (fluorine, chlorine, bromine, iodine), n is 1 or 2, R ¹ is a hydroxyl group, a lower alkoxy group (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.) or 4-amino-1,2,3,4-tetrahydro- represented by an amino group, R ² is hydrogen, a lower alkanoyl group (acetyl, propionyl, isopropionyl, butyryl, isobutyryl, etc.) or a carbamoyl group. The present invention relates to 2-naphthoic acid derivatives and salts thereof. Special Publication No. 43-22097, Chem.Pharm.Bull.
14, 324 (1966), J.Med.Chem., 21 , 1105
(1978) describes compounds in which X corresponds to hydrogen or methoxy in the above general formula (), which are useful as synthetic intermediates for certain types of analgesics. The present inventors synthesized various derivatives having a partial structure of gamma-aminobutyric acid (hereinafter abbreviated as GABA) in their structures, and investigated their usefulness.
As a result, the compounds of the present invention showed little protective effect against effects in the central nervous system, such as convulsions or lethality, induced by GABA antagonists such as bicuculline and picrotoxin, although this was unexpected. The present invention was completed based on the discovery that the drug also has strong diuretic and blood pressure lowering effects. On the other hand, the above-mentioned known compounds had extremely weak effects, but these effects were practically not observed. In the general formula (), compounds in which R ² is hydrogen are:
For example, it is manufactured by the following methods 1 to 3. Method 1 General formula (In the formula, X, n, and R ¹ have the same meanings as above.) A method for reducing an oxime compound represented by the following. This reduction is preferably a catalytic reduction, in the presence of a metal catalyst such as Raney nickel, platinum oxide or palladium on carbon, in an inert solvent (preferably a lower alkanol such as methanol, ethanol or a lower alkanoic acid such as acetic acid). If desired, ammonia is added to prevent polymerization, and the temperature is from room temperature to 150°C, preferably from 50 to 100°C, at normal pressure or from 50 to 150°C.
It is carried out under atmospheric pressure of hydrogen. In addition to hydrogen, hydrazine can be used as a hydrogen source. Also,
It can be reduced with metallic sodium in methanol-containing liquid ammonia, or it can be reduced with hydrochloric acid, acetic acid, etc. using zinc, tin, etc. Method 2 General formula (In the formula, X, n, and R ¹ are as defined above, and Y is a halogen atom, methylsulfonyloxy group, p-
Indicates a reactive residue such as a tolylsulfonyloxy group. ) A method of ammonolyzing a compound represented by the following in water or lower alkanol. Method 3 General formula (In the formula, X, n, and R ¹ have the same meanings as above.) A method of subjecting a compound represented by the following to a Leucart reaction. That is, it is produced by melt-reacting the compound of general formula () with urea, ammonium formate, etc. at 150 to 200°C in the presence of formic acid, and then hydrolyzing the product. In the general formula (), when a compound in which R ² is hydrogen is reacted with a reactive derivative of lower alkanoic acid (acid halide, acid anhydride, etc.), a compound in which R ² is lower alkanoyl is obtained, and potassium cyanate Alternatively, when it is reacted with sodium cyanate in a hydrous lower alkanol, a compound in which R ² is carbamoyl is obtained. Furthermore, when a compound in which R ¹ is a hydroxyl group is esterified with a lower alkanol in the presence of a mineral acid such as hydrochloric acid or sulfuric acid, a compound in which R ¹ is a lower alkoxy is obtained, and the free carboxylic acid or its ester compound is reacted with ammonia. can lead to compounds in which R ¹ is amino.
Conversely, N-lower alkanoyl compounds and ester or amide compounds can be converted into amino compounds and free carboxylic acids, respectively, upon hydrolysis. The compound ( ) of the present invention thus obtained is obtained as a diastereoisomer because the 2- and 4-positions of the tetralin ring are asymmetric carbons, but
The mixture is heated to 60-200°C, preferably 100-140°C.
When heated and melted in (In the formula, X and n have the same meanings as above.) A 1,4-methano-2-benzazepin-3-one derivative represented by the following formula is obtained. Since the compound of general formula () is a neutral compound, the 2,4-trans compound (hereinafter abbreviated as trans form) can be extracted and separated using an acid or an alkali. Also, general formula ()
A cis-amino acid can be obtained by hydrolyzing the compound with an acid or an alkali. Since the cis and trans forms separated here are racemic forms, the ester form may be converted into an optically active carboxylic acid (tartaric acid, dibenzoyltartaric acid, camphorsulfonic acid, diacetyltartaric acid, etc.) as appropriate.
phenylsuccinic acid, mandelic acid, malic acid, lactic acid, etc.), or a carboxylic acid form with a protected amino group is prepared with an optically active base (brucine,
Each optically active substance can be obtained by optical resolution using natural alkaloids such as quinine and cinchonidine, optically active α-phenethylamine, α-amino acid ester, etc.).
