(5 SUBSTUTh1) PHEUTYLAMIN
(71) 1, ALEXANDER THEODOR
SHULGIN, a citizen of the United States of
America, of 1483 Shulgin Road, Lafayette,
State of California 94549, United States of
America, do hereby declare this invention, for which I pray that a patent may be granted to me, and the method by whid it is to be per- formed, to be particularly described in and by the following statement:~
The present invention relates to novel sub stituteel phenylbutylamines which are useful for enhancing the learning capacity of mam- mals, to a method of preparing the novel com- pounds and to a method of enhancing the learning capacity of mammals.The invention also relates to compositions useful in the method of enhancing the learning capacity of mammals.
Numerous compounds structurally related to amphetamine (methyiphenethylamine) have been prepared and reported in the literature and are the subject matter of various patents.
Of particular interest with respect to the compounds disclosed herein are U.S. Patent
No. 3,547,999: Chemistry and Structure
Activity Relationships of the Psychotomimetics which appeared in the book, Psychotomimetic
Drugs, Ed. D. H. Effron, Raven Press 1970 and Shulgin, A. T., Sargen, T. and Naranjo,
C.: and Structure-Activity Relationships of One-Ring Psychotomimetics, Natere, 221537 (1969). These prior an references disclose compounds closely related to the compounds of the present invention. However, none of the compounds is disclosed as having the activity of the compounds of the present invention.The Shulgin article in Psychoto- mimetic Drugs at pages 35-36 indicates that a "four-chain compound" had been synt thesized; however, the particular compound synthesized is not named, the structure is not disclosed, the method of preparation is not disclosed and no utility is disclosed in the article.
Accordingly the present invention provides a compound of the general formula
wherein R1 is a (lower)alkyl, cyclopropyl, or cyclopropylmethyl group and R2 and R each represent a (lower)alkyl group.
TheF present invention also provides a pharmaceutical composition useful for enhancing
the learning capacity of mammals which com
prises an effective amount of a compound selected from the group consisting of a racemic compound of the formula
wherein Rl is a (lower)alkyI, cyclopropyl or cyclopropyl-methyl group and R2 and R each represent a (lower)alkyl group, an optically active dextrorotatory or levorotatory isomer or a pharmaceutically acceptable nontoxic salt thereof and a pharmaceutically acceptable carrier.
In another aspect the present invention provides a method of enhancing the learning capacity of mammals which comprise admistering to said mammal an effective amount of a compound of formula I or the dextrorotarory or levorotatory isomer or pharmaceutically acceptable nontoxic salt thereof.
The compounds of formula I contain an asymmetric carbon atom and thus normally occur as a racemic mixture of the dextro- and levoratatory optical isomers. Both the dextroW and levoratatory isomers of these compounds' as well as the racemic mixtures may be used in the composition and method described above and are considered to be an integral part of the invention.
The present inventon includes within its scope the dexoro- and levorotatory isomers of the compounds of formula I; and the pharmaceutically acceptable nontoxic salts thereof.
The pharmaceutically acceptable nontoxic salts include the organic and inorganic acid addition salts, e.g. the hydrochloric, sulfuric, p-toluene sulfonic, methane sulfonic, tartaric, fumaric, hydrobromic, hydriodic, glycolic, citric, maleic, phosphoric, succinic and acetic acid salts. Such salts may be prepared by con ventional methods by reacting the free base with the desired acid on about an equivalent basis.
By the term "(lonver)alkyl" as used herein is meant both straight chain and branched chain alkyl groups containing from 1 to 4 carbon atoms, i.e. methyl, ethyl, propyl, iso propyl, butyl, sec-butyl, isobutyl and t-butyl.
The preferred embodiment of the present invention consists of the dexb and levo- rotatory isomers of the compound of the formula
and the pharmaceutically acceptable nontoxic salts thereof. The most preferred embodiment is the levorotatory isomer of formula II.
Another preferred embodiment is. the compound of formula I wherein R1 is ethyl and R2 and R3 are each methyl, or a pharmaceutically acceptable nontoxic salt thereof.
Still another preferred embodiment is the compound of formula I wherein R1 is methyl and R1 and Rs are each ethyl, or a pilarma- ceutically acceptable nontoxic salt thereof.
