Claims
- 1. A method of treating diseases of the circulatory organs selected from the group consisting of renal insufficiency, cardiac insufficiency and hypertension in a patient which comprises administering to said patient a therapeutically effective amount of a compound or its salt and wherein said compound is selected from the group consisting of 7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline, 7-hydroxy-4-(3,4-dihydroxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline, and 4-(3,4-dihydroxyphenyl)-7-methanesulfonylamido-1,2,3,4-tetrahydroisoquinoline.
- 2. The method according to claim 1 wherein the compound is 7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline or its salt.
- 3. The method according to claim 1 wherein the compound is 7-hydroxy-4-(3,4-dihydroxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline or its salt.
- 4. The method according to claim 1 wherein the compound is 4-(3,4-dihydroxyphenyl)-7-methanesulfonylamido-1,2,3,4-tetrahydroisoquinoline or its salt.
Priority Claims (8)
| Number |
Date |
Country |
Kind |
| 62-75439 |
Mar 1987 |
JPX |
|
| 62-129368 |
May 1987 |
JPX |
|
| 62-200562 |
Aug 1987 |
JPX |
|
| 62-200563 |
Aug 1987 |
JPX |
|
| 62-226184 |
Sep 1987 |
JPX |
|
| 62-227398 |
Sep 1987 |
JPX |
|
| 62-247590 |
Sep 1987 |
JPX |
|
| 62-254012 |
Oct 1987 |
JPX |
|
FIELD OF THE INVENTION
This application is a divisional of U.S. Ser. No. 173,376 filed Mar. 25, 1988, now U.S. Pat. No. 4,876,261 issued Oct. 24, 1989.
The present invention relates to a compound of the formula (1) or its salt and a process for producing the compounds; The compounds have the effect to dilate neophrovascular tracts; ##STR5## wherein ##STR6## represents the formula ##STR7## (wherein R.sup.4 is a hydrogen atom or lower alkylsulfonyl); R.sup.1 is hydrogen, lower alkyl, hydroxyl, halogen, amino, or lower acylamino;
(The above definitions in the formula (I) and groups are interpreted to be the same, hereinafter.)
The compounds act directly upon dopamine receptor present in renal vascular tracts, and are used as nephrovascular dilators.
This invention relates to amino-substituted tetrahydroisoquinoline derivatives represented by the following general formula (I). ##STR9## or salts thereof, which are compounds useful as medicines; to a process for preparing the same; and to medicines containing the same as active ingredient.
The kidney is an important organ which participates in maintaining homeostasis of the circulatory system. If blood circulation insufficiency occurs in this organ for some causes, renal functions will lower to break up homeostasis of the circulatory system, thus inducing, maintaining or aggravating diseases of circulatory organs, such as hypertension and cardiac insufficiency.
Vasodilators and diuretics have been used for the treatment of these diseases, but no vasodilator is so far known which has a positive effect to dilate renal vascular tracts. It is also known that conventional diuretics tend to upset the balance among electrolytes. Dopamine shows diuretic and nephrovascular dilating effects, but also has unfavorable effects (vasoconstricting and heart-rate increasing effects). In addition, it cannot be orally administered and its effect is not well maintained. Thus, there is no drug presently available which is suited for clinical use.
Under the circumstances, we have tried to develop new compounds which act directly upon dopamine receptor present in renal vascular tracts, and which can be orally administered and maintain the effect over long periods. This invention wa accomplished on the basis of the result of such studies.
Thus, this invention relates to compounds represented by the general formula (I) and salts thereof, to a process for preparing the same, and to nephrovascular dilators containing the same as active ingredient.
The compounds of this invention have an asymmetric carbon atom at 4-position-4 of the tetrahydroisoquinoline ring, and all the optical isomers based on this asymmetric carbon and mixtures thereof are included in this invention.
Compounds (I) are capable of forming salts, of which pharmacologically acceptable ones are also included in this invention. These are inorganic salts, such as hydrochlorides, hydrobromides, sulfates, phosphates and nitrates; and organic salts, such as maleates, fumarates, benzoates, ascorbates, methanesulfonates and tartrates.