Alternatively, if an optically active carboxylic acid derivative at the 2-position of the general formula is used as a starting material, each optically active form can be obtained by simply separating the cis form and trans form as described above. The compound of the present invention may optionally contain an acid (hydrochloric acid, sulfuric acid,
inorganic acids such as phosphoric acid, nitric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, citric acid) or with inorganic bases (e.g. sodium hydroxide, sodium bicarbonate, potassium hydroxide, Calcium hydroxide, etc.), acid or
It can be a base addition salt. As is clear from the above, the compound of the present invention () includes all diastereoisomers, cis isomers, trans isomers, optically active isomers, and salts thereof. The diuretic activity of the compounds of the present invention is shown below. The trans form has stronger activity than the corresponding cis form. Test method Lipschitz et al. method (WLLipschitz, Z.
Haddian, A. Kerpsser, J. Pharmacol.Exp.
Therap., 79 , 97 (1943)), 6 male rats (body weight 180-220 g) were used in each group, and after fasting for 18 hours, they were also fasted for 3 hours. 100 of the test drug
An amount equivalent to mg/Kg was suspended in physiological saline equivalent to 25 ml/Kg and administered orally, and each animal was placed in a metabolic cage and urine was collected for up to 6 hours. The activity was expressed as a percentage increase over the control group using the following formula. Test group average urine volume - control group average urine volume / control group average urine volume x 100 = percentage increase [Table] Under these conditions, known compounds and their esters, 4-amino-1, 2,3,4-
Tetrahydro-2-naphthoic acid hydrochloride, trans-4-amino-1,2,3,4-methyltetrahydro-2-naphthoic acid hydrochloride, trans-4
-amino-6,7-dimethoxy-1,2,3,4
-Ethyl-tetrahydro-2-naphthoate hydrochloride showed no significant difference from the control group. Furthermore, no diuretic activity was observed for GABA itself even at a high dose of 1000 mg/Kg. When the compound of the present invention is used as an antihypertensive diuretic,
itself or appropriate pharmacologically acceptable excipients;
Mix with carriers, diluents, etc. to form tablets, capsules,
It can be administered orally or parenterally in the form of granules, powders, or injections. In the case of oral administration, the dosage is usually about 10 mg to 500 mg per day for adults.
These are administered once or in divided doses,
It may vary depending on age, weight, and/or the severity of the condition being treated and response to treatment. The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited thereto. Example 1 7,8-dichloro-4-hydroxyimino-
Add 265 g of ethyl 1,2,3,4-tetrahydro-2-naphthoate (melting point 133-135°C) to 1 part of ethanol.
Then, 130 ml of 12% ethanolic ammonia and 27 g of Raney nickel were added, and the hydrogen pressure was 65 atm and the internal temperature was 75°C.
Refund with. Hydrogen absorption stops in about 3 hours.
After cooling, the catalyst is removed and the liquid is concentrated. Ethyl acetate was added to the residue and cooled, and the precipitated crystals were taken to obtain 6,7-dichloro-1,4-methano-2,3, which is a cis-ring closed product with a melting point of 196-200°C.
75 g of 4,5-tetrahydro-1H-2-benzazepin-3-one are obtained. Rinse the liquid once with water,
After drying, concentrate and heat on an oil bath at 130°C for 3 hours. After cooling, ethyl acetate was added to collect the precipitated crystals, and an additional 14 g of the ring-closed product was recovered. After diluting the solution by adding 1 part of ethyl acetate, 150 ml of 20% hydrochloric acid water is added and stirred, and white needle crystals are precipitated, which are sucked off.
trans-4-amino-7,8-dichloro-1,
76 g of crude crystals of ethyl 2,3,4-tetrahydronaphthoate hydrochloride are obtained. The aqueous layer of the liquid is separated, extracted several times with water, and the aqueous layer is saturated with sodium chloride to recover 23 g of crystals. This product has a melting point of 249 when recrystallized from ethanol.
