HU190019B - Process for preparing 8-alkoxy-carbonyl-amino/-4-aryl-2-methyl-tetrahydro-isoquinoline derivatives - Google Patents

Abstract

The present invention relates to a compound of formula (I) wherein R is lower alkyl optionally substituted by halogen, phenyl (lower) alkyl or phenyl and X is hydrogen or halogen, and to the acid addition salts thereof, that a) a compound of formula II is ring-closed; b) reacting an amino compound of formula (III) with a halogenic acid ester of formula (IV) wherein H is halogen and then converting the compound of formula (1) thus obtained into an acid addition salt. The novel compounds of formula (I) can be used in medicine because of their valuable effects on the central nervous system, especially as antidepressants and / or antiparkinsonian agents.

Description

The present invention relates to the preparation of pharmaceutically active novel 8- (alkoxycarbonylamino) 4-aryl-2-methyl-tetrahydroazoquinoline derivatives.

8-Amino-4-aryl-2-alkyl-tetrahydro-isoquinoline derivatives of an amino group, which are acyl substituted with an acyl group derived from saturated or unsaturated aliphatic carboxylic acids having up to 6 carbon atoms, aromatic carboxylic acids or C 7 -C 10 arylaliphatic carboxylic acids, are disclosed in 1,164,192. s. United Kingdom Patent No. 4,866,198. These compounds have central nervous system stimulating and timoleptic properties. Similar derivatives are disclosed in U.S. Patent No. 1,670,848. Published German Patent Application No. 1,795,829; They are also disclosed in published patent application in the Federal Republic of Germany.

The present invention relates to a process for the preparation of 8- (alkoxycarbonylamino) 4-aryl-2-methyltetrahydroisoquinoline derivatives of formula (I):

R is lower alkyl, phenyl (lower) alkyl or phenyl optionally substituted with halo; and

X is hydrogen or halogen) and pharmaceutically acceptable acid addition salts thereof, such that

a) ring closure of a compound of formula II (wherein R and X are as defined above) or

b) reacting an amino compound of formula III (wherein X is as defined above) with a halogen formic acid ester of formula IV (wherein H 2 is halogen, preferably chlorine or bromine) and R is as defined above) and, if desired, converting the compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt.

As used herein, the term "lower alkyl" refers to straight or branched C 1 -C 4 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.). The term "halogen" includes fluorine, chlorine and bromine.

The acid addition salts of the compounds of formula (I) are pharmaceutically acceptable salts of inorganic or organic acids (e. , maleic acid, tartaric acid, benzoic acid, salicylic acid, etc.).

Particularly preferred novel compounds of the formula I are 8- (ethoxycarbonylamino) 4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline and pharmaceutically acceptable acid addition agents. salts thereof, in particular its hydrochloride.

Process (a) of the present invention is preferably carried out in the presence of an acidic catalyst. For this purpose, mineral acids (e.g. hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.) or Lewis acids (e.g. aluminum chloride, bromofluoride, zinc chloride, tin chloride, etc.) may be used. It is very advantageous to work in the presence of a sulfuric acid catalyst.

The reaction is carried out in a solvent medium. Suitable solvents are halogenated hydrocarbons (e.g., methylene chloride, chloroform, etc.). The reaction may be carried out at a temperature of 0 to 80 ° C, depending on the activity of the catalyst used.

The compounds of formula (I) can be isolated from the reaction mixture by methods known per se. If a sulfuric acid catalyst is used, it is preferable to use cl to pour the sulfuric acid solution on ice, basify it, and then treat the compound of formula I with an organic solvent, e.g. chloroform - extraction.

The compounds of formula (II) used as starting materials in process (a) of the present invention are reacted by reacting compounds of formula (V) (wherein X is as above) and a compound of formula (IV) wherein H and R are as defined above. The reaction may be carried out in a manner analogous to that described below for process b).