The compounds of formula I are prepared as exemplified below by reducing a 2-nitro-1- (2,5 - (lower)alkoxy - 4 - (lower)aIkyl- phenyl)-butene 1 of the formula
wherein R1, R2 and Ra are as described above, with, for example, lithium aluminum hydride in the presence of a ncnftactive solvent medium. Suitable solvents include diethyl ether, tetrahydrofuf, diethylene glycol, dimethyl ether and the like.The reaction pro- ceeds at temperatures from about 0 C. to 1500 C. Preferably the reaction is carried out at the boiling temperature of the reaction mixture and under reflux and about 2 moles of lithium aluminum hydride per mole of butene are used. The preferred solvent is ether.
The general procedures for the preparation of tbe compounds of this invention and the starting materials are described in U.S. Patent
No. 3,547,999.
The racemic compounds of formula I may be resolved by forming a mixture of the two diastereoisomeric salts of said compounds with a detttrorotatory ring-substituted tarunilic acid, e.g., nitro, chloro or bromo substituted, separating said diastereoisomeric salts by fractional crystallization and converting the separated diastereoisomeric salts to the respect tive optical isomers of the compound, prefer- ably by treatment with a strong base, e.g.
sodium carbonate, potassium carbonate and the like. (+) -2'-Nitrotartranilic acid and (+)2'-chlorotartranilic acid are particularly use ful in the resolution of the racemic compounds of Formula I. The general resolution procedure using tartranilic acids is described in U.S.
3,452,086 and by T. A. Montzka et al. J.
Org. Chem. 33, 3993 (1968).
The compounds of formula I in the form of racemic mixtures or their dextrorotatory or levorotatory isomers possess learning enhance ment activity making them useful for enhancing the learning capacity of mammals. The compounds while stmcturally related to amphetamine do not produce amphetamine like central nervous system stimulant activity in mammals
The learning enhancement activity of the compounds of this invention was determined by the shuttle box acute acquisition, pole climb acute acquisition and pole climb chronic avoidance acquisition tests.
Shuttle Box-Acute Acquisition
Male hooded rats (500--700 gm.) were used as experiental subjects. The compounds are administered either subcutaneously or orally 30 minutes prior to shuttle box test.
(shuttle box-manufactured by Lehigh Valley
Electronics Co.). Each trial is 60 seconds long consisting of a 5 second avoidance period, during which the animal is required to move to the other side of shuttle box to avoid shock, and a 5 second shock period, if the animal fails to move during the avoidance period. During these 10 seconds the cue light is lit on the other side of the test box but turned off if the animal moves to the other side of the box. The rat is given a maximum of 100 trials or until it acquires the ability to avoid 8 shocks out of 10 consecutive trials. Its score is the number of the trial which is the last trial prior to avoiding 8 shocks out of 10.
Pole aimbAcute Acquisition-
Male hooded rats (200--300 gms.) were used as experimental subjects. The compounds are administered subcutaneously 30 minutes prior to placement of the animal into the pole climb chamber (Cook, L, and Weidley, E.
(1957), Ann. N.Y. Sci., 66, p. 740). Each trial is 60 seconds long consisting of a 5 second avoidance period, during which a sound is sounded and the animal has to jump up onto the pole and a 5 second shock period if the animal fails to jump. During the avoidance and shock periods the tone and electric shock are turned off if the animal jumps onto the pole.
The animal is given a maximum of 100 trials or until it acquires the ability to avoid 8 shocks out of 10 consecutive trials. Its score is the number of the trial which is the last trial prior to attaining avoidance of 8 to 10 con; secutive trials.
Pole Clim--Chronic Avoidance Acquisition--
A similar procedure was used as in the pole climb-acute acquisition procedure described above but each animal was given 20 trials every day and the number of avoidances was determined. With each day there was an im provement in the performance; the number of avoidance responses increased.
When (+) - 2 --amino - 1- (2,5-dimeth- oxy - 4 - methylphenyl)butane hydrochloride and the dextrorotatory and levorotatory isomers were tested according to the foregoing procedures the following results were obtained.