~251°C (decomposition). When ethyl trans-4-amino-7,8-dichloro-1,2,3,4-tetrahydronaphthoate is optically resolved using dibenzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid, an optically active dextro compound is obtained. and Levo body, respectively. Dextro compound hydrochloride: Melting point 209-213℃, [α] _D = +38.6 (1%, methanol) Levo compound hydrochloride: Melting point 208-213℃, [α] _D = -37.4 (1%, methanol ) Example 2 6,7-dichloro-1,4-methano-2,3,
29 g of 4,5-tetrahydro-1H-2-benzazepin-3-one is suspended in 300 ml of 20% hydrochloric acid, and a hydrolysis reaction is carried out for 40 hours with heating and stirring. After cooling, the precipitated crystals were collected to obtain 32 g of crude crystals of cis-7,8-dichloro-4-amino-1,2,3,4-tetrahydro-naphthoic acid hydrochloride.
Add 500 ml of ethanol to this, and slowly introduce dry hydrochloric acid gas for 8 hours while stirring under reflux. After cooling, the precipitated crystals were collected and recrystallized from 95% ethanol to give cis-7,8-dichloro-4-amino-1,2,3 as white needle-like crystals with a melting point of 239-245°C (decomposition). , 29 g of ethyl 4-tetrahydro-naphthoate hydrochloride are obtained. Example 3 6,7-dichloro-4-hydroxyimino-
Dissolve 60 g of methyl 1,2,3,4-tetrahydro-2-naphthoate in 300 ml of methanol and 300 ml of 10% ammonia-methanol, add 8 g of Raney nickel, and hydrogenate at 60 atmospheres. The mixture is heated and stirred at 70 to 80°C for 7 hours, and after cooling, the catalyst is removed and the solvent is distilled off. Add acetone to the semi-solid residue, cool it, and remove the crystals.
-dichloro-1,4-methano-2,3,4,5-
Tetrahydro-1H-2-benzazepine-3-
17g of onion is obtained. Concentrate the mother liquor and heat to 110-120℃
After heating for 2 hours and cooling, the mixture is crystallized from acetone and collected to obtain an additional 3 g of a closed ring. Concentrate the mother liquor, add ethyl acetate, add 100 ml of 10% hydrochloric acid, and stir well to precipitate white needle crystals. If you take this, trans-4-
10 g of crystals of methyl amino-6,7-dichloro-1,2,3,4-tetrahydro-2-naphthoate hydrochloride are obtained. An additional 3 g was recovered from the mother liquor. When this product is recrystallized from methanol, its melting point is
White needles are obtained at 262-263°C (decomposition). Example 4 trans-4-amino-6,7-dichloro-
3.6 g of methyl 1,2,3,4-tetrahydro-2-naphthoate hydrochloride is dissolved in 50 ml of methanol and 15 ml of 28% aqueous ammonia, and ammonia gas is blown into the solution at 30 to 40°C for 8 hours. The solvent is distilled off, water is added, the precipitated crystals are collected and dissolved in methanol, and methanolic hydrochloric acid is added. Aspirate the precipitated crystals. When recrystallized from methanol, trans-4-amino-6,7-
dichloro-1,2,3,4-tetrahydro-2-
1.6 g of naphthalene carboxamide hydrochloride is obtained. Example 5 trans-4-amino-6,7-dichloro-
Dissolve 1.5 g of methyl 1,2,3,4-tetrahydro-2-naphthoate in 20 ml of pyridine, add 10 ml of acetic anhydride under ice cooling, and leave overnight. Concentrate the reaction solution and pour water into the residue. When the precipitated crystals are sucked out and recrystallized from ethanol, the melting point is 182 ~
trans-4-acetamide-6,7- at 184°C
dichloro-1,2,3,4-tetrahydro-2-
1.5 g of methyl naphthoate are obtained. Example 6 trans-4-amino-6,7-dichloro-
3.1 g of methyl 1,2,3,4-tetrahydro-2-naphthoate hydrochloride is dissolved in 100 ml of 50% methanol by heating, and a solution of 1.2 g of potassium cyanate dissolved in 10 ml of water is added dropwise. After the completion of the dropwise addition, the reaction was carried out at 50 to 60°C for 2 hours, and then cooled on ice. The precipitated crystals were collected, washed with water, and recrystallized from a mixed solvent of methanol and acetone. 6,7-dichloro-4-ureido-1,2,
Methyl 3,4-tetrahydro-2-naphthoate
1.7g is obtained. Compounds of Examples 7 to 21 in the list of examples below are produced in the same manner as in the above examples. [Table] [Table]

Claims (1)

[Claims] 1. General formula (In the formula, X is a halogen atom, n is 1 or 2
, R ¹ represents a hydroxyl group, a lower alkoxy group or an amino group, and R ² represents a hydrogen atom, a lower alkanoyl group or a carbamoyl group. ) A 4-amino-1,2,3,4-tetrahydro-2-naphthoic acid derivative or a salt thereof.