In the definitions of the formula (I) compounds, "lower alkyl" means C.sub.1 to C.sub.5 straight or branched chain alkyl, and the examples of "lower alkyl" are methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, pentyl, etc. "Lower acyl" means C.sub.1 to C.sub.6 straight or branched chain acyl, and the examples of "lower acyl" are formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc. The examples of "halogen" are fluorine, chlorine, bromide or iodine. The compounds of this invention have an asymmetric carbon atom at 4-position of the tetrahydroisoquinoline ring, and, as the case may be, in lower alkyl and/or lower acyl, and all the optical isomers based on this asymmetric carbon and mixtures thereof are included in this invention. Compounds (1) of this invention may be prepared by the methods described below. ##STR10## (wherein R.sup.8 and R.sup.7 are hydroxyl groups which may optionally be protected; and R.sup.5 is hydrogen atom or a protective group for the nitrogen atom; A' is 2- (or 3-)thienyl, or other monovalent A group.
This method comprises cyclization of a compound represented by the general formula (II), followed by removal of the protected groups when required. As examples of the protective groups for hydroxyls in the starting material (II), may be mentioned linear or branched lower alkyls such as methyl, ethyl, isopropyl and tertbutyl, and aralkyls such as benzyl and phenethyl. As the protective group for the nitrogen atom, may be used linear or branched lower alkyls such as methyl, ethyl, isopropyl and tertbutyl, aralkyls such as benzyl and phenethyl, and substituted or unsubstituted acyl groups such as acetyl and trifluoro-acetyl. The above other monovalent A means ##STR11## (R.sup.4 may mean an amino-protective group in addition to the R.sup.4 groups as defined before.)
Compound (I) can be prepared by subjecting a compound represented by the general formula (II) to intramolecular cyclization by the action of a cyclizing agent capable of forming carbonium ion from the alcoholic hydroxyl in compound (II), such as hydrochloric acid, sulfuric acid, sulfuric acid in trifluoracetic acid, polyphosphoric acid, esters of polyphosphoric acid, methanesulfonic acid in dichloromethane, hydrogen bromide, and Lewis acids (e.g., boron trifluoride, aluminum chloride and stannic chloride).
There is no special limitation upon the reaction temperature; the reaction is carried out under ice cooling or under reflux condition, with the reaction time being properly set in each case depending on other factors.
When the reaction product thus obtained contains protective groups, these are removed by catalytic reduction (e.g., catalytic hydrogenation) or by treatment with boron tribromide, hydrobromic acid, aluminum chloride, trimethylsilyl iodide or hydroiodic acid. The protective group on the nitrogen atom may be removed simultaneously with the protective groups on hydroxyl groups, or in a separate step (for example, by treatment with cyanogen bromide, hydrochloric acid or ammonia water, hydrogenation in the presence of a catalyst, or other suitable methods). ##STR12##
Compounds (I) of this invention can be prepared by reduction of a nitro compound represented by the general formula (III), followed by removal of the protective groups when required.
This reduction may be effected by the use of a sulfur compound, such as sodium sulfate, sodium hydrosulfide, sodium dithionite and ammonium sulfide; by catalytic reduction in the presence of platinum, platinum black, palladium-carbon (Pt-C) or Raney nickel, or by reduction using a metal hydride such as lithium aluminum hydride. Any solvents inert to the reaction may be used, including alcohols such as methanol, ethanol and isopropanol, tetrahydrofuran, diethyl ether, dioxane, benzene and toluene. The reaction is carried out at a temperature properly set depending on the type of reducing agent used (under ice cooling or at elevated temperatures). The protective groups of the nitrogen atom and hydroxyl groups can be simultaneously removed in this reducing step if the reaction is conducted under proper conditions.
The compounds (I) of this invention thus formed are isolated and purified in the form of free amine or a salt thereof by commonly employed techniques, for example, extraction, crystallization, recrystallization and various types of chromatography.
Compounds (I) of this invention may be prepared by the method described below. ##STR13## (wherein R is hydrogen atom or a halogen atom; R.sup.1 ' and R.sup.4 ' are each hydrogen atom or a protective group or the nitrogen atoms; and R.sup.2 ' and R.sup.3 are each hydroxyl group which may optionally be protected).
This method comprises cyclization of a compound represented by the general formula (II), followed by removal of the protective groups when required. As examples of the protective groups for hydroxyls in the starting material (II), may be mentioned linear or branched lower alkyls of 1 to 5 carbon atoms such as methyl, ethyl, isopropyl and tertbutyl, and aralkyls such as benzyl and phenethyl. As the protective groups for the nitrogen atoms, may be used tri(lower)alkylsilyl groups such as trimethylsilyl; acyl groups, such as formyl, acetyl, propionyl, trifluoroacetyl, tert-butoxycarbonyl, methoxyacetyl, methoxypropionyl and benzyloxycarbonyl; and aralkyls such as benzyl and benzhydryl. Compounds (I) of this invention can be prepared by subjecting a compound represented by the general formula (II) to intramolecular cyclization by the action of a cyclizing agent capable of forming carbonium ion from the alcoholic hydroxyl in compound (II), such as hydrochloric acid, sulfuric acid, sulfuric acid in trifluoroacetic acid, polyphosphoric acid, esters of polyphosphoric acid, methanesulfonic acid in dichloromethane, hydrobromic acid, hydrogen fluoride, and Lewis acids (e.g., boron trifluoride, aluminum chloride and stannic chloride).
