CS204004B2 - Process for preparing condensed derivatives of pyrimidine - Google Patents

Abstract

The compounds of the general formula I in which R denotes hydrogen or C1- to C6-alkyl, R<1> denotes C1- to C6-alkyl, R<2> and R<3> independently of one another denote hydrogen or C1- to C6- alkyl, m represents 0 and n represents 1, have analgesic, anti-inflammatory PG-antagonistic and antidepressant actions. These compounds are prepared by reducing a fused pyrimidine derivative of the general formula II. <IMAGE>

Description

The present invention relates to a process for the preparation of novel fused pyrimidine derivatives of the general formula I,

where it means

R is C 1 -C 6 alkyl,

R ¹ is alkyl having 1 to 6 carbon atoms and

R ² represents: hydrogen or .alkylovou group having 1 to 6 carbon atoms, and their optically active isomers and physiologically acceptable Isola.

The compounds produced by the process of the invention exhibit valuable pharmacological effects, for example analgesic, anti-inflammatory, PG-antagonistic and antidepressive. In addition, some of these compounds have other beneficial effects on the nervous system and antilipemic effects.

The compounds of the formula I are prepared according to the invention by the condensation of the pyrimidine derivatives of the formula II,

where

R @ ¹ , R @ ¹ and R @ ² are as defined above, either in the form of optically active compounds or in the form of the racemate or the salts of the compounds of the formula II reduce catalytic hydrogenation or complex metal hydride.

Thus, this reduction can be carried out either as catalytic hydrogenation or using a complex metal hydride.

In the catalytic hydrogenation, the reduction is carried out either at atmospheric pressure or at an overpressure in the range of 0.098 to 1.471 MPa. Possible catalysts are palladium, preferably supported on activated carbon as a carrier, or Raney nickel.

The metal complexes which can be used are sodium borohydride, sodium bis (2-methoxyeithoxy jaluminium hydride, potassium borohydride, lithium analimino hydride). aromatic hydrocarbons such as benzene, toluene, or ether, preferably diethyl ether, tetrahydrofuran or dioxane.

In catalytic hydrogenation, the reaction medium is evaporated after filtering off the catalyst. If the reduction is carried out with complex metal hydrides, the treatment depends on the solvent. After the excess reducing agent has been decomposed, the solvent is evaporated using organic solvents. When working in an aqueous medium, the reaction mixture is shaken, preferably with chloroform or benzene, and the compound of formula I is obtained by evaporating the organic phase. The starting materials used are the condensated pyrimidine derivatives of the formula II or their salts, preferably the chlorides, bromides, imethyl sulfates, etc. The reaction temperature is in the range of 0 to 150 ° C.

The preparation of the fused pyrimidine derivatives of the formula I can also be started from optically active fused pyrimidine derivatives of the formula II.

The fused pyrimidine derivatives of the general formula I have valuable pharmacological effects and can therefore be used in the pharmaceutical industry. Individual representatives of this class of compounds exhibit analgesic, anti-inflammatory, PG-antagonistic and antidepressant activity, while others of the compounds of the invention exhibit further beneficial effects on the nervous system and have antilipemic activity.

The pharmacological activity of these compounds is shown in the typical representative of this group of compounds, namely l, 6 _{ax-dimethyl-4-oxo-6,7,8,9,9a-hexahydro AX-4H-pyrido} [l, 2-a Pyrimidine-3-carboxamide. (Ch-127) Table 1 shows the results of toxicity tests.

Table 1

Toxicological data on the l, 6 _{ax-dimethyl-4-oxo-6,7,8,9,9a-hexahydro-4H ax-ругШо1} [1,2-а] руг1пй41п-3-кагЬохатк1и (CH-127 )

Experimental animals Route of administration LD50 (mg / kg) oral 370 rats · intravenous210 subcutaneous280 mice oral360

The toxicity values obtained by intravenous administration are compared in Table 2 with the toxicities of the known analgesic PROBON, and given the different molecular weights of both compounds, the molar values of intravenous toxicity are also shown in the table. The table shows that CH-127 is approximately 1.5 X less toxic than PROBON when administered intravenously.

