GB2160862A

GB2160862A - Benzoquinolizines

Info

Publication number: GB2160862A
Application number: GB08513893A
Authority: GB
Inventors: Terence James Ward
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1984-06-28
Filing date: 1985-06-03
Publication date: 1986-01-02
Also published as: GB8513893D0; GB8416432D0; GB2160862B; US4604398A

Description

1 GB 2 160 862 A 1

SPECIFICATION

Benzoquinolizines The invention relates to certain novel benzoquinolizines, to processes for preparing the benzoquinoli- 5 zines, to their use and to pharmaceutical compositions containing them.

The novel compounds of the present invention are benzoquinolizines of the general formula (1) R 1 ' g 1 N.

2/ (1) R 4 CO"--- N 1 R 3 and their pharmaceutically acceptable acid addition salts. In formula (1), R, and R2 which may be the 20 same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, R3 represents lower alkyl and R4 is lower alkoxy or lower alkoxy carbonyl.

The term "lower" as used herein means that the radical referred to contain 1 to 6 carbon atoms, Pref erably such radicals contains 1 to 4 carbon atoms.For example, a lower alkyl group may be methyl, ethyl, propyl or butyl and a lower alkoxy group may be methoxy, ethoxy, propoxy or butoxy. When R, and/or 25 R2 represents halogen the substituent may be, for example, fluorine, chloride or bromine.

Preferably both R, and R2 are hydrogen.

Preferably R4 is lower alkoxy.

The compounds of the invention may be prepared by reacting a reactive derivative of an acid of for- mula R4COOH (11) (111) (where R4 has the meaning given above) with a benzoquinolizine of the general formula R 1 11 N NH. R 3 or an acid addition salt thereof (wherein R1, R2 and R:1 are as defined above) and, if required, converting a free base into a pharmaceutically acceptable acid addtion salt. The reactive derivative of the acid can be, for example, the acid halide or anhydride. Preferably it is the acid halide, i.e. a compound formula R4COX (V) 50 (where R4 is as defined above and X is halogen, preferably chlorine). The reaction is generally carried out under basic conditions.

The starting materials of general formula (111) are known or can be prepared by known methods.

If in the process described above the compound of the invention is obtained as an acid addition salt, 55 the free base can be obtained by basifying a solution of the acid addtion salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addi tion salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solu tion with an acid, in accordance with conventional procedures for preparing acid addition salts from base compound.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesul phonic and p-toluenesulphonic acids.

2 GB 2 160 862 A 2 The compounds of the invention possess two asymmetric carbon atoms and hence can exist in various stereochernical forms. In addition they can exist as cis or trans isomers; It will be realised that if the starting material of formula (111) is a mixture of isomers the product of formula (1) will also be a mixture of isomers unless the mixture is separated by standard procedures. The preferred compounds of the in- vention are the trans isomers in which the -NR3.COR4 group is in the equatorial position, i.e. compounds of the general formula (VI) R (V0 10 R 2 3 4 H NR. COR 15 and the pharmaceutically acceptable acid addition salts thereof. These compounds can be prepared by the methods described above from the corresponding trans isomer starting material. Resolution of a racemiG final product or intermediate may be carried out by known procedures so as to give the product as an optically active enantiomorph The compounds of the present invention possess pharmacological activity. In particular the compounds possess U-2-adrenoceptor antagonistic activity in warm blooded animals and hence are of value in conditions where antagonism of the a,-adrenoceptor is desirable, for example, as anti depressants, in treatment of diabetes and in inhibiting blood platelet aggregation.

The compounds of the invention are tested for aradrenoceptor antagonistic activity on the rat field stimulated vas deferens preparation using a modification of the method of Drew, Eur. J. Pharmac., 1977, 42, 123-130. The procedure is described below.

Desheathed vasa deferentia from sexually mature rats were suspended in a 6 ml organ bath in Krebs solution at 37' and bubbled with 5% C02 in oxygen. Platinum ring electrodes were positioned above and 30 below the tissue for field stimulation, the-stimulus parameters being 0.1 Hz 1 ms pulse width at supra maximal voltage. Twitch responses were recorded isotonically with a 0.5 g loading. Clonicline hydrochlo ride was used as the a-adrenoceptor agonist and cumulative concentration- response curves were constructed for the inhibition of twitch obtained with clonicline in the range 0.125 to 4 ng ml -I. After washing out clonidine, the twitch response quickly recovered and an antagonist was then introduced into 35 the Krebs reservoir. Clonicline concentration-response curves were repeated 90 min after introduction of the antagonist. The concentration of clonidine producing 50% inhibition of twitch before and after intro duction of antagonist were obtained and the dose-ratio for clonidine was calculated. Various concentra tions of the antagonists were used.

