SI8610624A8 - Process for preparing optical active trans (-)-1beta-ethyl-1alpha-hydroxymethyl-1,2,3,4,6,7,12,12b alpha - octahydroindolo /2,3-a/ quinolizine - Google Patents

Description

and its acid addition salts.

The compound of formula (I) has excellent pharmaceutical efficacy, in particular cardiovascular, in particular peripheral vasodilatory and antihypoxic efficacy.

A technical problem

There was a need to prepare a novel compound, which had excellent pharmacological properties, by a technologically advantageous process.

The state of the art

In Hungarian patent file no. 170 495 (British Patent No. 1,499,546) discloses 1,1-disubstituted octahydroindolo / 2,3-a / quinolizines which may carry in position 1, inter alia, substituents identical to those present in the compound of the invention. In these compounds, however, the configuration of the substituents in positions 1 and 12b of hydrogen is not specified; in addition, the specifically described compounds are without exception racemic, although optically active compounds and separation processes are also generally described in the description and claims.

Known racemic compounds have vasodilatory properties, this efficacy can be observed in both peripheral and cerebral circulation, i.e. the vasodilatory efficacy of these compounds is not selective. In sharp contrast, the compound of the present invention has a selective peripheral vasodilatory effect. A further difference between the known compounds and the compound of the invention is that the former do not have antihypoxic efficacy, whereas in the case of the compound of the invention the peripheral vasodilatory efficacy is accompanied by antihypoxial efficacy.

According to Helv. Chim. Acta, 60, 1801 (1977) racemic trans-1-ethyl-1-hydroxymethyl-1,2,33,6,7,12,12b-octahydroindolo / 2,3-a / quinolizine is prepared by reduction of the corresponding racemic trans compound containing aldehyde the group in position 1 obtained as an intermediate in the synthesis of vincamine. However, this article does not mention the separation of the compounds obtained, does not mention the corresponding optically active compounds or any pharmaceutical efficacy they may have.

Following the procedure described in Gaz. Chim. Italiana 111,

257 (1981), racemic trans-1-ethyl-1-hydroxymethyl-1,2,3,4,6,7,12,12b-octahydroindolo / 2,3-a / quinolizine was prepared by heating 1-ethyl-hexahydroindolo / 2,3-a / quinolizinium perchlorate and aqueous formaldehyde solution in acetonitrile in the presence of disopropylethylamine. This article also refers to the racemic compound. However, the corresponding optically active derivatives, separation of the prepared compound or any pharmaceutical efficacy of this compound or its derivatives have not been described.

Description of solution to a technical problem with implementation examples

Surprisingly, we found that the optically active trans - (-) -1 -e 1-1 O -hydroxy-methyl-1,2,3,4,6,7,12,12b o / -octa is hydroindolo / 2, 3-a / quinolysin of formula (I), not specifically described in the art and not yet prepared, has excellent selective peripheral vasodilation efficiency as opposed to the racemic compound having a non-selective general vasodilation efficiency. A further significant difference is that the optically active compound of the invention is selectively peripherally vasodilatory effective at very low doses (e.g., 0.03 mg / kg iv doses), whereas the corresponding racemic compound is active at doses higher by about 2 orders of magnitude (eg 1 mg / kg iv dose). A further unexpected advantage of the compound of the invention is its additional antihypoxic efficacy, which, in combination with selective peripheral vasodilatory efficacy, provides new therapeutic options. The corresponding racemic compound has no antihypoxic efficacy at all.

A process for the preparation of compounds of formula (I) and its acid addition salts is characterized by separating a 1: 1 mixture of derivative 1 (X-ethyl-1-p-acyloxymethyl-1,2,3,4,6,7,12, 12b-octahydroindolo / 2,3-a / quinolysine of formula (Ila)

(Ha) c ₂ h ₅ and a derivative of 1 fl) -ethyl-1 N * - acyloxymethyl-1,2,3,4,6,7,12,12b {X octahydroindolo / 2,3-a / quinolizine of formula ( Ilb)

(Ilb) in which

R ^{1 is} hydrogen, alkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety, optionally substituted arylcarbonyl or aralkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety, and optionally hydrolyzed the new optically active derivative-ethyl-1 ^ acyloxymethyl-1 , 2,3,4,6,7,12,12bcA - octahydroinodlo / 2,3-a / quinolysine of formula (III)

R is alkylcarbonyl having from 1 to 6 carbon atoms in the alkyl moiety, optionally substituted aryl or aralkylcarbonyl with 1 to carbon atoms in the active moiety, and optionally treating new (-) - 1 S-ethyl 1-1 "1-hydroxymethyl- 1,2,3,4,6,7,12,12b << Octahydroindolo / 2,3-a / quinolizine of formula (I) with acid.