TABLE 1
Acute Avoidance Acquisition by Breeder Rats in the Shuttle Box
No. Trials required to
Compound Dose (mg/kg) No. of Animals reach 80% Avoidance (+)-2-amino-1-(2,5- 1 sc 8 57 dimethoxy-4-methyl- 5 sc 10 58 phenyl)butane hydro- 10 sc 10 47 chloride 10 po 9 58 (-)-2-amino-1-(2,5- 1 Sc 9 65 dimethoxy-4-methyl- 5 sc 10 43 phenyl)butane hydro- 10 sc 9 39 chloride 10 po 7 66 (+)-2-amino-1-(2,5- 1 sc 6 67 dimethoxy-4-methyl- 10 sc 8 37 phenyl)butane hydrochloride
Saline 20 85
TABLE 2
Acute Avoidance Acquisition by Adult Rat in the Pole Climb
No.Trials required to
Compound Dose (mg/kg sc) No. of Animals reach 80% Avoidance (+)-2-amino-1-(2,5- 10 10 85 dimethoxy4-methyl- phenyl)butane hydrochloride (-)-2-amino-1-(2,5- 10 10 65 dimethoxy-4-methylphenyl)butane hydrochloride
Saline 10 100
TABLE 3
Chronic Avoidance Acquisition by Adult Rats in the Pole Climb
(12 Rats Used) No.Avoidances/240 Trials
(+)-2-amino-1-(2,5-di- (-)-2-amino-1-(2,5-di methoxy-4methyl-phenyl)- methoxy-4-methyl-phenyl)-
Treatment Day butane hydrochloride butane hydrochloride Saline
5 mg/kg sc 5 mg/kg sc
-1 17/240 18/240 20/240
1 56/240 63/240 51/240
2 76/240 85/240 63/240
3 91/240 108/240 77/240
4 103/240 101/240 94/240
The above test results disclose that the racemic mixture (+) - 2 - amino - 1 - (2,5dimethoxy - 4 - methylphenyl)butane hydro- chloride, and the dextrorotatory and levo rotatory isomers exhibit learning enhancing activity, the levorotatory isomer appeared to exhibit greater activity than the dextro rotatory isomer.No increase in locomotion activity was observed after administration of the racemic mixture or either of the isomers.
The compounds of formula I may be administer as the free bases or in the form of their nontoxic addition salts. They may be compounded and formulated into pharmaceutical preparations in unit dosage form for oral or parenteral administration with organic or irrorganic solid materials or liquids which are pharmaceutically acceptable carriers. Some examples of the carriers which can be used are gelatin capsules, sugars, cellulose derivatives such as carboxymethykellulose, gelatin; talc, magnesium stearate, vegetable oil such as peanut oil, etc., liquid petroleum, glycerin, sore bitol, ethanol, agar, elixirs, syrups and water including sterile water. The composition may take the form of tablets, powders, granules, capsules, suspensions, solutions and the like.
The compounds of formula I when administered orally or parenterally in an effective amount produce learning enhancement in mammals. An oral dosage range of about 0.1 to about 0.5 milligrams per kilogram of body weight is a convenient dosage for producing learning enhancement in mammals. However, in general, the particular dosage most suitable for a particular application, as might be expec ted, wi vary with the age, weight and general health of the mammal under treatment and the degree of learning enhancement required. After talking into consideration these factors and any other factors to be considered, one skilled in the art of treating diseases of mammals can readily determine the appropriate dosage.
The following examples afe intended to
Illustrate the invention described herein with nut unduly restricting it. Examples 1 to 3 relate to the preparation of intermediate derivatives.
Example 1.
Preparation of 2,5-Dimethoxytoluene
To a solution of 50 g. potassium hydroxide in methanol is added to 50 g. of toluhydroquinone. The resulting solution is heated on a steam bath, and an excess of methyl iodide (75 mL) is added through an effective reflux conderser. The addition is continued over several hours, and the resulting combination heated at reflux for several additional hours. At this time, the reaction mixture is brought to room tem erature, acidified with hydrochloric acid, and exhaustively extracted with methylene chloride.
The organic phase of the above extraction is washed with 5% sodium hydroxide solution (to remove all phenolic byproducts), then with water. The solvent remaining is concentrated by evaporation, yielding a residual neutral oil (36.9 g.). This upon distillation yielded 2,5dimethoxytoluene as a pale amber liquid (b.p.
105-1110C X 20 mm/Hg). The base washes yield, after acidification and extraction, 14.1 gv of a mixture of the two possible monomethylated derivatives which can be recycled in a subsequent repetition of the methylation step.
Example 2.
A solution of 40 ml. phosphorus oxychioride (POCl3) and 45 ml. of N-methylformanilide is allowed to stand at ambient temperature for 50 minutes. There is then added 15.2 g. of 2,5-dimethoxytoluene and the resulting solution is heated on the steam bath for 140 minutes. The extremely dark viscous reaction mixture is added to 2 liters of water, and allowed to stir for several hours to complete the hydro lysis of the reaction intermediates. The solid product is removed by filtration, and after washing with water and air-drying yields of 16.6 g. of reddish crumbly crystals. This solid product is extracted with 2 X 125 ml. of boiling hexane, which on cooling deposits 12.1 g.
of pale cream-coloured crystals. Recrystallization from boiling hexane, yields a brilliant white product, 2,5-dimethoxy4-methylbenz aldehyde.