These results were plotted in the manner described by Arunlakshana & Schild, Br.J.Pharmac. Chemo- 40 ther., 1959, 14, 48-58 and the values of pA, and slope were calculated. The compounds of the invention possess potent %-adrenoceptor antagonistic activity.For example, methyIjNmethyI-N-(1,3,4,6,7,1 1 bu_-hex ahydro-2H-benzo[al quinolizin-20-yl)l carbarnate, a representative compound of the invention, has been found to have a pA, for a,-adrenoceptor antagonistic activity of 7.87.

The compounds of the invention generally antagonise the 0-2-adrenoceptors to a much greater extent 45 than the (xl-adrenoceptors. The a, antagonistic activity can be evaluated by a number of different meth ods. One method involves assessing the activity on the isolated anococcygeus muscle of the rat. The method is based on that of Gillespie, Br.J.Pharmac., 1972, 45, 404-416.ln the procedure male rats (250 360g) are killed by a blow on the head and bled.The two anococcygeus muscles are removed from their position in the midline of the pelvic cavity, where they arise from the upper coccygeal vertebrae. The 50 muscles are suspended in 5 ml organ baths in Krebs solution containing 10- 4M ascorbic acid, to prevent drug oxidation. The tissues are gassed with a 95% oxygen, 5% C02 mixture and maintained at 37'. Longitudinal muscle contractions are recorded using isotonic transducers. Cumulative dose response curves are then obtained to phenylephrine or in some cases methoxamine, both agents being presyn aptic alpha adrenoceptor agonists.The concentration range of phenylephrine or methoxamine used us 55 0.02 to 0.8pg.ml-1. The agonist is then washed from the bath and the test drug added to the bathing medium at a concentration of 10-6M. After 30 min equilibration with the test drug a further agonist dose response curve is obtained. The washing, equilibration and agonists dosing procedures are then repeated using 10-5M and 10--4M solutions of the test drug. Estimates of the pA, value for the test drug as an antagonist of phenylephrine or methozamine were made from the agonist dose-ratios using the method 60 of Arunlakshana & Schild, Br. J. Pharmac. Chemother., 1959, 14, 48-58.

The pA, values for a., antagonistic activity for methylf N-methyI-N-(1,3, 4,6,7,1 1 ba-hexahydro-2H-benzo[a] quinolizin-2p-yl)l carbamate has been found to be 6.15 and the %'% selectivity [ie. antilog of (0-2pA2 (x,pA2)] for this compound is 52.3.

3 GB 2 160 862 A 3 The invention further provides a compound of formula 1 or a pharmaceutically acceptable acid addition salt for use in antagonising a2- adrenoceptors in a mammal.Also provided is the use of a compound of formula (1) or a pharmaceutically acceptable acid addflon salt thereof for the manufacture of a medicament for use as an antidepressant, in the treatment of diabetes or in inhibiting blood platelet aggrega5 tion.

The invention also provides a pharmaceutical composition comprising a compound of general formula (1) or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid and a liquid, Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatine cap- 10 sules), suppositories and pessaries.A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compres sion aides, binders or tablet-disinteg rating agents; it can also be an encapsulating material. In powders the carrier is a finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compresion properties in suitable proportions and compacted in the shape and size 15 desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably 1 to 80% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidine, low melting waxes and ion exchange resins.

The term "composition" is intended to include the formulation of an active ingredient with encapsulat- 20 ing material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions,syrups, elixirs and pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a phar maceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharma- 25 ceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solibilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo- regulators. Suitable examples of liq uid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including 30 monohydric alcohols and polyhydric alcohols e.g. glycerols) and their derivatives, and oils (e.g. fraction ated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for 35 example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be adminis tered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredi- 40 ent; the unit dosage forms can be packaged compositions, for example packeted powders, vials, am poules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient. The 45 invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The following Examples illustrate the invention:

Example 1

Methyl{N-methyl-N-(1,3,4,6,7, 1 lbot-hexahydro2H-benzo[al quinolizin-2Pyi} carbamate An ice-cold, stirred solution of 2p-m ethyl am i no1,3,4,6,7,11beL- hexahydro-2H-benzo[aJ quinolizine (2.16g) and triethylamine (1.159) in dichloromethane (25cm3) was treated slowly with a solution of methyl chloroformate (0.959) in dichloromethane (25CM3). The clear solution was kept at room temperature for 2 days, then washed with water (2 x 25CM3) and dried (M9S04). Filtration and evaporation afforded a red- 55 brown oil (2.78g) which was dissolved in hot methanol (5CM3) acidified with ethanolic HCI, diluted with methyl acetate (20cm3) and kept at 5' for 3 days. The crystals were collected by filtration and recrystal lised twice from methanolmethyl acetate to give pure title compound as the hydrochloride threequarter hydrate (0.64g), colourless microneedles, m.p. 163-185' (dec).