The compounds of formula (II) thus obtained, after isolation or preferably without, can be cyclized to the desired final product of formula (I).

Process b) of the present invention is carried out in a manner known per se. Preferred compounds of formula (IV) are those which contain a chlorine atom at the point of dilution. The reaction is carried out in an organic solvent medium. The reaction medium is preferably aromatic solvents (e.g. benzene, toluene, xylene, etc.). Preferably, heating is carried out, particularly at the boiling point of the reaction mixture. The reaction may optionally be carried out without solvent. The reaction is preferably carried out in the presence of an acid acceptor, e.g. tertiary amines such as triethylamine or quinoline may be used.

The reaction mixture may be worked up by methods known per se. It is advantageous to concentrate the reaction mixture, basify the residue (with ammonium hydroxide) and extract the desired compound of formula (I) with an organic solvent (e.g. chloroform).

Compounds of formula (III) used as starting materials in process (b) of the present invention may be prepared by cyclization of compounds of formula (V) (wherein X is as defined above). The reaction may be carried out analogously to process a) of the present invention.

The compounds of formula (I) may, if desired, be converted into their pharmaceutically acceptable acid addition salts. The salt formation can be carried out in a manner known per se by reacting a compound of formula I and preferably a stoichiometric amount of the appropriate acid in an inert organic solvent.

Compounds of formula (III) and (V) are known (British Patent No. 1,164,192).

The compounds of formula I exhibit valuable antidepressant and / or antiparkinsonian activity.

Compounds of general formula (I) are pharmaceutically active compounds and inactive non-toxic solid or liquid

-2190019 in the form of pharmaceutical compositions containing cochlear carriers. The formulations may be formulated for oral (e.g., tablet, capsule, dragee, solution, emulsion or suspension) or parenteral (e.g., injection solutions). As a carrier, e.g. talc, starch, magnesium stearate, magnesium carbonate, calcium carbonate, water, alcohols, polyalkylene glycols, etc.). The pharmaceutical compositions may also contain conventional pharmaceutical excipients (e.g. wetting agents, disintegrating and flavoring additives, coloring agents, etc.).

The pharmaceutical compositions may be prepared by methods well known in the art of pharmaceutical manufacture.

The activity of the compounds of formula I is confirmed by the following tests:

1. Acute toxicity, s.c. DL50 after 96 hours of treatment.

2. Haloperidol Ϊ3 pmol / kg induced catalepsy in half of the mice inhibited by s.c. dose.

3. Minimum i.p. that increases or decreases spontaneous motility of mice. dose.

4. Catalysis of tetrabenzine at 110 pmol / kg was inhibited in half of the mice by s.c. dose.

5. S.c., which inhibits ocular closure induced by 79 pmol / kg tetrabenzine in half of the mice. quantities.

6. Minimum s.c. for inhibition of rectal temperature reduction after a dose of 1.6 μηιοΐ / kg reserpine. dose in the mouse.

7. The lowest i.v. dose of dopamine to increase blood pressure and mucosa effect. dose in cats.

8. The smallest stereotype-inducing s.c. dose per rat.

9. Following the electrolytic lesion of the substantia nigra, the dose causing the rat to exhibit characteristic rotating behavior.

10. A dose that produces a significant decrease in prolactin levels in rats ovariectomized three weeks prior to treatment with 0.073 pmol / kg of estradiol for 4 days.

The following test compounds are used:

Compound A = Example 1.

IC

Further details of the process are set forth in the following examples, without limiting the invention to these examples.

Example 1

Preparation of 8- (Ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinol

A solution of 8-amino-4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline (13.1 g, 0.047 mol) in anhydrous benzene (300 ml) was treated with 6.8 g (0, 0625 moles) of ethyl chloroformate in 60 ml of anhydrous benzene. After refluxing for 2.5 hours, the benzene was distilled off in vacuo, the residue was dissolved in water (10 mL), basified with concentrated ammonium hydroxide (10 mL) and extracted with chloroform (3 X 100 mL). The chloroform solution was dried over anhydrous sodium sulfate, evaporated and the residue was recrystallized twice from ethanol. 7.3 g of the title compound are obtained in the form of white crystals. Yield 45.6%, m.p. 155 ° C.