2

In the formulas above, R and R as alkyl may represent any straight or branched alkyl of 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl group 1 2 etc. As the aryl group, R and R may represent a mono- or polycyclic (separate or fused) aromatic hydrocarbon group, such as e.g. a phenyl, diphenyl or naphthyl group, etc. The term aralkyl is used to refer to any combination of the aryl and alkyl groups identified above.

- 6 Racemic compounds of formulas (Ila) and (Ilb) used as starting materials in the process of the invention are prepared according to the method described in Hungarian patent no. 170 495 (British Patent No. 1,499,546)]

The separation of the compounds of formulas (Ila) and (Ilb) can be carried out in a known manner. According to a preferred embodiment, a separation of e.g. with optically active acid, preferably D-tartaric acid, dibenzoylD-tartaric acid, camphensulfonic acid, etc.

Separation is generally carried out in a suitably selected inert organic solvent such as an aliphatic ketone, e.g. acetone, aliphatic alcohol or in an aqueous mixture of such solvents.

The acid addition salts formed with the optically active acid are separated into the corresponding pairs of diastereomeric salts and optionally from the salt of the left-handed trans compound of formula (III) to release the corresponding base. The release of the base is preferably effected by dissolving or suspending the salt in water or a mixture of water-miscible water and organic solvent, such as a halogenated aliphatic or aromatic hydrocarbon, linear or cyclic ether, e.g. dichloromethane, chloroform, ether, toluene, etc .; the resulting solution or suspension is basified with an inorganic base such as alkali carbonate, e.g. potassium or sodium carbonate, ammonia, etc .; and optionally a left-handed trans base of formula (III) is extracted with any of the water-immiscible organic solvents mentioned above. A left-handed trans base of formula (III) may e.g. is isolated from its solution in a water-immiscible organic solvent by evaporation. If desired, the crude new trans compound of formula (III) is further purified by recrystallization from a suitable solvent such as an aliphatic alcohol of 1 to 6 carbon atoms, e.g. methanol.

Hydrolysis of the left-handed trans compounds of formula (III) is preferably carried out in an alkaline medium. Suitable bases are alkali alcohols, e.g. sodium methylate, etc. Hydrolysis is preferably carried out in an inert organic solvent, more preferably in an aliphatic alcohol of 1 to 6 carbon atoms, e.g. methanol. On the other hand, hydrolysis can be carried out with an inorganic base in an aqueous / alcoholic medium. The hydrolysis temperature is generally between 60 ° C and 100 ° C, and preferably the reaction mixture is boiled in the inert organic solvent used. Hydrolysis is complete in a short time.

The compound of formula (I), prepared by the procedure described above, can optionally be converted to its acid addition salts by acid metabolism by known methods. Such acids are inter alia inorganic acids, e.g. hydrohalic acids (e.g. hydrochloric and hydrobromic acid), sulfuric, phosphoric acid, and perhalogen acids, e.g. perchloric acid, etc .; organic carboxylic acids such as e.g. formic, acetic, propionic, glycolic, maleic, hydroxymalein, fumar, amber, wine, ascorbic, citric, apple, salicylic, milk, cinnamon, benzoic, phenylacetic, p-aminobenzoic, p-hydroxybenzoic, p-amino, etc. salicylic. ; alkylsulfonic acids such as e.g. methanesulfonic acid, ethanesulfonic acid, etc .; cycloaliphatic sulfonic acids, such as cyclohexylgulfonic, naphthylsulfonic, sulfanilic acid, etc .; amino acids, e.g. aspartic, glutamic, N-acetylaspartic, Nacetyl glutaric acid, etc.

The formation of salts can be carried out e.g. in an inert organic solvent, such as an aliphatic alcohol of 1 to 6 carbon atoms, by dissolving the compound of formula (I) in the solvent and adding the selected acid or its solution with the same solvent to the first solution until it is slightly acidic (pH 5 to 6 ), then the acid addition salt is eliminated and can be removed from the reaction mixture e.g. by filtering.

The compound of the invention may optionally be further purified, e.g. recrystallization.

The vasodilatory performance of a compound of formula (I) was tested in anesthetized dogs. Electromagnetic flow meters (Hellige) were installed on the femoral artery and the internal cervical artery of animals and the amount of blood flowing through the veins, in ml / min, was determined. Average arterial pressure was measured with a Statham pressure sensor connected to a polyethylene cannula introduced into the artery. The number of beats per minute was determined from a pulsatile blood pressure component with a frequency meter. All measured parameters were continuously registered on a multichannel polygraph.

