HU190598B - Process for preparing new octahydro-indolo/2,3-a/quinolizine derivatives - Google Patents

Abstract

Novel racemic and optically active octahydro-insolo-(2,3a)-quinolyizine derivs. of formula (I) and their salts are prepd. by treating a racemic or optically active 14-oxo-eburnane deriv. of formula (II) or its acid addn. salt with a base. In the formulae R1 = H, or alkyl with 1-4C, R2 = 2-4C alkyl, A = H, Y = H, A and Y together be an oxo gp. - The cpd. of formula (I) resulting from the base treatment, (R = H) is opt. transformed into the acid addn. salt and/or opt. esterified, then opt. transesterified. The resulting racemic cpd. of formula (I) is opt. resolved.

Description

This invention relates to new racemic and optically active I octahydro-indolo (2,3-a) quinolizine derivative of the formula wherein R ^l is hydrogen or C1-4 alkyl, ^R2 is ethyl and A is hydroxyl and Y are hydrogen or A and Y together represent an oxo group, and the salts thereof, by preparing a racemic or optically active 14-oxo-eburnan derivative of formula II wherein R ² , A and Y are or an acid addition salt thereof, with an alkali metal or alkali earth metal hydroxide, carbonate, bicarbonate and, if desired, a compound of formula I, wherein R ¹ is an alkali metal or alkaline earth metal, R ² , A and Y are an acidic treatment of a compound of formula I wherein R ^{1 is} as defined above R ² , A and Y are as defined above, liberated by acid treatment or, if desired, the compound of formula I, wherein R ¹ , R ² , A and Y are as defined above, is converted into the acid addition salt and / or a compound of formula - wherein R ^l is hydrogen, R ^2, A and Y are as defined above - is esterified.

The compounds of formula I have valuable therapeutic effects, some of which have cholesterol-lowering and / or antispasmodic effects, and inhalants have antiallergic, vasodilatory, antihypoxic effects.

In the above formulas, R ^{1 as a C} 1 -C 4 alkyl group is a straight or branched group such as methyl, ethyl, n-propyl, i-propyl, η-butyl, sec-butyl and tert-butyl. pose.

The starting compounds of formula II can be prepared as described in Hungarian Patent Application No. 187,139 by deoxygenation and subsequent partial reduction of the corresponding eburnan derivative containing the A and Y positions at position 15.

The process of the invention is carried out at a temperature of from 20 ° C to 100 ° C, depending on the starting materials used.

The reaction time of the invention may vary from 5 minutes to 5 hours depending on the starting materials used, the temperature and the reaction conditions.

Depending on the solubility conditions of the starting materials and the final products, the reaction according to the invention may be carried out in organic solvents which are inert to the reaction, for example in C 1 -C 6 alkanols such as methanol, ethanol, various mixtures of water and ethers. If necessary, a solubilizer such as halogenated hydrocarbons such as chloroform, dichloromethane and mixtures of the above may also be used.

In the process according to the invention, the compounds of the formula I, in which R ¹ is hydrogen, R ² , A and Y are defined above, are first formed with the base used. The invention also encompasses salts of compounds of Formula I with other bases, such as organic bases such as alkylamines, dialkylamines, pyridine, morpholine. If desired, these salts can be liberated by acid treatment of compounds of formula I wherein R ¹ is hydrogen, R ² , A and Y are as defined above.

The compounds of formula I of the present invention wherein R ¹ is hydrogen, R ² , A and Y are as defined above may be converted into acid addition salts with an organic or inorganic acid, if desired.

In the process of the present invention, the compounds of formula ¹ wherein R ¹ is hydrogen, R ² , A and Y are as defined above may be subjected to esterification if desired. The esterification is preferably carried out with a C 1 -C 4 diazoalkane, preferably diazomethane or diazoethane. As the solvent, a mixture of organic protic polar and organic aprotic apolar solvents, such as a C 1 -C 6 alkanol such as methanol, ethanol, and a halogenated hydrocarbon such as dichloromethane, chloroform, aliphatic or cyclic ethers such as diethyl ether. , tetrahydrofuran, dioxane. The esterification may be carried out at a temperature of -10 ° C to 20 ° C, preferably about 0 ° C.