Analysis calculated for C ₁₉ H ₂₁ ClN ₂ O ₂ (344.845):

C, 66.19; % H, 6.14; N, 8.12; Cl, 10.28; found:

C, 66.79; H, 5.89; N, 8.42. Cl, 10.56.

Example 2

Preference of 8- (Ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

7.3 g (0.0212 mol) of the base prepared in Example 1 are suspended in 50 ml of ethanol and then 10 ml of hydrogen chloride-saturated ethanol are added under cooling. The mixture was turbid with 200 ml of ether and the precipitation was completed by rubbing. The excellent product is filtered off and washed with ether. 8.1 g of the title compound are obtained in the form of a white powder with a yield of nearly 100%, m.p. 145-150 ° C (dec.).

test Compound 1 2 3 ED YOU ED +/- YOU THE 2176 55 40 7.9- 275 II. spreadsheet test Compound 7 8 Test 9 10 THE 1.3 21 39 26

Table I Test ed ₂ 4 5 6 ED TI ED TI ED TI ^E ° ⁴ 13 167 1.6 1360 26 84 4.2 Analysis: C 19 H 22 Cl 2 N 2 O 2 formula (381.30) 55 date; C, 59.85; H, 5.82; N, 7.35. Cl, 18.60; Cl, 9.30; found: C, 59.74; % H, 6.06; N, 7.17; Cl% = 18.54: 60 Cl, 9.21.

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Example 3

Preparation of 8- (Ethoxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline

To a solution of 5.5 g (0.023 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline in 50 ml of anhydrous benzene, 3.4 g (0.031 mol) of ethyl chloroformate in 30 ml of of anhydrous benzene. The reaction mixture was refluxed for 3 hours, the benzene was evaporated in vacuo, the residue was dissolved in water (5 mL), basified with 30% aqueous sodium hydroxide solution and extracted with chloroform (3 X 50 mL). The chloroform solution was dried over anhydrous sodium sulfate and evaporated. The residue is washed with a little cold ethanol and then recrystallized from ethanol. Yield: 3.0 g (37.5%) of the title compound as white crystals, m.p. 178 ° C.

Analysis: (346.86) calculated C _I9 H ₂₂ N ₂ O ₂ Calcd: C% = 73.84; H, 7.15; % N, 9.02; Found: C, 73.96; H, 7.51; N, 8.95.

Example 4

Preparation of 8- (Ethoxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline

N- (2-Aminobenzyl) -1-phenyl-2-methylamino-1-ethanol (2.6 g, 0.01 mol) was dissolved in ether (30 ml). Anhydrous pyridine (0.79 g, 0.01 mol) was added to the solution, followed by reaction with 1.3 g (0.012 mol) of ethyl chloroformate at 15 ° C under vigorous stirring. The reaction mixture containing the white precipitate was stirred at room temperature for 30 minutes, then poured into ice water (30 ml), the aqueous phase was extracted with ether (3 X 100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. 2.8 g of N- [2- (ethoxycarbonylamino) benzyl] -1-phenyl-2-methylamino-1-ethanol are obtained in the form of a yellow-white oil which is further purified without further purification.

The oily residue (2.8 g) obtained in the first paragraph was dissolved in dichloromethane (40 ml), and the solution was added dropwise to 15.4 ml of concentrated sulfuric acid under stirring and cooling at 5 ° C for 30 minutes. After stirring for a further 20 minutes at this temperature, the reaction mixture is poured onto 60 g of ice, made basic with cooling and stirring with 30% sodium hydroxide solution, extracted with chloroform (6 X 80 ml), dried over anhydrous sodium sulfate and concentrated. evaporate in vacuo. 2.3 g of the title compound are obtained as a yellow-white solid, which is recrystallized from ethanol. Yield: 2.0 g (64.5%), white crystals melting at 174 ° C.