For comparison, in addition to the new compound of the invention / the compound of formula (I) /, the respective right-handed trans compound and the known corresponding racemic trans compound were tested.

The new left-handed trans compound of the invention has no effect on the number of beats and cervical blood flow at the dose used. All three compounds had a transient, slightly hypotensive effect. The reduction in blood pressure was about 20% for the known racemic compound, 6% for the (+) - isomer and 7 to 10% for the (-) isomer of the invention. We have found that the new left-handed trans compound of the invention is extremely effective in increasing blood pressure in the femoral artery. For comparison, we also tested structurally distinct pentoxifylline, a widely used peripheral vasodilator. The results obtained are shown in Table 1.

Each compound was tested on several animals. We calculated the average of the individual responses. The tables indicate the number of animals (n), the average value of the parameters measured and the percentage changes.

In the case of intravenous (i.v.) administration, baseline output and maximal change were evaluated.

Table 1

Effect of test compounds on blood flow in the femoral artery in the case of i.v. giving

Compound dose (mg / kg) n blood flow (acre / min) % duration effects- toast (min.) basic max. change racerana 1.0 5 60 146.6 +144 15.6 0.03 2 60 75 +25 1 (+) 1.0 4 42.5 54.5 +28 3.7 0.03 2 62 62 0 0 (-) 0.01 6 40,2 63 +57 2.3 0.03 7 42.3 99.6 + 135 9.6 pentoxy- filin 2.0 5 49,6 60.6 +22 1.5

The results reported in Table 1 indicate that the peripheral vasodilatory performance of the new trans - (-) - stereoisomer of the invention is superior to that of pentoxifylline. In addition, a comparison with the corresponding racemic compound and the (+) - isomer shows that the (-) - stereoisomer of the invention is unexpectedly about 100 times more potent peripheral vasodilator than the corresponding (+) - stereoisomer and about 30 times more active than the corresponding racemic compound.

Although, in exceptional cases, one of the two possible stereoisomers may essentially have the same efficiency as the corresponding racemic compound and thus the other isomer is completely ineffective, i.e. only one of the two stereoisomers is responsible for efficiency, this is not the case with the present invention. Our tests have led to the completely unexpected result that the peripheral vasodilatory performance of the left-handed trans stereoisomer of the invention is about 30 times higher than the efficiency of the corresponding racemic compound.

Further, on the basis of the results shown in Table 1, it is important that the most effective dose of the new left-handed trans compound of the invention is only 0.03 mg / kg, while both the known racemic trans compound and the new right-handed trans compound are most effective at dose 1.0 mg / kg. According to the data in the table, the corresponding right-handed trans stereoisomer was completely ineffective and the known racemic trans compound was found to be about 6 times less effective than the (-) compound of the invention when administered at this low dose. (0.03 mg / kg). Moreover, even this low efficiency of the racemic compound lasts only 1 minute, while the duration of the (-) - trans compound of the invention is about 10 times longer, i.e. about 10 minutes.

The antihypoxial efficacy of the novel left-handed trans compound of the invention was tested in alert mice in normobaric hypoxia. Five male mice were placed in a 3 liter glass cylinder, which was continuously rinsed with a gas mixture of 96% nitrogen and 4% oxygen. For each animal, we measured the time between placing the animals in a glass cylinder and their death for a maximum duration of minutes. Animals that were alive after 2 times the average death time of untreated animals (6.2 minutes), i.e. who were alive 12.4 minutes after the start of the experiment were considered protected. The reference substances were administered to 20 animals each intraperitoneally at a dose of 50 mg / kg body weight 30 minutes before placing the animals in a glass cylinder, whereas the dose (-) of the trans isomer of formula (I) of the invention was 25 mg / kg. We determined the average of the times elapsed before the death of the animals, calculated the percentage difference from the average control time obtained with the untreated animals, and called it the change in survival time (see Table 2). Number of animals protected, i.e. the number of animals still alive 12.4 minutes after being placed in hypoxia medium as the most important performance characteristic is also indicated in the table.

The antihypoxic efficacy of the new left-handed trans compound of the invention was, on the one hand, compared to that of the corresponding racemic trans compound and the corresponding right-handed trans stereoisomer, and on the other, comparative studies were performed with other racemic trans compounds described in British Pat. 1, 499,546. The purpose of recent comparative tests was to determine, if other structurally related compounds were also found, that the left-handed trans isomer had significantly higher and qualitatively different efficiencies compared to the corresponding right-handed or racemic trans compound. The results of this test are also shown in Table 2.