Example 3.
Preparation of 2-Nitro-1-(2,5-Dimeioxy- 4-Methylphenyl)-Butene 1
A mixture of 31.6 g. of 2,5-dimethoxy-4- methylbenzaldehyde, 20.2 ml. of nitroprepane, 6 ml. cyclohexylamine, and 50 ml. benzene is kept at reflux in a Dean Stark apparatus for 24 hours. Cooling results in the spontaneous crystallization of an orange product, which on filtration and drying weighs 14.9 g.
Recrystallization from methanol yields the product 2 - nitro - (2,5 - dimethoxy - 4methylphenyl)-butene-1 as an orange crystalline material, mp. 115 C.
Example 4.
Preparation of (+)-2-Amino-1-(2,5-Di-
methoxy-4-Methylphenyl) Butane
A suspension of 16 g. lithium aluminum hydride in 750 ml. anhydrous ether is brought to reflux, and through a Soxhlet thimble, 19.2 g. of 2 - nitro - 1 - (2,5 - dimethoxy - 4methylphenyl)-butene-1 is added. The reflux
is maintained for 24 hours, then the reaction
mixture is cooled externally with ice, and 500
ml. of a 20% solution of sulfuric acid is added
cautiously. The two phase result is separated,
and the aqueous fraction washed with ether.
To this fraction is added 400 g. potassium
sodium tartrate and the pH adjusted with
aqueous sodium hydroxide until greater than
9. The product is extracted with methylene
chloride, which when removed leaves a clear,
colorless oil, (+) - 2 - amino - 1 - (2,5
dimethoxy - 4 - methylphenyl) butane. This
is dissolved in ether, and saturated with an
hydrous hydrogen chloride. The crystalline
hydrochloride of (+) - 2 - amino - 1 - (2,5
dimethoxy-4-methylphenyl) butane thus oh
obtained, after filtration and washing with addi
tional anhydrous ether, weighed 12.0 g.
Example 5.
When in the procedure of Example 4, 2nitro - 1 - (2,5 - dimethoxy - 4 - methyl phenyl)-butene-l is replaced by an equal molar amount of 2 - nitro - 1 - (2,5 - dimethoxy - 4 - ethyl
phenyl) -butene-1, 2- nitro - 1 - (2,5 - dimethoxy -4- propyl-
phenyl)-butene-l,
2 - nitro - 1 - (2,5 - dimethoxy - 4 - iso propyiphenyl) -butene- 1,
2 - nitro - 1 - (2,5 - dimethoxy - 4 - butyl
phenyl ) -butene- 1,
2 - nitro - 1 - (2,5 diethoxy - 4 - methyl phenyl)-butene-1,~~
2 - nitro - 1 - (2,5 - dipropoxy - 4 - methyl phenyl)-butene-l,
2 - nitro - 1 - (2,5 - diisopropoxy - 4 methyl phenyl)-butene-1,
2 - nitro - 1 -(2,5 - dibutoxy - 4 - methyl phenyl)-butene-l,
2 - nitro - 1 - (2 - methoxy - 5 - ethoxy - 4 methylphenyl)-butene-l,
2- nitro - 1- (2- ethoxy -5- methoxy -4-
methylphenyl ) -butene- 1, 2 - nitro - 1 - (2,5 diethoxy - 4 - ethyl
phenyl)-butene-1, and 2 - nitro - 1 - (2,5 - diethoxy - 4 - propyl
phenyl ) -butene- 1, 2 - nitro - 1 - (2,5 - dimethoxy - 4 - cycl
propylmethylphenyl)-butene-1, and 2 - nitro - 1 - (2,5 - dimethoxy - 4 - cyclo- propylphenyl) -butene- 1 there are obtained
() - 2 - amino - 1 - (2,5 - dimethoxy - 4
ethylphenyl) -butane, (#) - 2 - amino - 1 - (2,5 - dimethoxy - 4-
propylphenyl)-butane, () - 2 - amino - 1 - (2,5 - dimethoxy - 4
isopropylphenyl)-butane, (#) - 2 - amino - 1 - (2,5 - dimethoxy - 4 butylphenyl) -butane,
(#) - 2 - amino - 1 - (2,5 - diethoxy - 4
methylphenyl ) -butane, () -2- amino - 1 - (2,5 - dipropoxy methylphenyl) -butane, (#) - 2 - amino - 1 - (2,5 - diisopropoxy-
4-methylphenyl) -butane, () -2- amino - 1 - (2,5 - dibutoxy
methylphenyl) -butane, (+) - 2 - amino - 1 - (2 - methoxy - 5-
ethoxy-4-methylphenyl ) -butane,
(+) - 2 - amino - 1 - (2 - ethoxy - 5
methoxy-4-methylphenyl ) -butane, (#) - 2 - amino - 1 - (2,5 - diethoxy -4-
ethylphenyl ) -butane,
(#) - 2 - amino- 1 - (2,5 - diethoxy - 4
propylphenyl) -butane
(#) - 2 - amino - 1 - (2,5 - dimethoxy - 4 - cyclopropylmethylphenyl) -butane,
(#) - 2 - amino - 1 - (2,5 - dimethoxy - 4
cyclopropylphenyl)-butane respectively.