There is no specific limitation upon the reaction temperature; the reaction is carried out under ice cooling or under reflux conditions, with the reaction time being properly set in each case depending on other factors.
When the reaction product thus obtained contains protective groups, these are removed by catalytic reduction (e.g., catalytic hydrogenation) or by treatment with boron tribromide, hydrobromic acid, aluminum chloride, trimethylsilyl iodide or hydroiodic acid. The protective groups on the nitrogen atoms may be removed simultaneously with the protective groups on hydroxyl groups, or in a separate step (for example, by treatment with cyanogen bromide, hydrochloride acid or ammonia water, hydrogenation in the presence of a catalyst, or other suitable methods). ##STR14##
Compounds (I) of this invention can be prepared by reduction of a carbonyl compound represented by the general formula (III), followed by removal of the protective groups when required. The carbonyl compounds (III) used in this reaction may be obtained by subjecting an alcohol represented by the following general formula (IV) ##STR15## to intramolecular cyclization by the action of a cyclizing agent, such as hydrochloric acid, sulfuric acid, sulfuric acid in trifluoroacetic acid, polyphosphoric acid, esters of polyphosphoric acid, methanesulfonic acid in dichloromethane, hydrobromic acid, hydrogen fluoride, and Lewis acids (e.g., boron trifluoride, aluminum chloride and stannic chloride).
A carbonyl compound (III) thus obtained is treated with a reducing agent, such as borane, diborane, lithium aluminum hydride, sodium borohydride plus propionic acid, aluminum hydride diisobutyl and aluminum hydride bis(2-methoxyethoxy)sodium, and the protective groups are removed as required, giving a compound (I) of this invention. Any solvents inert to the reaction may be used, for example, tetrahydrofuran, diethyl ether, benzene and dioxane. The reaction is carried out at a temperature properly set depending on the type of reducing agent used (under ice cooling or at elevated temperatures). The protective groups can be removed by the methods described in Method 1.
The compounds (I) of this invention thus formed are isolated and purified in the form of free amine or a salt thereof by commonly employed techniques, for example, extraction, crystallization, recrystallization and various types of chromatography.
Compounds (I) of this invention and salts thereof are efficiently absorbed when administered orally because of the high liposolubility, and are effective for treating diseases of circulatory organs, such as renal insufficiency, cardiac insufficiency and hypertension.
Compounds (I) of this invention and salts thereof are efficiently absorbed when administered orally and are effective for treating diseases of circulatory organs, such as renal insufficiency, cardiac insufficiency and hypertension. In the treatment of hypertension, in particular, these compounds are expected to provide an etiologically effective medicine unlike conventional symptomatic drugs.
Compounds (I) of this invention and salts thereof have the effect to dilate nephrovascular tracts, and this action is exerted through dopamine receptor. Therefore, these compounds also have the effect to dilate vascular tracts of other organs, and directly act upon renal tubules, thus showing diuretic effect. In addition, these compounds are expected to be effective for the prevention of oliguria during and after operation and for the treatment of visceral hyperfunction, edemas, arterioscrelosis and blood coagulation.
These pharmacological effects were confirmed by the test described below.
Male and female mongrel dogs weighing 11 to 16 Kg were subjected to anesthesia with pentobarbital (30 mg/Kg i.v.), and artificial respiration was started by means of a cannula inserted into the trachea of each dog. During the whole course of test, pentobarbital was continuously administered (3 to 5 mg/Kg/hr) into the vein of right forelimb to maintain a constant anesthetic condition. A cannula for drug administration was inserted into the vein of right thigh. The systemic blood pressure was measured by means of a pressure transducer, with a cannula inserted into the artery of right thigh. The heart rate was measured using a cardiotachometer driven by pulse waveform.
Incision was made from the flank to the posterior wall of the peritoneum to expose the kidney, a probe was set to the renal artery, and the rate of renal blood flow was measured with an electromagnetic blood flowmeter. After setting the probe, an injection needle for drug administration connected to a polyethylene tube was inserted at the origin of the renal artery.