Table 2

Toxicological data related to PROBON and compound CH-127 in intravenous application

Compound LD 50 (mg / kg) PROBON 220 CH — 127 210

Molecular weight Molar toxicity mM / kg

362.41 ~ ~ 60

223.27 0.94

Table 3 shows the analgesic effect of CH-127 and PROBON obtained in the hot plate test [J. Pharm. Exp. Ther. 80, sitr. 130 (1944); Kiserletes Orvostudomány 2, p. 295 (1950)], and in Table 4, the data obtained from a test in which test compounds induce convulsions of experimental animals [Fed. Why. 15, p. 494, (1956); J. Pharm. Exp. Ther. 133, p. 400 (1961)].

WITH

T a h at 1 k and 3

Comparison of the analgesic effect of PROBON, and compound CH-127 in tesil with hot plate in mice

Compound Route of Administration EDs'o (mg / kg) mol molar ED 50 (mM / kg)

PROBON initravenosní 52 0.14 subcutaneous 66 0.18 CH — 127 intravenous 13 0,058 subcutaneous 25 0.11

Table 4

Comparison of the analgesic effect of PROBON and compound CH-127 in a test in which mouse convulsions induce mouse convulsions

Compound

Method of application

ED 50 (mg / kg)

Molar ED50 Therapeutic in ^ d ^ ex (mM / kg) (LD50 / ED50)

PROBON oral 380 intravenous  140 subcutaneous 215 CH — 127 oral 58 intravenous 34 subcutaneous 43

Table 5

Comparison of the anti-inflammatory effect of CH-127 with that of phenylbutazone in various edema tests in the paw of rat application: oral) carrageenan edema CH-127: ED 30 = = 15 mg / kg [Proc. Soc. Exp. Biol.phenylbutazone: ED30 = 111, stt. 544 (1962)] - 60 mg / kg kaolin edema CH-127 (EDo) = = 33 mg / kg

1.05 2.9 0.38 - 0.59 - 0.26 6.2 0.15 0.19 - [Sheet. Int. phenylbuitazone: - ED 50 = Pharmacodyn. 132, page 16 (1961)] - 95 mg / .kg dextran edema CH-127: ED3O = • 51 mg / kg [Sheet. Int. phenylbuitazone: ED30 = Pharmacodyn, 102, p. 33 - (19555)] = 220 mg / kg

The inhibitory effect of CH-127 does not change in adrenalectomized rats (see Table 2), ie the anti-inflammatory effect is independent of endogenous steroids.

Table 6

Anti-inflammatory effect of CH-127 compounds on normal and adr-enalectomized rats (carrageenin edema, oral administration) dose (mg / kg) inhibition of edema (%) on normal in adrenalectomized rats

Table 7

Synergistic effect of CH-127 when co-administered with other anti-inflammatory agents

Compound Dose (mg / kg) Inhibition of edema (%) (carrageenan edema, oral administration) CH — 127 CH — 127 Indomethacin Suprofen Suprofen-CH — 127 Indomethacin + CH-127 Indomethacin-i-CH-127 6.25 18 25 30,4 2,5 24 1.25 26,4 1.25 + 25 65.7 2.5 6.25 41 2.5 ψ 25 83

As shown in the test results, compound CH-127, administered orally, is more effective than the analgesic PROBON; even the therapeutic index is more favorable.

Also the analgesic and anti-inflammatory effect of the other compounds of formula I is comparatively good.

The fused pyrimidine derivatives of formula I are useful in combination with other analgesic, anti-inflammatory or other active compounds. For example, these compounds have a synergistic effect with morphine, 14-hydroxyazidomorphine, Fentanyl, Indomathacin, Azidomorphine, Azidocodeine. This property of the compounds according to the invention is of importance, for example, for anesthesia in surgery.

The compounds of formula (I) may be used as active ingredients in medicaments, the compositions further comprising conventional non-toxic, inert, solid or liquid fillers and carriers.

The pharmaceutical compositions may take the form of solid or liquid substances, for example tablets, capsules, dragees, etc., optionally solutions, suspensions, emulsions, etc. Suitable carriers for this purpose are, for example, talc, calcium carbonate, magnesium stearate, water, polyethylene glycol, etc.

Said compositions - may optionally contain customary auxiliaries and additives, for example emulsifying agents, - dispersing agents, etc.