The compounds of formula I obtained by esterification, wherein R ¹ is C 1 -C 4 alkyl, R ² , A and Y are as defined above, may be converted, if desired, to an acid addition salt with an organic or inorganic acid.

For example, the following acids may be used to form the acid addition salts of the starting compounds of formula II and the compounds of formula I. Inorganic acids such as hydrogen halides such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, perhalic acids such as perchloric acid, and the like. Organic carboxylic acids such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, succinic acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, phenylacetic acid amino salicylic acid, etc. Alkylsulfonic acids such as methanesulfonic acid, ethanesulfonic acid and the like. Cycloaliphatic sulfonic acids such as cyclohexylsulfonic acid. Arylsulfonic acids such as p-toluenesulfonic acid, naphthylsulfonic acid, sulfanylic acid and the like. Amino acids such as aspartic acid, glutamic acid, N-acetyl aspartic acid, N-acetylglutaric acid and the like.

The formation of the racemic or optically active compound of formula I in the above solvent may be carried out in an inert organic solvent, such as a C 1-6 aliphatic alcohol, followed by the addition of the appropriate acid or a solution of the acid in the above solvent. while the mixture becomes slightly acidic (about pH 5-6). The precipitated acid addition salt may then be isolated from the reaction mixture by any suitable means, such as filtration.

When a starting material of formula II is used in the process of the present invention, wherein A is hydroxy and Y is hydrogen, then the resulting target compounds of formula I also represent A and Y. Conversely, when starting from a compound of formula II wherein A and Y together represent an oxo group, the resulting target compound of formula I will also mean that A and Y together represent an oxo group.

When a racemic starting material of formula II is used in the process of the invention, the compound of formula I obtained by the process of the invention is also racemic. Starting from optically active compounds of formula II, the resulting target compound of formula I, depending on the substituents, will either retain its optical activity or racemize. For example, when an optically active starting compound of formula II is a hydroxy group, Y is hydrogen and R ² is as defined above, compounds of formula I can prepared according to the invention also remains optically active, and the substituent R ² and the the hydrogen atom at position 3 of the starting compound at position 3b in the final product retains its relative spatial position. Conversely, if, for example, in the optically active compound of formula II, A and Y together represent an oxo group and R ² is as defined above, the compound of formula I obtained by the process of the invention may lose its optical activity, racemize and The position of the hydrogen atoms in the final product at position 12b and the R ² substituent may also change.

The racemic and optically active compounds of the formula I obtained by the process of the present invention, or their salts, may, if desired, undergo further purification, such as recrystallization. The range of solvents suitable for recrystallization is determined by the solubility and crystallization properties of the material to be crystallized.

The active ingredient of the formula I is formulated in pharmaceutical compositions with non-toxic, inert, solid or liquid carriers and / or excipients suitable for parenteral or enteral administration in pharmaceutical formulations. Suitable carriers are, for example, water, gelatin, lactose, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil, and the like. It can be used. The active ingredient may be in the form of standard pharmaceutical compositions, for example solid (round or square tablets, dragees, capsules, such as hard gelatin capsules, pills, suppositories, etc.) or liquid (e.g., oily or aqueous solution, suspension, emulsion, syrup, in the form of injectable oily or aqueous solutions or suspensions, etc.). The amount of solid carrier can vary widely, preferably from about 25 mg to about 1 g. The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers, flavoring agents, perfumes, and the like. may also be included. The compositions may also optionally contain other pharmaceutically acceptable compounds of known value without exhibiting synergistic effects. Preferably, the composition is formulated in a unit dosage form appropriate to the desired route of administration. The pharmaceutical compositions may be prepared by conventional techniques, which include, for example, sifting, mixing, granulating, and pressing or dissolving the ingredients in the appropriate compositions. The compositions may be subjected to other conventional pharmaceutical operations (e.g., sterilization).

The invention is further illustrated by the following non-limiting examples.