4 GB 2 160 862 A 4 Example 2

Ethy1jN-Methy1-N-(1,3A6,7, 1 1bu_-hexahydro-2H-benzo[a1 quinolizin-2pyl)l carbarnate A solution of ethyl chloroformate (0.62g) in clichloromethane (25cM3) was added slowly to an ice-cold solution of 2P-m ethyl am in o-1,3,4,6,7,1 1 ba-hexahydro-2H- benzo[a]quinolizine (1.08g) and triethylamine (0.55g) in dichloromethane (25CM3). The clear solution was stirred briefly at room temperature, then al- 5 lowed to stand for 5 days when tIc showed essentially complete reaction. The mixture was washed with water (2 x 25cm3), dried (MgSO,), filtered and evaporated to an orange- red syrup (1.46g). This was dis solved in ethanol (3cm3), acidified with ethanolic hydrogen chloride, diluted with ethyl acetate (JOCM3) and cooled. The precipitated crystals were collected by filtration and recrystallised twice from ethanol ethyl acetate to give the title compound as the hydrochloride, quarterhydrate (0.75g) after drying at 600/ 10 1 ml (higher temperatures led to partial loss of HCI), m.p. 216-2180(dec).

Example 3 Ethyl{N-methyl-N-(1,3,4,6.7. l lbu--hexahydra-2H-benzo[a] quinolizin-20-yi)}oxamate An ice-cold, stirred solution of 2p-methylamino-1,3,4,6,7,1 1 boL- hexahydro-2H-benzo[al quinolizine 15 (2.16g) and triethylamine (1.15g) in dichloromethane (25cm3) was slowly treated with a solution of ethyl oxaly] chloride (1.36g) in dichloromethane. The mixture was then kept at room temperature for 48h, washed with water (2 x 25cm3) and dried (M9S04). Filtration and evaporation afforded a red-brown syrup (3.21g). This was dissolved in ethanol (5cm3), acidified with ethanolic HCI and the solvent evaporated.

The residual gum was crystallised from ethanollethyl acetate. The crystals were recrystallised twice from 20 ethanol-ethyl acetate. The pale-yellow crystals of title compound, hydrochloride, hydrate (0.609) had m.p. 196-212'(dec).

Claims

1. A benzoquinolizine of the general formula R 1 1 R Y N 1 R 4 CO N '1.1 R 3 (1) or a pharmaceutically acceptable acid addition salt thereof, wherein R, and R2 which may be the same or different each represent hydrogen, lower alkyl, lower alkoxy or halogen, R3 represent lower alkyl and R4 40 is lower alkoxy or lower alkoxy carbonyl.

2. A compound according to Claim 1 wherein R3 is methyl.

3. MethylfN-methyl-N-(1,3,4,6,7,llba-hexahydro-2H-benzo[ajquinolizin-2pylfcarb amateoraphar- maceutically acceptable acid addition salt thereof.

4. Ethylf N-m ethyl-N -(1,3,4,6,7,11 bcx-hexa hyd ro-2H-benzo [a] q u i nol izin-2p-yl)f ca rba mate or a ph a rma- 45 ceutically acceptable acid addition salt thereof.

5. EthVIjN-methyI-N-(1,3,4,6,7,1 1 ba-hexa hyd ro-2H-benzo [a] q u i nol izi n-2p-yl)f oxa mate or a ph arma ceutically acceptable acid addition salt thereof.

6. A process for preparing a compound claimed in Claim 1 which comprises reacting a reactive deriv ative of an acid of formula R4COOH (where R4 has the meaning given in Claim 1) with a benzoquinolizine of the general formula R 1 1 R 2g N NH. R 3 GB 2 160 862 A 5 or an acid addition salt thereof (where W, R2 and R3 are as defined in Claim 1) and, if required, converting a free base into a pharmaceutically acceptable acid addition salt.

7. A process as claimed in Claim 6 wherein the reactive derivative of the acid is the acid halide or 5 anhydride.

8. A process for preparing a compound claimed in Claim 1 substantially as hereinbefore described with reference to any one of the Examples.

9. A compound whenever prepared by the process claimed in any one of the Claims 6 to 8.

10. A pharmaceutical composition comprising a compound claimed in any one of Claims 1 to 5 and 9 10 in association with a pharmaceutical ly acceptable carrier.

11. A compound as claimed in any one of Claims 1 to 5 and 9 for use in antagonising a,-adrenoceptors in warm blooded animals.

12. The use of a compound as claimed in any one of Claims 1 to 5 and 9 for the manufacture of a medicament for use as an antidepressant, in the treatment of diabetes or in inhibiting blood platelet aggregation.

Printed in the UK for HMSO, D8818935, 11 85, 7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.