The invention is illustrated by the following examples without being limited thereto.

Example 1

23,5,5,6-Dimethyl-3 (N-methylcarbamoyl) -14-dioxoil, 6,7,8-tetrahydro-4 H -pyrrolo [1,2-a] pyrimidine is hydrogenated in 300 ml of ethanol in the presence of 15 g of activated carbon containing 10% - palladium at atmospheric pressure and room temperature. After uptake of 1 mole of hydrogen, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue - with 2X - recrystallized from ethanol. Yield l, 6 _{(l ^} -dlmethyli3- (N-methylcarbamoyl-I4 oxoil, 6,7,8,9,9aaxihexahydroi4H-pyridoi [1, 2-a] pyrimidine 0 melting at. 203 DEG -204 DEG C.

in the presence of 4.5 g of activated carbon containing 10% palladium. After uptake of 1 mole of hydrogen, the catalyst was filtered off and the filtrate was evaporated. reduced pressure. The residue was recrystallized three times from ethanol. Thus obtained -with - 2.6 gl 6e idimethyl _FL-4-oxOil, 6,7,8,9,9aaχ-hexahydro-4H-pyrido [1,2-a] ρyrimldiri3 xamidu-carboxylate of melting -teplotě range 205 to -206 ° C.

Analysis calculated:

% C, 59.18;% H, 7.67;% N, 18.82.

% H, 7.68;% H, 18.85;

Example -3

The procedure is as described in Example 2, but using (-) 1, 1,6 _and 4-dlmethyl-4-oxoil, 6,7,8-tetrahydro-4 H -pyrido 1,2-a starting material. ] pyrrol imidir ikarboxamidu ^ ([a] ₀ 2 ° - -70 °, C = 2, methanol). In - 40% yield is obtained (-) -1,6θ ₍₎ -4-θ ^ 1-4ioxOil, 6,7,8,9,9a-xihexahydroi4H _and pyridci ^[1,2 -я pyrim'idin ^j-3 - ^to arboxam'i ^d (Jalo ²⁰ - - -227 °, c - 1, ethanol), melting range 221-222 ° C.

Analysis calculated:

59,18% C, 7,67-% Н, - 113,82% N n strength from:

59.31% C, 7.71% H, 18.80% N

Example 4

The procedure was as described in Example 2, but the starting material used was 1'-1, 6a-dimime-4-oxx-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] acid amide. pyrimidine-3-carboxylic acid ([α] D ²⁰ = + 70 °, - c = 2, - in methanol). In 41% yield, (+) -1,6'-idimethyl-4-oxo-1,6,7-hexahydro-4H-pyrido [1,2-a] pyrimidin-3-carboxamide () was obtained. [.alpha.] D @ 20 = + 228 DEG (c = -1 in ethanol). The product melts at 220-222 ° C.

Analysis calculated:

% H, 7.67;% N, 18.82

ПЯ lp * 7PH o * ^: 59.19 «/ o C, 7.80« / o H, 18.75% N

Analysis calculated-:

60.74 ° C, 8.07% H, 17.71% N found:

% C, 60.03;% H, 8.03;% N, 17.83

Example 2

6.6 g of 1,6-dimethylethylloxo-1,6,7,3-tetrahydro-1H-pyrido [1,2-b] pyrimidine-3-carboxamide is hydrogenated in ~ 300 ml of methanol at atmospheric pressure and temperature.

Example 5

14.5 g of (+) 1, 6axidimethyl-410X0,6,6,7,3-ietrahydrof4H-pyridyl [1,2-aa-pyrimidine-3-carboxamide - ([α] D ² ° - this salt: + 37.5 °) (c - 2 in methanol) is dissolved in 150 ml of water and the solution is cooled to a temperature below 20 ° C. To this solution was added dropwise 1.82 g of sodium borohydride in 13 ml of water, followed by stirring at room temperature for 2 hours. The pH of the solution is adjusted to 7 and the solution is shaken twice with 50 ml of chloroform each. The organic phases were combined and evaporated under reduced pressure. The evaporation residue is recrystallized from ethanol. 7.8 g of (+) -l, 6-dimethyl-4 _ax-DXO-l 6,7,8,9,9aa _X hexahydro-4H-pyrido [1,2-a] Pyrimidin-3- carboxaimide '([α] _ο ³⁰ = + 268 °, c = 1 in ethanol). The product melts at a temperature in the range of · 209 to 210 ° C.