Example 1 (-) - 14,15-Dioxo-eburnan (3oc, 16cc) (starting material)

2.0 g (6.2 mmol) of (+) - 14-oxo-15-hydroxyimino-eburnan (3oc, 16oc) was heated in 12 ml of a 15% aqueous hydrochloric acid solution in a water bath for 1-1.5 hours. The cooled reaction mixture was basified to pH 9 with concentrated aqueous ammonium hydroxide solution under ice-cooling, and the desired organic material was extracted with dichloromethane (3 x 30 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and the solvent removed from the filtrate by distillation in vacuo. The residual oil was crystallized from ethanol (4 mL).

1.50 g of the title compound are obtained.

Yield: 78.5%.

TLC showed the final product to have an Rf greater than its starting material (KG-G, benzene: methanol = 14: 3).

Melting point: 161-162 ° C (ethanol).

[α] D = -38 ° (c = 0.96, chloroform).

Found: C, 74.00; H, 66.54; N, 9.08. Found: C, 74.00; H, 66.54; Found: C 74.32%, H 66.68%, N 9.29%.

IR (KBr): 1735, 1720 cm ^-1 (CO).

MS (m / e,%): 309 (M + 1, 24), 308 (M ', 100), 307 (66), 279 (22), 252 (70).

¹ H-NMR (CDCl 3, δ): 8.50-7.25 (4H, m.

aromatic), 4.39 (1H, s, 3-H), 1.03 (3H, L,

J = 7 Hz, CH2C / ft).

¹³ C-NMR (CDCl 3, δ: 194.2 (CO-15). 153.3 (CO-14), 134.0 (C-13), 130.2 (C-2), 129.7 ( C-8), 125.3 (C-10). 125.1 (C-11), 118.5 (C-9),

116.7 (C-12), 115.2 (C-7), 52.9 (C-3), 52.2 (C-16), 50.7 (C-5), 44.26 (C -19), 27.3 (C-17), 23.2 (C-20), 20.3 (C-18); 16.5 (C-6), 9.1 (C-21).

Example 2 (-) - 14-Oxo-15oc-hydroxy-eburnan (3oc, 16oc) (starting material)

Dissolve 4.00 g (13 mmol) of (-) - 14,15-dioxoeburnane (13 mmol) prepared in Example 1 in 40 mL of absolute methanol by heating and then add 240 mg (6.5) in ice-cooling at 0 ° C. moles) of sodium borohydride.

The reaction was monitored by TLC. The starting material had an Rf greater than the final product (KG-G, dichloromethane.'methanol = 20: 1).

After completion of the reduction, the excess reducing agent was quenched with glacial acetic acid under ice-cooling and the solvent was removed by distillation in vacuo. The residue was dissolved in 15 ml of dichloromethane and extracted with 10 ml of 10% aqueous sodium carbonate solution. The separated aqueous layer was repeatedly extracted with dichloromethane (2 x 10 mL), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered and the solvent removed from the filtrate by distillation in vacuo. The remaining 4.6 g of oil was dissolved in 8 ml of methanol and the pH of the solution was adjusted to 2 with hydrochloric acid methanol.

3.33 g of the title crystalline compound are obtained in the form of hydrogen chloride.

Yield: 85.5%.

Melting point: 225 DEG C. (dec.).

Rotation of the salt (αc) d = -67 °; (0:) 546 =

-78 ° (c = 1, dimethylformamide).

IR (KBr): 3380 (OH), 1722 ^cm-1 (CO).

MS (m / e,%): 311 (M + 1, 22), 310 (M +, 100), 309 (65), 281 (3.4), 263 (4, 1), 253 (21), 240 (3, 3), 224 (4), 212 (3, 2), 168 (3), 167 (2, 8).

1 H-NMR (CDCl 3, δ): 8.35-7.25 (4H, m, aromatic), 4.38 (1H, s, 15H), 4.06 (1H, s, 3-H), 3, 48 (1H, s, OH), 1.07 (3H, t, J = 5Hz, CH 2 Cl 2).