Example 5

Preparation of 8- (butoxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinol

2.4 g of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.01 mol) in 100 ml of anhydrous benzene were treated with 1.4 g (0.012 mol) of chloroformic acid butyl ester. A solution of 10 ml of anhydrous benzene was added and the mixture was refluxed for 2 hours. After cooling, the precipitated solution was diluted with ice water (50 ml), basified to pH 9 with concentrated ammonium hydroxide solution, the benzene phase was separated, the aqueous phase was extracted with 2 x 20 ml benzene, and the benzene solution was dried over anhydrous sodium sulfate. evaporate in vacuo to give 3.6 g of an orange oil. After recrystallization twice from ethanol, 1.8 g (52.9%) of the title compound are obtained. White powder. Mp 106 ° C.

Analysis: Calculated for C ₂₁ H ₂₆ N ₂ O ₂ (M = 338.454): C, 75.43; H, 6.63; N, 8.37. Found: C, 75.19; H, 6.44; N, 8.57.

Example 6

Preparation of 4-dimethyl-8H-chloroethoxycarbonylamino) -2-methyl-1,2,3,4-tetrahydroisoquinoline

3.5 g of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.015 mol) are dissolved in 100 ml of anhydrous benzene and mixed with 1.28 g of anhydrous pyridine (0.016 mol) and 2.14 A solution of 0 g of chloroformic acid 0-chloroethyl ester (0.015 mol) in anhydrous benzene (10 ml) was added dropwise with stirring and cooling at room temperature. After stirring for 1 hour at room temperature, the reaction mixture is poured into 50 ml of ice water, the organic phase is separated off and the aqueous phase is extracted with additional 3 x 30 ml of benzene. The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 4.5 g of the title compound as a yellow-white solid. Recrystallized twice from ethanol

2.7 g (52%) of a white crystalline solid are obtained. 154 ° C.

Analysis calculated for C ₁₉ H ₂₁ ClN ₂ O ₂ (M = 344.845):

C, 66.18; H, 6.14; N, 8.12; Cl% = 10.28; found:

C, 66.29; H, 6.24; N, 8.10; Cl, 10.38.

Example 7

84Benzyloxycarbonylamino) -4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline and maleinate salt

4.6 g of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.02 mol) are dissolved in 100 ml of anhydrous benzene and added dropwise at 18 ° C with stirring. 90% Benzyloxycarbonyl chloride (5.2 mL, 0.03 mol) was added and the reaction stirred for 2 hours. The reaction mixture was quenched with 150 ml of ice water and made basic with ice-cooling with 30% sodium hydroxide solution (10 ml). The benzene layer was separated and the aqueous layer was extracted with further 2 x 150 mL benzene, dried over anhydrous sodium sulfate and evaporated. The residue was stirred with 150 ml of ether, cooled, the solid was filtered off and washed with cold ether. Yield: 4.7 g of the title compound as a yellowish-white compound. Mp 142-6 ° C. Recrystallization from ethanol gave 3.6 g (49%) of a white crystalline solid. Mp 147-8 ° C.

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Analysis: Calculated for C24H24N2O2 (? = 372.474): C, 77.39; H, 6.49; N, 7.50; Found: C, 77.50; H, 6.78; N, 7.70.

The above base (2.4 g, 0.0064 mol) was suspended in ether (70 ml) and treated with a solution of maleic acid (0.75 g, 0.0064 mol) in ethanol (5 ml), stirred for 10 minutes and then cooled to 0 ° C. The precipitated material is filtered off, washed with ethanol-ether 1: 9 and ether, and recrystallized from ethanol. 2.4 g (79%) of a white powder are obtained. Mp 166-7 ° C.