Analysis calculated:

59.18% -C, 7.67% Η, 18.82% N found ·:

% H, 7.65;% N, 18.84. Example 6

The procedure was as described in Example 5, but using (-) -1,6,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidin-O-carboxamide [[a] ² 0 = -37.5 °, c = 2, methanol). In 79% yield, (-) - 1,6ax-dimethyl-4-oxo-1,6,7,8,9,9a and _X -hexahydro-4H-pyrido {1,2-a] pyrimidine-3- are obtained. carboxamide, m.p. 209-210 ° C.

[α _D 30 = -261 ° (c - 1 in ethanol)

Analysis calculated:

% H, 7.67;% H, 18.82;% N found:

% H, 7.71;% N, 18.78

Example 7

9.0 g of 1,6-dimethyl-4'-oxo-O-N-methylcarbamoyl) -1,6,7,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine monomethyl sulfate was dissolved in 100 ml of water. The solution is cooled to below 10 ° C and 1.8 g of sodium borohydride are added in portions over 15 minutes. After stirring for 2 hours, the pH of the solution was adjusted to between 3 and 4 by addition of hydrochloric acid. The solution was then extracted with chloroform. The organic phase is dried over sodium sulphate, filtered off and evaporated under reduced pressure. 5.5 g, 6α-dimethyl-4-oxo-3- (N-methylcarbonyl-4-yl) -1,6,7,8,9,9a-hexahydro-4H-pyridoph 1,2-a are obtained. pyrimidine. After recrystallization from ethanol, the product melts at 177-179 ° C.

Analysis calculated:

% C, 60.74;% H, 8.07;% N, 17.71.

% H, 8.11;% N, 17.72

Example 8

Solution for injection

· Do calibrated glass flask 40,000 ml with an accuracy of ± 1 g · Weigh 2,000 gl _6A -diш · ethyl-4-oxo-lla, 6,7,8,9,9aa _X -hexal hy dr o-4H- pyrldo [1,2-a] pyrimidine-3-carboxamide of drug grade. The flask is then filled up to the mark with distilled water of a purity suitable for injection, thereby adding. active substance · fully dissolves. The solution is filtered in a known manner and then filled in 2 ml portions of ampoules which are then sterilized for 30 minutes at 120 ° C. Celsius.

Example 9

Combined solution for injection

Weigh, to the nearest + 1 g, 500 g of 16a _X- dimethylethyl-4-o-o-1,6,6,7,8,9,9a-hexahydro-4H-pyridoi into a 10 000 ml graduated glass flask [ 1,2-a) pyrimidine-3-carboxamide of drug purity. Weigh to the next flask 1 g of azidomorphine and 100 ml of a 2% sodium hydrogen carbonate solution. Make up to the first flask with approximately 9 liters of distilled water, of purity for injection, and add 8 g of sodium pyrosulphite as soon as the weighed substance has dissolved. After dissolving the compound, the azidomorphine solution is added. Then, with stirring, make up to the mark. The resulting solution was filled with ampoules of 1 ml each and sterilized at 100 ° C for 90 minutes.

Example 10

Cípky

500 gl 6a _{X-dimethyl-4-oxo-6,7,8,9,9ιaaχ} Hexal-y ^ (^^ ^o-41 ^^ - p ^ i'ido [1,2- jpyrímidin The 3-carboxamide is ground to a particle size below 10 μπι · and weighed into a vessel equipped with a heating apparatus and stirrer, then 25 g of colloidal silicic acid and 25 kg of suppository in the molten state are added. heated to a temperature of 45 [deg.] C., is processed in a manner known per se in a molding machine to a suppository of 2.5 g.