C-NMR (CDCl3, i): 170.52 (C-14), 133.94 (C-13), 131.41 (C-2), 130.40 (C-8), 124.44124, 21 (C-11 / C-10), 118.24 (C-9), 115.94 (-12), 113.42 (C-7), 73.87 (C-15). 53.74 (C-3), 50.50 (C-5), 44.76 (C-19), 43.49 (C-16), 25.05-24.82 (C-17 / C- 20), 20.19 (C-18), 16.72 (C-6), 8.35 (C-21).

Example 3 (±) - Loc-Ethyl-l- (1'-oxo-2'-carboxyethyl) -1,2,3,4,6,7,12,12b0-ocahydroindole (2,3 (-a) quinolizine

A solution of 4.00 g (13.0 mmol) of (-) - 14,15-dioxoeburnane (3a: 16 ° C) in Example 1 in a mixture of methanol (10 mL) and dichloromethane (10 mL) was treated with (0 mmol) in a solution of sodium hydroxide in 15 mL of water was heated in a water bath for 30 minutes.

Most of the solvent was removed in vacuo, the residue was dissolved in water (10 mL), and the solution was adjusted to pH 6 with acetic acid under ice-cooling. The crystalline precipitate is filtered off, washed with methanol and twice with 10 ml of water and dried. 4.13 g of the title compound are obtained.

Yield: 96.7%.

Melting point: 184-185 ° C (water).

(o:) d = 0 ° (c = 1, 0.5% aqueous sodium hydroxide).

IR (KBr): 3400-3000 (broad, OH, NH), 2800-2740 (Bohlmann bands), 1700 (CO),

1610 cm ^-1 (carboxylate).

MS (m / e,%): 326 (M ¹ , 0.5), 325 (0.3), 308 (100), 307 (77), 279 (20), 252 (40), 251 (58).

1 H-NMR (NaOD) (D 6, δ): 0.42 (3H, 6, J = 7Hz, CH 2 CH 3).

Example 4 (-) - 11c-Ethyl-l'-hydroxy-2'-carboxyethyl-1,2,3,4,6,7,12,12boc-octahydroindole (2,3 —A) quinolizine

A solution of 4.00 g (11.52 mmol) of (-) - 14-oxo-15β-hydroxybiburnan (3cc, 16oc) hydrochloride prepared in Example 2 in 40 mL of ethanol was treated with 25 mL of 10% aqueous sodium -hydroxide solution is refluxed for 2 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 mL) and the pH of the solution was adjusted to 5-6 with acetic acid under ice-cooling. The crystalline solid was filtered off, washed with distilled water (2 x 5 mL) and dried to give 3.67 g of the title compound.

Yield: 97.1%.

Melting point: 218-220 ° C (dec.).

[α] 25 D = -25.5 ° (c = 1.2% aqueous sodium hydroxide).

Elemental results based on the formula C19H24NZO3 (MW 328.40):

Calculated: C 69.49%, H 7.37%, N 8.53%; Found: C, 69.21; H, 7.56; N, 8.92.

IR (KBr): 3380 (broad, OH, indole NH),

1630 cm ^-1 (carboxylate).

MS (m / e,%): 328 (M ', 63.5), 327 (44.4),

311 (39.4), 283 (100), 253 (17.3).

Example 5 (-) - 1cc-Ethyl-l- (1'-hydroxy-2'-methoxycarbonylethyl) -1,2,3,4,6,7,12,12bcc-octahydroindole (2,3 (-a) quinolysin

3.00 g (9.15 mmol) of (-) - loc-ethyl-1 fl- (1 * -hydroxy-2'-carboxyethyl) -1, 2,3,4, prepared according to Example 4. A suspension of 6,7,12,12boc-octahydroindolo (2,3-a) quinazoline in 10 ml of methanol / 8 ml of dichloromethane at 0 ° C in 40 ml of diazomethane in dichloromethane (see Vogel: Practical Organic Chemistry, 3E, 971). After dissolving the solid (1.5-2.5 hours), the solvent was removed in vacuo. The remaining oily residue, about 3.4 g, was crystallized from methanol (5 mL). 2.44 g of the title compound are obtained.

Yield: 77.8%.

Melting point: 164-166 ° C (methanol).

[α] D = -103 ° (c = 1, chloroform).