Table 2

Effect of test compounds on survival time and protection of mice in hypoxia medium

Compound

Change in average survival time relative to control (%)

Percentage of Protected Animals (%) Known (+) - 1-Hydroxymethyl Derivative / Bri + 25 Patent Pat.

1,499,546, in formula (II) ^X is R ¹ hydrogen / new (+) - 1-hydroxy- + 15 methyl derivative new (-) - 1-hydroxy methyl derivative +75 / formula (I) / ** known ( +) - 1-acetoxymethyl derivative (British patent no.

1,499,546, in formula (II) methyl / new (+) - 1-acetoxy-+3 methyl derivative is a new (-) - 1-acetoxy- +31 methyl derivative / formula (III), R ² is methyl / known (+) - 1-propionyloxy methyl derivative / British-11 ski patent No. 1,499,546 in formula (II) ^X is

R ¹ ethyl continuation of the table new (+) - 1-propionyloxy- +38 20 methyl derivative new (-) - l-propionyloxymethyl derivative / formula -6 0 (III), R ² is ethyl) x expression formula (II) is used by referring to a 1: 1 mixture of compounds of formulas (Ila) and (IIb) xx dose 25 mg / kg.

The results reported in Table 2 indicate that> the new (-) trans stereoisomer of the invention has significant antihypoxial efficacy, i.e. significantly improves hypoxia tolerance of body tissues and organs even in small doses. The corresponding (+) trans isomer and the corresponding racemic trans compound are virtually devoid of this efficiency. Antihypoxia efficacy is very favorable according to the therapeutic indication because in diseases accompanied by vasoconstriction, blood supply to tissues and organs is significantly reduced, hypoxia occurs and tissue necrosis results. Therefore, a combination of vasodilating effect with increasing cell resistance to hypoxia is a therapeutically advantageous combination.

Known racemic and right-handed trans compounds have no antihypoxic efficacy even at higher doses. Namely, the 10% protection frequency is not statistically significant, since untreated animals may also be shown to be protected to about the same extent.

It can further be seen that of the tested structurally related compounds, only the new left-handed trans isomer of the invention exhibits this significant and novel efficacy when compared to the corresponding racemic and right-handed trans compounds. Neither the racemic trans 1-acetoxymethyl or 1-propionyloxymethyl derivatives described in British Patent 1,499,546, nor the corresponding novel optically active left-handed compounds of formula (III) obtained by separation of the preceding compounds, or the corresponding right-handed compounds have any significant antihypoxic efficacy.

The new left-handed trans compound of formula (I) can be advantageously used in therapy, especially in the treatment of diseases accompanied by vasoconstriction. The expected therapeutic dose is 0.01 to 1.0 mg / kg body weight for parenteral administration and 0.5 to 5.0 mg / kg body weight for oral administration.

For therapeutic purposes, the novel compound of formula (I) and its physiologically acceptable salts can be converted into preparations. The invention therefore also relates to pharmaceutical compositions containing as an active ingredient a compound of formula (I) or a physiologically acceptable acid addition salt thereof, together with pharmaceutical carriers and / or vehicles. Carriers suitable for this purpose and suitable for parenteral administration as well as other additives may be used. Solid or liquid compounds can be used as carriers, e.g. water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil, etc. The compounds may be converted into preparations such as conventional pharmaceutical preparations, e.g. in solid form (spherical and angular pills, dragees, capsules, eg hard jelly capsules) or in liquid form (oily or aqueous solutions or suspensions for injection). The amount of solid carrier can be varied over a wide range, preferably between 25 mg and 1 g. The compositions also optionally contain conventional pharmaceutical additives such as preservatives, wetting agents, osmotic pressure adjusting salts, buffers, flavoring agents and flavoring agents.

The compositions of the invention optionally contain a compound of formula (I) together with other known active ingredients. Single doses are selected according to the route of administration. The pharmaceutical compositions are prepared by conventional techniques such as sieving, mixing, granulating, compressing or dissolving the active ingredients. The resulting compositions are then additionally typically treated as sterilized.

The invention is explained in detail by the following non-limiting examples.