Analysis: Calculated for C ₂₈ H ₂₈ N ₂ O ₆ (M = 488.544): C, 68.84; H, 5.98; N, 5.73. Found: C, 68.76; H, 5.95; N, 5.82.

Example 8

Preparation of 8- (Ethoxycarbonylamino) -4- (p-fluorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

To a solution of 8.1 g (0.03 mol) of N- (2-aminobenzyl) -1- (p-fluorophenyl) -2-methylamino-1-ethanol in 90 ml of ether was added 2.37 g (0 Anhydrous pyridine (3.00 g, 2.4 ml) and ethyl chloroformate (3.96 g, 0.036 mol, 3.45 ml) were added with stirring and ice-cooling at 5 ° C. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water (300 ml) and extracted with ether (3 X 300 ml). The organic layer was washed with water (3 X 50 mL), dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting light brown oil (10.1 g, 96%) was dissolved in dichloromethane (120 mL) and added dropwise to concentrated sulfuric acid (48 mL) over 40 minutes with stirring and cooling at 5-8 ° C. The mixture was stirred at this temperature for a further 40 minutes, made basic with 200 ml of ice water, made basic with 30% sodium hydroxide solution, separated and the aqueous phase was extracted with 3 x 100 ml of ether, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish white solid (8.2 g) was recrystallized twice from ethanol. 6.5 g (71.4%) of the title compound are white crystals. M.p. 163 ° C.

Analysis: Calculated for C ₁₉ H ₁₂ FN ₂ O ₂ (M = 328.39): C, 69.49; H, 6.45; N, 8.53. Found: C, 69.64; H, 6.67; N, 8.64.

Example 9

Preparation of 4-Phenyl-8-phenoxycarbonyl-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline

To a solution of 2.4 g (0.01 mol) of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline in 120 ml of anhydrous benzene was added 2.05 g (0.013 mol) of chloroformic acid. A solution of phenyl ester in 15 ml of anhydrous benzene was added dropwise with stirring at room temperature. After stirring for 1 hour at 25 ° C, the reaction mixture was poured into 100 ml of ice water, basified with concentrated ammonium hydroxide, and the layers were separated. The aqueous phase was extracted with 4 x 80 ml benzene, the combined organic phases were washed with 3 x 30 ml water, dried over anhydrous sodium sulfate and evaporated. 2.9 g of a yellow-white solid are obtained, which is recrystallized from benzene followed by ethanol. 6

1.25 g (34.8%) of the title compound are obtained as white crystals. 121 ° C (b).

Analysis: Calculated for C 23 H 22 N 2 O 2 (M = 358.44): C, 77.07; H, 6.19; N, 7.82; Found: C, 76.74; H, 6.28; N, 7.88.

Claims (17)