Elemental results based on the formula C20H26N2O3 (MW = 342.43):

Found: C, 70.15; H, 7.65; N, 8.18; Found: C, 70.42; H, 7.78; N, 8.03.

IR (KBr): 3360 (indole NH), 3450-2900 (broad, OH), 2810-2750 (Bohlmann bands), 1710 cm ^-1 (CO).

MS (m / e,%): 342 (M +, 64.1), 325 (34), 310 (100), 283 (86.0), 253 (30.2).

¹ H-NMR (CDCl 3, δ): 7.85 (1H, s, indole NH), 7.50-6.96 (4H, m, aromatic), 5.52 (1H, broad, OH), 4, 60) 1H, s, Ctf-OH), 3.53 (1H, s, 12b-H), 3.03 (3H, s, OCHa), 1.10 (3H, t,

J = 7 Hz, CH 2 -CR 3).

Example 6 (-) - Loc-ethyl-10- (1'-hydroxy-2'-carboxyethyl) -1,2,3,4,6,7,12,12boc-octahydroindolo (2, 3-a) quinolizine hydrochloride

5.00 g (15.25 mmol) of (-) - 1? -Ethyl-1? - (1'-hydroxy-2'-carboxyethyl) -1, 2,3,4, prepared according to Example 4, 6,7,12,12bac-octahydroindolo (2,3-a) quinolizine To a suspension of 10 ml of methanol is added methanolic hydrochloric acid under stirring and ice-cooling to pH 1-2. After the solid has dissolved, 5-8 ml of ether are added to the solution. The precipitated crystals are filtered off, washed with a little methanol and dried.

Thus, 4.36 g of a cinnamic salt is obtained.

Yield: 78.4%.

Melting point: 192-194 ° C.

Example 7 (±) - Ice-Ethyl-1β- (1-oxo-2'-carboxyethyl) -1,2,3,4,6,7,12,12h6-octahydroindole (2, 3-a) Sodium salt of quinolizine

1.00 g of (±) - Loc-ethyl-1β- (1'-oxo-2-carboxylethyl) -1,2,3,4, -6,7,12,12bfl, prepared according to Example 3. To a suspension of octahydroindolo (2,3-a) quinolizine in 5 ml water and 5 ml methanol, add 5% aqueous sodium hydroxide solution to bring the pH of the solution to

7-8. The solvent was removed in vacuo and the residue was triturated with ethanol (4-5 mL) and the resulting crystals were punctured.

0.92 g of the title salt is obtained.

Yield: 86%.

IR (KBr): 3380 (indole NH), 1700 (CO), 1615 cm ^-1 (carboxylate).

Claims (3)

PATENT CLAIMS A process for the preparation of a novel racemic and optically active octahydroindolo (2,3-a) quinolizine derivative of the Formula I wherein R ¹ is hydrogen or C 1 -C 4 alkyl, R ² is ethyl, A is hydroxyl and Y are hydrogen or A and Y together represent an oxo group, and their salts, characterized in that a racemic or optically active 14-oxo-eburnone derivative of the Formula II wherein R ² , A and Y are Or an acid addition salt thereof, as defined in formula I, with an alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate and, if desired, a compound of formula I, wherein R ¹ is an alkali metal or alkaline earth metal, R ² , A and Y are as defined above, a compound of formula I wherein R ¹ is hydrogen, R ² , A and Y are liberated by treatment with eavas or, if desired, converting a compound of formula I wherein R ¹ , R ² , A and Y are as defined above into an acid addition salt and / or optionally a compound of formula I which -5π In formula 19U598, R ¹ is hydrogen, R ² , A and Y are as defined above - esterified. 2. A process according to claim 1 wherein the esterification is carried out with a diazoalkane. 3. A process for the preparation of a pharmaceutical composition, wherein the racemic or optically active compound of formula I is prepared according to claim 1, wherein R ¹ is hydrogen or C 14 alkyl, R ² is ethyl, A is hydroxy. and Y is hydrogen or A and Y together are oxo - or salts thereof are admixed with pharmaceutically acceptable carriers and / or excipients and converted to a pharmaceutical composition.