EXAMPLE 1 (+ 1 H -ZZ-acetyloxymethyl-1H-ethyl-1,2,3,4,6,7,12,12b) ioctahydroindolo / 2,3-a / quinolizine and (-) - 1CC-acetyloxymethyl1 / N -ethyl-1,2,3,4,6,7,12,12b d - octahydroindolo / 2,3-a / quinolizine

A solution of 1.1319 g (7.54 mmol) of D-tartaric acid in 25 ml of absolute acetone was added to a hot solution of 1.3619 g (7.54 mmol) of (+) -1-acetyloxymethyl-1-ethyl-1,2. 3,4,6,7,12,12b octahydroindolo / 2,3-a / quinolizine (British Patent No. 1,499 546) in 25 ml absolute acetone. The mixture was allowed to stand at room temperature for 24 to 28 hours. The precipitated crystals were filtered off and, after washing with a minimum amount of acetone, 2.00 g of the corresponding tartrate was obtained. Dissolve the salt in 50 ml of distilled water and adjust the solution to pH 8 with a 5% aqueous solution of sodium carbonate while cooling with ice water. The alkaline solution is extracted three times with 20 ml of dichloromethane each. The combined organic solution was dried over solid anhydrous magnesium sulfate and then evaporated in vacuo. The remaining oil was crystallized from methanol. 1.20 g (97.4%) of the right-handed title compound are obtained as a crystalline substance.

Melting point: 122 ° C to 123 ° C = + 38,7 ° (c = 1, dichloromethane)

Evaporation of the mother liquor after separation in vacuo afforded 1.65 g of solid foam. By following the procedure described above and crystallizing the product from methanol, 1.00g (81.2%) of the left-stranded title compound is obtained.

Melting point: 122 ° C to 123 ° C = -37,5 ° (c = 1, dichloromethane)

EXAMPLE 2 (+) -1 c / - ethyl-1 H -hydroxymethyl-1,2,3,4,6,7,12,12b fyoctahydroindolo / 2,3-a / quinolizine and (-) - 1 / ^ -ethyl-1 <4 ~ - hydroxymethyl-1,2,3,4,6,7,12,12b 4- 4- octahydroindolo / 2,3-a / quinolizine

a) 1.95 g (5.97 mmol) (+) -1 N -acetyloxymethyl-1 H ^-7 ethyl-1,2,3,4,6,7,12,12b / N - octahydroindolo / 2,3 -a / quinolysin prepared according to Example 1 was dissolved in 100 ml of hot methanol and, after the addition of 0.05 g (0.92 mmol) of sodium methylate, the mixture was refluxed for 30 minutes. The reaction mixture was allowed to cool to room temperature, then poured into 300 ml of distilled water, the precipitated white crystals were filtered off and washed with cold water.

1.65 g (97.6%) of the right-handed title compound are obtained as a white crystalline substance.

Melting point: 220 ° C to 221 ° C / <^ / _D = + 110,4 ° (c = 1, dimethylformamide)

b) By essentially acting as in point a) but starting from (-) - 1 -acetyloxymethyl-1; S-ethyl-1,2,3,4,6,7,12,12bx octahydroindolo / 2 , 3-a / quinolysin ^ prepared according to Example 1, yield 1.60 g (94.2%) of the left-stranded title compound as a crystalline substance.

Melting point: 220 ° C to 221 ° C / O / S with -108,0 ° (c = 1, dimethylformamide)

The hydrobromide of the left-handed title compound is prepared from 10 times volume of hot acetone with 48% aqueous hydrobromic solution.

Melting point: 280 ° C to 282 ° C

Melting point after crystallization from methanol: 285 ° C to 287 ° C.

Claims (3)

PATENT APPLICATIONS A process for the preparation of optically active trans - (-) 1 H-ethyl-1 H -hydroxymethyl-1,2,3,4,6,7,12,1,4-octahydroindolo / 2,3-a / quinolysin of formula (I) and its acid addition salts, characterized in that a 1: 1 mixture of the derivative 1 - - til - 1 - T - acyloxime til - 1,2,3,4,6,7 is separated; 12,12b $ octahydroindolo / 2,3-a / quinolysine of formula (Ila) and derivative 1 (N-ethyl-1 <i> A - acyloxymethyl-1,2,3,4,6,7,12,12b ^ octahydroindolo / 2,3-a / quinolysine of formula (Ilb) in which R is hydrogen, alkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety optionally substituted arylcarbonyl or aralkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety, and optionally hydrolyzed the new optically active derivative (-Jl / ^ - ethyl-lc ^ - acyloxymethyl-1,2,3,4,6,7,12,12bct -octahydroindolo / 2,3-a / quinolizine of formula (III) (HI) in which p R alkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety, optionally substituted aryl or aralkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety, and optionally obtained new (-) 21 1 β-ethyl-1 OC-hydroxymethyl-1,2,3,4,6,7,12,12b (X-octahydroindolo / 2,3-a / quinolizine is treated with acid. Process according to claim 1, characterized in that the separation is carried out with D-tartaric acid. Process according to claim 1, characterized in that the hydrolysis is carried out under alkaline conditions.