Claims A process for preparing 8- (alkoxycarbonylamino) -4-aryl-2-methyltetrahydroisoquinoline derivatives of formula (I): R is lower alkyl and X is hydrogen or halogen) and their pharmaceutically acceptable acid addition salts, characterized in that a) cyclizing a compound of formula II (wherein R and X are as defined above); obsession b) reacting an amino compound of formula III (wherein X is as defined above) with a halogen formic acid ester of formula IV (wherein H 2 is halogen, preferably chlorine or bromine, and R is as defined above); and, if desired, converting the compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt. (Priority: June 4, 1982). Process for carrying out process a) according to claim 1, characterized in that the ring closure is carried out in the presence of a catalyst. (Priority: June 4, 1982). 3. The process according to claim 2, wherein the acid catalyst is a mineral acid or a Lewis acid. (Priority: June 4, 1982) The process of claim 3 wherein the acid catalyst is sulfuric acid. (Priority: June 4, 1982) Method a) according to claim 1 and steps 2-4. A process according to any one of claims 1 to 3, characterized in that the reaction is carried out in a halogenated hydrocarbon. (Priority: June 4, 1982) 6. A process according to claim 5, wherein the reaction is carried out at 0 to 80 ° C. (Priority: June 4, 1982) 7. The process according to claim 1, wherein the compound of formula IV wherein R is as defined above is used in place of diluted chlorine. (Priority: June 4, 1982) 8. A process according to claim 7, wherein the reaction is carried out in the presence of an acid scavenger. (Priority: June 4, 1982) 9. A process according to claim 8 wherein the acid acceptor is triethylamine or lanolin. (Priority: June 4, 1982) Process b) according to claim 1 and steps 7-9. A process according to any one of claims 1 to 4, wherein the reaction is carried out in an aromatic hydrocarbon -5190019, preferably benzene. (Priority: 06.04.1982) 11. A process according to claim 10, wherein the reaction is carried out under heating, preferably at the boiling point of the reaction mixture. (Priority: June 4, 1982) 12. A process according to claim 1, wherein 8- (ethoxycarbonylamino) -4- (p-chlorophenyl) -2-methyl-1,23,4-tetrahydroisoquinoline and hydrochloride, characterized in that: (a) starting material is a compound of formula (II) wherein R is ethyl and X is p-chloro; obsession b) reacting a compound of formula (III) wherein X is a p-position with a compound of formula (IV) wherein R is ethyl (wherein Kg is as defined in claim 1) and optionally the 8- (ethoxy) carbonylamino) 4- (p-chlorophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline is converted to its hydrochloride. (Priority: 06.04.1982) 13. A process for the preparation of a pharmaceutical composition comprising the administration of a compound of formula I (wherein R and X are as defined in claim 1) or a pharmaceutically acceptable acid addition salt thereof prepared according to claim 1 as an active ingredient, admixed with toxic, solid or liquid pharmaceutical carriers and converted to a pharmaceutical composition. (Priority: June 4, 1982) 14. A process for preparing 8- (alkoxycarbonylamino) 4-aryl-2-methyl-tetrahydroisoquinoline derivatives of the formula (I): R is lower alkyl or phenyl (lower) alkyl optionally substituted with halogen; and X is hydrogen or halogen) and their pharmaceutically acceptable acid addition salts, characterized in that a) cyclizing a compound of formula II (wherein R and X are as defined above); obsession b) reacting an amino compound of Formula III (wherein X is as defined above) with a halogen formic acid ester of Formula IV (wherein Kg is halogen, preferably chlorine or bromine, and R is as defined above); ) and, if desired, converting the compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt. (Change priority: May 31, 1983) 15. A process for the preparation of a pharmaceutical composition comprising the step of producing a compound of formula (I) as defined in claim 14. A salt of a pharmaceutically acceptable acid addition salt thereof (wherein R and X are as defined in claim 14), or a pharmaceutically acceptable acid addition salt thereof, with an inert, non-toxic solid or liquid pharmaceutical carrier and formulated into a pharmaceutical composition. (Priority of amendment: 31.05.1983) 16. A process for preparing 8- (phenoxycarbonylamino) -4-aryl-2-methyl-tetrahydroisoquinoline derivatives of the formula (I): R is phenyl and X is hydrogen or halogen) and their pharmaceutically acceptable acid addition salts, characterized in that a) cyclizing a compound of formula II (wherein R and X are as defined above); obsession b) reacting an amino compound of formula III (wherein X is as defined above) with a halogen formic acid ester of formula IV (wherein Kg is halogen, preferably chlorine or bromine, and R is as defined above); ) and optionally converting the compound of formula (I) thus obtained into a pharmaceutically acceptable acid addition salt. (Priority: 20/11/1984) 17. A process for the preparation of a pharmaceutical composition, characterized in that it is one of the following. A compound of formula (I) (wherein R and X are as defined in claim 16) or a pharmaceutically acceptable acid addition salt thereof prepared by the process of claim 1. The active ingredient is admixed with inert, non-toxic solid or liquid pharmaceutical carriers and formulated into a pharmaceutical composition. (Priority: 1984).