Each of the compounds tested was quickly injected in the form of a 0.2 ml solution, followed by continuous injection of physiological saline (0.5 ml/min) to ensure its rapid spreading in the renal artery.
All the test values are expressed as percentage change in the rate of blood flow, with the value immediately before administration taken as 100%.
Administration of the compounds of this invention to the renal artery of dogs put under anesthesia at doese of 0.3 to 100 .mu.g showed increases in the rate of blood flow proportional to the amounts administered, with an increase of about 35% being observed at the highest dose. And, some compounds at doses of 0.3-30 .mu.g showed increases with an increase of about 40% being observed at the highest dose (30 .mu.g).
Preparations containing, as active ingredient, at least one of the compounds (I) and salts thereof of this invention may be manufactured in the form of tablets, powder, beadlets, granules, capsules, pills, injections, suppositories, ointment or poultice by using carriers, excipients and other commonly employed additives, and are orally (including sublingual application) or parenterally administered.
The suitable daily dose of the compounds of this invention should be determined with consideration given to the physical conditions, body weight, age, sex and other factors of particular patients, but is normally 50 to 100 mg for adults (given all at a time or subdivided in several doses)
m-Nitrobenzaldehyde (1.8 g) was added to a suspension of .alpha.-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride in 25 ml methanol, triethylamine (2.8 ml) was further added dropwise at room temperature with stirring, and the resulting solution was heated under reflux for 30 minutes. After cooling, sodium borohydride (1.45 g) was added in small portions with stirring under ice cooling, and the mixture was stirred at room temperature for one hour and concentrated. The residue was treated with chloroform and water, and the chloroform layer was collected, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ether/n-hexane, affording 3.3 g of pure .alpha.-[(3-nitrobenzylamino)methyl]-3,4-dimethoxybenzyl alcohol, m.p. 105.degree.-107.degree. C.
To a solution of 3.3 g .alpha.-[3-nitrobenzylamino)methyl]-3-4-dimethoxybenzyl alcohol obtained in Reference Example 1 in 50 ml methanol, was added 0.6 g Raney nickel, and the mixture was subjected to hydrogenation at room temperature. After confirming complete absorption of hydrogen gas, the reaction mixture was filtered, the filtrate was concentrated, and the residue was recrystallized from ethyl acetate.
.alpha.-[[(4-methoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (m.p. 110.degree.-112.degree. C.).
.alpha.-[[(4-methoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (m.p. 115.degree.-116.degree. C.).
.alpha.-[[(3-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol.
.alpha.-[[(4-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol.
.alpha.-[[(2-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (m.p. 103.degree.-104.degree. C.).
1.0 g of .alpha.-(aminomethyl)-3.4-dimethoxybenzyl alcohol hydrochloride was suspended in 5 ml of methanol, and after adding thereto 0.85 g of 2,3-dimethoxybenzaldehyde, 0.63 ml of triethylamine was added dropwise to the mixture while stirring at room temperature.
The mixture was heated under reflux for 30 minutes, and 0.24 g of sodium boron hydride was added slowly to the mixture while stirring under ice cooling. After the foaming stopped, the mixture was concentrated. The residue was subjected to a separating procedure with chloroform and water, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 1.07 g of .alpha.-[[2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 96.degree.-97.degree. C.
(1) To 1.56 g of 3-methoxy-2-methylbenzoic acid, was added 2.03 g of thionyl chloride, and the mixture was heated under reflux for 30 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. The residue was dissolved in 8 ml of toluene, and the solution was added dropwise to a mixture of 2.0 g of .alpha.-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride and 1.52 ml of pyridine and 20 ml of isopropyl alcohol under ice cooling while stirring. The temperature of the mixture was reverted to room temperature, and after 30 minutes, the reaction solution was concentrated. The residue was dissolved in ethyl acetate, washed with 1N aqueous HCI, saturated aqueous NaHCo.sub.3 solution, and water, successively, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 2.41 g of .alpha.-[N-3-methoxy-4-methylbenzoyl)amidomethyl]-3,4-dimethoxybenzyl alcohol, m.p. 106.degree.-109.degree. C. (2) 1.02 g of .alpha.-[N-(3-methoxy-4-methylbenzoyl)amidomethyl]-f,e-dimethoxybenzyl alcohol was dissolved in 10 ml of tetrahydrofuran, and 1M boran-tetrahydrofuran solution (10.8 ml) was added dropwise to the mixture under an argon gas stream under ice cooling. The mixture was heated under reflux for 2.5 hours, and after ice cooling, 0.44 ml of methanol was added dropwise, and the mixture was heated under reflux for 30 minutes. The mixture was cooled with ice, and after adding thereto 0.9 ml of conc. hydrochloric acid, the mixture was heated under reflux for 30 minutes, and concentrated. The residue was dissolved in water, washed with ether twice, and basified, and extracted with chloroform twice. The chloroform layers were collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from chloroform-n-hexane, giving 560 mg of .alpha.-[[(3-methoxy-2-methylbenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 135.degree.-136.degree. C.