Resolution of 2 - Amino-1-(2,5-dimethoxy-4-
methylphenyl)butane.
Example 6.
A. (+) - 2 - Amino - 1 - (2,5-dimethoxy-
4methylphenyl ) butane hydrochloride.
(i) - 2 - Amino - 1 - (2,5 - dimethoxy- 4-methylphenyl)butane (17.9 g., 80.2 mmoles) and 10.82 g. (40.1 mmoles) of (#)-2'-nitro- tartranilic acid were dissolved in 85 ml. of hot 95% ethanol. The solution was cooled, seeded with salt previously obtained on a test tube scale, and allowed to stand undisturbed at room temperature (20-25 C.) until crystallization was complete (at least 18 hours). The solid was filtered, sucked as free of mother Iiquor as possible, and washed with 10 ml. of cold (-150C.) 95% ethanol in two portions. The mother liquor and washings were reserved for recovery of the (-)-isomer. The product was air-dried to give 12.32 g. (62.5%) of fluffy, yellowish crystals.Two recystalliza- tions in a like manner from 10 ml./g. of 95% ethanol gave 8.64 g. of the pure (+)-2'-nito- tarranilic acid salt of (+)-2-amiro1-(2,5- dimethoxy -4- methylphenyl)butane, mp.
155.5-157 C.
Anal. Calcd. for C23H81N3O9:
C, 55.97; H, 6.33; N, 8.52.
Found:
C, 55.63; H, 6.19; N, 8.43.
This salt was dissolved in 100 ml. of hot ethanol. The solution was cooled and poured into excess dilute potassium carbonate solu tion. The mixture was extracted with two portions of ether; the combined ether extracts were washed with dilute potassium carbonate solution, dilute sodium bicarbonate solution, and three portions of water. Drying and evaporation of the solvent gave 3.8 g. of pure (+)-2 amino - 1 - (2,5 - dimethoxy - 4 - merhyl- phenyl)butane as a light yellow oil which crystallized upon standing, [α]36626+155.3 (c 1.273, 95% ethanol). The salt was formed with HCI gas in anhydrous ether. The solid was filtered, washed with ether and air-dried to give 4.34 g. of slightly yellowish powder.Recrystallization from 105 ml. of 2-propanol provided 3.70 g. of pure (+)-2-amino-1-(2,5- dimethoxy - 4 - methylphenyl)butane hydro chloride as colorless, fluffy needles, mp. 245 2460C., [α]36523+49.8 (c 1.000, 95%
EtOH). The overall yield was 35% of available (+ )-isomer.
- Anal. Calcd. for C13H21NO2HCl:
C, 60.10; H, 8.54; N, 5.39;
Cl, 13.65.
Found:
C, 59.79; H, 8.57; N, 5.18;
Cl, 13.57.
B. (-) - 2 - Amino - 1 - (2,5 - dimethoxy
4-methylphenyl )butane hydrochloride.
The mother liquor from isolation of the (+)-isomer was evaporated and the residue was converted to the free base as described above. The oil thus obtained and 9.37 g. (36.1 mmoles, 0.9 molar equiv.) of (+)-2'-chloro- tartranilic acid were dissolved in 85 ml. of hot 95% ethanoL The solution was cooled, seeded with salt previously obtained on a test tube scale, and allowed to stand undisturbed at room temperature until crystallization was complete (at least 18 hours). The solid was flIteted, washed with 10 ml. of cold (15 ) 95% ethanol, and air-dried; 13.22 g. of light yellowish, fluffy crystals was obtained (76%).