Example 11

Dragee

1000 gl, 6 _ax- dimethyl-4-oxo-1,6,7,8,9,9a _ax -hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide of drug grade is homogenized 300 g of crystalline cellulose and 150 g of potato starch; with the addition of a solution of 10 g of gelatin, the homogeneous mass is then granulated in 300 ml of water. After drying, the granulate is re-granulated, homogenized by adding a mixture of 40 g of talc and 5 g of stearic acid, and the resulting mass is then compressed into 200 mg tablets having both convex faces. The tablets thus obtained are then coated in a conventional manner to form a dragee.

Example 12

Anti-inflammatory ointment for skin treatment

1200 g of cetyl alcohol and 400 g of sorboxethenstearate are dissolved in 400 g of liquid paraffin at 45 ° C. Then 2000 g of white petrolatum are added and the molten liquid mass is optionally filtered. 500 g of 1,6α-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide are then dissolved at 65 ° C. ° C in 5400 g of distilled water, and a solution of 3 g propyl p-oxybenzoate and 7 g methyl p-oxybenzoate in 90 g ethanol was added. The resulting solution is immediately mixed in a suitable homogenizer with the above mass to form a homogeneous ointment. After cooling, the ointment is filled in a manner known per se into tubes or cups.

Example 1 a d 13

Combined anti-inflammatory ointment for skin treatment

200 g of cholestherin, -300 g of cetyl alcohol, 275 g of white beeswax and 525 g of lanolin are treated at 55 ° C with 6500 g of white Vaseline to form a homogeneous melt; the melt is optionally filtered. Then is dried at 55 ° C, homogenized -500 gl _x 6-dimethyl-4-oxo-6,7,8,9,9a-octahydro _AX hex-4-pyridoj - 1,2a -] pyrimidine-3-carboxamide, ground to a 100 mesh particle size, and 20 g of colloidal Pyrimycin in 2200 g of distilled water, and the mixture is then added to the above mass. The resulting mixture is then processed to a homogeneous ointment in a suitable homogenizer. The cooled ointment is then, in a manner known per se, filled with tubes or crucibles, or applied to a bandage mulch and sintered under sterile conditions.

Example 14

Eye drops

In 10 liters of water was dissolved 11 g of borax, 22 g of-Sodium-chloride, 115 g of boric acid and 1 g pyrcsiřičitanu and to this solution was added to 100 gl, 6 _ax -dimethyil-4-o xo-1,6,7 , 8,9,9a-hexahydr-o-4H-pyrido [1,2-a] pyrimidine-3-carboxamide. The solution is made up to 10,000 ml with distilled water and then filled into a 5 ml eye drop vial under sterile conditions in an appropriate apparatus.

Example 15

Combined eye drops

To a solution of 11 g of borax, 21.2 g of sodium chloride, 114 g of boric acid and 1 g of pyrosulphite in approximately 10 1 of water is added 200 mg of Primycin and the resulting solution is heated to boiling. Then dissolved in 100 gl něm- 6 _ax -diinethyl-4-oxo-6,7,8,9,9a-hexahydro _AX-4H-pyrido [1,2-a] pyrimidine-3-carboxamide and the volume is then adjusted to 10,000 million with distilled water. The solution is then filled into a 5 ml eye drop bottle in a suitable filler under sterile conditions.

Example 16

Combined powder backfill

A mixture of 35 g of the hydrochloride chloride oxy-tetracycline, 65 gl _ax dimethylethyl 6 - 4-oxo-6, l, _x 8,9,9ιaa hexahydro-4H-pyrido [1,2-a] pyrimidine 3-carboxamide, 250 g of urea and 9650 g of anhydrous lactose were homogenized in a finely powdered form. The particle size of the powder mixture is then adjusted by passing the mixture through a 100 mesh screen and filling the backfill.

Example 17 gl, 7-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide - is dissolved in 120 ml of water and the resulting solution - is cooled to a temperature below 20 ° C. A solution of 2.5 g of sodium borohydride in 20 ml of water was added dropwise to the solution, followed by stirring at room temperature for 2 hours. The pH of the solution is then adjusted to 7 and the solution is shaken three times with 50 ml of chloroform each. The organic phases are combined and evaporated under reduced pressure. The evaporation residue is recrystallized from ethanol to give 6-gl, 7e _q -dimethy-4-ox (-11, ¢ 7,1,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide, m.p. 242-244 DEG C. Yield: 89%.

Analysis:

calculated:

% H, 7.67;% N, 18.82.