.alpha.-[[(3-methoxy-2-nitrobenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (m.p. 92.degree.-94.degree. C.).
4-(3,4-dimethoxyphenyl)-7-methoxy-8-nitro-1,2,3,4-tetrahydroisoquinoline.
2-benzyl-4-(3,4-dimethoxyphenyl)-7-methoxy-8-nitro-1,2,3,4-tetrahydroisoquinoline (m.p. 118.degree.-119.degree. C.).
2-benzyl-4-(3,4-dihydroxyphenyl)-7-hydroxy-8-nitro-1,2,3,4-tetrahydroisoquinoline hydrobromide (m.p. above 180.degree. C. (decomposition)).
.alpha.-(cyano)-6-fluoro-3,4-dimethoxybenzyl alcohol.
.alpha.-(aminomethyl)-6-fluoro-3,4-dimethoxybenzyl alcohol hydrochloride (m.p. 223.degree.-226.degree. C.).
.alpha.-[[(2,3-dimethoxybenzylamino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (m.p. 110.degree.-112.degree. C.).
.alpha.-[[(3-methoxy-2-nitrobenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (m.p. 92.degree.-94.degree. C.).
4-(3,4-dimethoxyphenyl)-7-methoxy-8-nitro-1,2,3,4-tetrahydroisoquinoline.
2-benzyl-4-(3,4-dimethoxyphenyl)-7-methoxy-8-nitro-1,2,3,4-tetrahydroisoquinoline (m.p. 118.degree.-119.degree. C.).
8-amino-2-benzyl-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (m.p. 142.degree.-143.degree. C.).
.alpha.-(cyano)-6-fluoro-3,4-dimethoxybenzyl alcohol (m.p. 112.degree.-114.degree. C.).
.alpha.-(aminomethyl)-6-fluoro-3,4-dimethoxybenzyl alcohol hydrochloride (m.p. 223.degree.-226.degree. C.).
.alpha.-[(benzylamino)methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (m.p. 80.degree.-82.5.degree. C.).
.alpha.-[[(2-thenyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (m.p. 79.degree.-83.degree. C.).
.alpha.-[[(3-thenyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (a syrupy matter).
.alpha.-(cyano)-6-fluoro-3,4-dimethoxybenzyl alcohol (m.p. 112.degree.-114.degree. C.).
.alpha.-(aminomethyl)-6-fluoro-3,4-dimethoxybenzyl alcohol (m.p. 223.degree.-226.degree. C.).
.alpha.-[[[(2-acetamido-4-thiazolyl)methyl]amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (m.p. 173.degree.-175.degree. C.).
.alpha.-[[[(2-acetamido-4-thiazolyl)methyl]amino]methyl]-3,4-dimethoxybenzyl alcohol (m.p. 204.degree.-206.degree. C.).
.alpha.-[(3-nitrobenzylamino)methyl]-3,4-dimethoxybenzyl alcohol (m.p. 105.degree.-107.degree. C.).
.alpha.-[(3-aminobenzylamino)methyl]-3,4-dimethoxybenzyl alcohol (m.p. 84.degree.-86.degree. C.).
The above Reference Examples' compounds were prepared in a conventional manner.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
| 3376195 |
Allais et al. |
Apr 1968 |
|
| 4340600 |
Brenner et al. |
Jul 1982 |
|
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 0161501 |
Nov 1985 |
EPX |
| 1164192 |
Sep 1969 |
GBX |
Non-Patent Literature Citations (2)
| Entry |
| Jacob et al., "Chemical Abstracts", vol. 95, 1981, col. 95:54626p. |
| Riggs et al., "Chemical Abstracts", vol. 107, 1987, col. 107:51385q. |
Divisions (1)
|
Number |
Date |
Country |
| Parent |
173376 |
Mar 1988 |
|
Patent Grant
5079256