Two recrystallizations in a like manner from 10 ml./g. of 95% ethanol gave 7.99 g. (60% recovery) of pure, colorless (+ )-2'-chlor tartranilic acid salt of (- )-2-amin1-(2,5-di- methoxymethy1phenyl)butane2 mp. 182.5- 184 C.
Anal. Calcd. for C23H31ClN2O7
C, 57.19; H, 6.47; N, 5.80;
Cl, 7.34.
Found:
C, 56.91; H, 6.56; N, 5.90;
Cl, 7.16.
This salt was converted to the free base as described for the ( + )-isomer. Pure (-)-2- amino - 1 - (2,5 - dimethoxy - 4 - methylphenyl)butane (3.6 g.) was recovered as an almost colorless oil which crystallized upon standing, [α]36523.5-156,3 (c 1.274, 95% ethanol). The salt was formed with anhydrous
HCl and the colorless powder (4.18 g.) thus obtained was recrystallized from 110 ml. of 2
propanol to give 3.64 g of pure (- )-2-amino-
1 - (2,5 - dimethoxy - 4 - methylphenyl)butane hydrochloride as colorless, fluffy needles, mp. 245--2460C, [rr]s,,z"--49.90 (c 1.000, 95% ethanol). The overall yield was 35% of available (- )-isomer.
Anal. Calcd. for C1,H21NO2.HCl:
C, 60.10; H. 8.54; N, 5.39;
C1, 13.65.
Found:
C, 59.93; H, 8.70; N, 5.44;
Cl, 13.73.
Example 7.
When ini the procedure of Example 6 ( + )- 2 - amino - 1 - (2,5 - dimethoxy - 4 - methylphenyl)butane is replaced by an equal molar amount of each of the racemic compounds produced in Example 5 there are obtained the ine dividual dextrorotatory and levorotatory iso mers of each compound.
Example S.
Tablets are prepared from the following formulations.
Formulation A
Per tablet, mg.
2 - amino - 1 - (2,5 - di
methoxy - 4 - methyl
phenyl)butane hydro
chloride 10 Comstarch 100
Methylcellulose 400 175
Magnesium stearate 3
Total 288
Each tablet contains 10 mg. of active ingredient
Formulation B
Per tablet, mg.
2 - amino - 1 - (2,5 - di
methoxy - 4 - methyl
phenyl )butane hydro
chloride 10 Monocaldum phosphate 70
Dicalcium phosphate 70
Lactase 70
Magnesium stearate 3
Total 223
A mixture of monocalcium phosphate, dicalcium phosphate and lactose is prepared to which is added magnesium stearate and 2amino - 1 - (2,5 - dimethoxy - 4 - methylphenyl)-butane hydrochloride and then tabletted by conventional means. Each tablet contains 10 mg. of active ingredient
WHAT I CLAIM IS:1. A compound of the general formula
wherein Rl is a (lower)aLkyl, cyclopropyl, or cyclopropylmethyl group and R2 and R3 each represent a (lower)alkyl group.
2. The dextrorotatory or levoratatory isomer of the compound claimed in claim 1.
3. A compound as claimed in claim 1 or claim 2 wherein Rt, R2 and R3 are each a methyl group.
4. A compound as claimed in claim 1 or claim 2 wherein Rl is an ethyl group and R2 and R3 are each a methyl group.
5. A compound as claimed in claimed1 or claim 2 wherein Rl is a methyl group and R2 and R3 are each an ethyl group.
6. The levorotatory isomer of a compound as claimed in any one of claims 3 to 5.
7. The dextrorotatory isomer of a compound as claimed in daim 3.
8. A pharmaceutically acceptable nontoxic salt of a compound as claimed in any one of the preceding claims.
9. The hydrochloride salt of a compound as claimed in any one of claims 3 to 7.
10. A process for the preparation of a compound of the general formula
wherein Rl, R2 and R" are as defined in claim 1 and the dextrorotatory and levorotatory iso tuners and pharmaceutically acceptable nontoxic salts thereof; which process comprises reducing a compound of the formula
wherein R', R2 and R3 are as defined above at a temperature of from about OOC. to 1SO"C.
and, if desired, further performing either or both of the operations of (a) resolving the so- produced racemic product of formula I into its optical isomers by the steps of forming a mixture of the two diastereoisomeric salts of said
**WARNING** end of DESC field may overlap start of CLMS **.
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