% C, 58.95;% H, 7.60%;

EXAMPLE 18 g of 18-dimethyl-4-oxo-1,6,7,8-teibrahydro-4H-pyrid-o [1,2-a] pyrimidinicarboxamide is dissolved in 240 ml of water and the resulting solution is cooled. temperature below 20 ° C. Then, 5 g of sodium borohydride in 40 ml of water was added dropwise to the solution, after which many of the lepioin mixtures were added. The pH of the solution is then adjusted to 7 and the solution is shaken three times with 75 ml of chloroform. The O'ganic phases are combined and evaporated under reduced pressure. -Odpaření O- residue was recrystallized from methanol to give 12 g ^of l.8 _eq idimethy i4i o ^ ^ o}) -] ^, ^^ 6.78, 9aihexai hydro ^ H-pyridoj 1,2i] pyrimidine -3i.carboi xamide having a melting point of 215-217 ° C; Celsius. The resulting 12 g of product corresponds to a yield of 89% of theory.

Analysis calculated:

% H, 7.67;% N, 18.82.

% C, 59.26;% H, 7.76;% N, 19.03

EXAMPLE 19 g of 1S-Dinethylethyl-4-oxo-.alpha.-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide was hydrogenated in 300 ml of ethanol under atmospheric pressure and at room temperature in the presence of 4.5 g of activated carbon. 10% palladium. Once the hydrogen uptake ceased, the catalyst was filtered off and the filtrate was evaporated under reduced pressure to give 3.1 g, 8 _{° C (J-} ethyl-4-oxoil, 6,7,8,9,9a-hexahydro). -4H-pyrido [1,2-a] pyrimidine-3-carboxamide, corresponding to a yield of 90% of theory The melting point of the product obtained after recrystallization from methanol is in the range of 215 to 316 [deg.] C. breaks down the compound - to lower the melting point.

Example 20

5.94 g of Nif-enyl-1,6-dimethylmethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-carboxamide is hydrogenated under atmospheric pressure and at room temperature in 300 ml of ethanol in the presence of 1 g of activated charcoal containing 10% palladium. Once hydrogen uptake ceases, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. 5.9 g of an oily liquid are obtained which crystallizes slowly. The resulting crystals were recrystallized from ethyl acetate to give Niphenyl 1, O-dimethyl-4-oxo-1 H -O 4 and 1-hexahydro-4H-pyrido [1,2a]. β-pyrimidin-3-carboxamide having a melting point of 122 to 125 ° C. Yield 98%.

Analysis calculated:

H, 7.07; N, 14.04. Found:

H, 7.03; N, 13.84

Claims (6)

A process for the preparation of novel fused pyrimidine derivatives of the general formula I, wherein I is R is C1-C6 alkyl, R @ 1 is an alkyl group having from 1 to 6 carbon atoms and R @ ² is hydrogen or C1 -C6 alkyl, and their optically active isomers and physiologically acceptable salts thereof, characterized in that the condensed pyrimidine derivatives of the general formula II, wherein R ¹ , R ¹ and R 2 are as defined above, either in the form of the -optically active compounds or in the form of the racemate, or the salts of the compounds of the formula II are reduced by catalytic hydrogenation or by treatment with a complex metal hydride. 2. The process according to claim 1, wherein the catalytic hydrogenation is carried out in the presence of palladium on activated carbon or in the presence of Raney nickel catalyst. 3. The process according to claim 1, wherein the catalytic hydrogenation is carried out at a pressure of 0.098 to 1.471 MPa. 4. A process according to any one of claims 1 to 3, wherein the reduction is carried out at a temperature in the range of from 0 to 150 ^° C. 5. A process according to claim 1, wherein the complex metal hydride is sodium borohydride. -. [2-methoxyethoxy] aluminum hydride, potassium borohydride or lithium aluminum hydride. 8. A composition as claimed in claim 1, wherein racemic or optically active compounds of general formula (II) are used as starting materials. R is methyl, ^R1 is methyl and ^R2 is hydrogen. 7. A process according to any one of claims 1 to 6, wherein the compounds of formula I obtained in the form of a racomate or optically active compounds are converted into their physiologically acceptable acid addition salts.