IL33394A - 2-hydroxy and 2-etherified hydroxy-2,3-dihydro-5-aryl and 5-heteroaryl-1h-1,4-benzo-diazepines,processes for their preparation and pharmaceutical compositions containing them - Google Patents

Description

95 -FTE-3 SK-cm The term "lower alkyl" refers to both straight and branched^.chain saturated hydrocarbon radicals having up to six carbon atoms. Preferred are groups such as methyl, ethyl, propyl, isopropyl, n-butyl and t-butyL "Lower alkenyl" similarly refers to straight and branched-chain olefinic hydrocarbon radicals having up to six carbon atoms .and may be exemplified by 1-propenyl, 2-isopropenyl, 2-butenyl, 3-butenyl and 2-isopentenyl. The terms "lower cycloalkyl" and "lower cycloalkyl-lower alkyl" are limited similarly and may be exemplified by cyclopentyl, cyclohexyl and cyclopropylmethyl. Similarly the term "phenyl-lower alkyl" may be illustrated by phenethyl and benzyl. "Lower alkoxy" includes ether radicals wherein the lower alkyl moiety is as defined for "lower alkyl" above, such as for example, methoxy, ethoxy, propoxy and the like. "Lower alkanoyloxy" includes those acid radicals derived from alkanoic acids having up to 6 carbon atoms, and therefore comprises such radicals as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the branched-chain isomers thereof. The term "halogen" as used herein comprehends all four halogens, although, chloro is the preferred halogen species of this invention. 958-FTE- SK-cm In a preferred embodiment of this invention X is a 7-chloro substituent.

The term "polyfluoro-lower alkyl" refers to lower alkyl radicals substituted with more than one fluorine atom and includes such moieties as 2,2,2-trifluoroethyl, trifluoromethyl, 2, 2,3,3,3-penta-fluoropropyl and the like. In a preferred embodiment of this invention the polyfluoro-lower alkyl moiety has two a-hydrogen atoms, i.e. - wherein Rf is polyfluoroalkyl. Most preferably, R^. is tri-fluoromethyl, as in the 1- (2, 2, 2-trifluoroethyl) substituted compounds.

The pharmaceutically acceptable salts include those formed with both inorganic and organic acids such as hydrochloric acid, hydrobromic. acid, nitric, acid, sulfuric acid, acetic acid, formic acid, succinic acid,, jwaleic acid, p-toluenesulfonlc acid and the like. Further- ph.¾rmaooutioally acce able salt-s ago the J|-oxidOQ -of tho compounds of formula I-.

In solution the 2-hydroxy compounds of this invention can best be represented by the structure as indicated in formula II, an equilibrium existing between this 2-hydroxy form and the bridged 2,5-oxy form (III) 958-FTE-5 SK-cm (ID (in) In the solid state, the equilibrium may be in the direction of the bridged 2,5-oxy form. In any event, compounds of the formulae II and III will hereinafter be understood when the 2-hydroxy compounds of this invention are referred to. ΐΐΰ uuinpoundsof thi3 invention may be prepared according to methods known for the preparation of nr.mprmnr1<¾ hairi g a similar s ruc u e.- for the preparation of the compounds of this invention One preferred process /comprises subjecting a compound of the general formula IV (IV), - - SK-cn wherein X, R^, and R^ are as above defined^ to reduction of the keto group. The so-obtained compound of formula I having a free hydroxy group in position 2 may then, if desired, be etherified to the corresponding compound of formula I in which R). is lower A preferred embodiment of this process comprises adding a lithium aluminium hydride in a suitable inert solvent such as tetrahydrofuran or ether to the corresponding 2,3-dihydro-2-oxo-5-aryl-lH-l, -benzo- diazepine at reduced temperatures, e.g. about The reaction may be illustrated by the following reaction scheme: wherein R^ Rg, R^ and X are as previously defined, ^ is lower alkyl; and m has a value of 0, 1, 2 or 3. 958-FTE-7 SK-cm The reduction of the keto group may also be performed electrolytically or by means of an amalgam, preferably sodium amalgam, as a reducing agent.

If in the above reaction X represents a nitro group, this group will also, at least to a certain extent be attacked by the reduction. This will reduce the yield of the desired compound.

The corresponding 2-ethers can readily be prepared by reaction of the corresponding 2-hydroxy compounds of formula II with the appropriate alcohol (R^OH), alkyl or the grouping wherein n, Rr and Rg are as hereinbefore defined.

The starting compounds of general formula IV are well Imown and may for example be obtained according to the processes described in the Austrian Patent No. 275,528 and in the Belgian Patent No. 692,621.

A further possible process for the preparation of ^- - - 958-FTE-B SK-cm A further process for the preparation of the compounds ©f this invention /fl p pfpr'r'pd pmhnrl i m n o f fhi g pr-n ru- -H* comprises treating an aldehyde of formula VIII (below), with a base as illustrated in the following reaction scheme: ^ (VIII) (II) In the above ormulae R^, R^, R^ and X are as previously, defined.

A further possibility is the intramolecular condensation of a compound of the general formula X wherein R^, R≥, R^ and X are as previously defined, and L is a free amino group or a blocked amino group, such as a salified amino group, for example -NHg.HCl, benzyloxycarbonyl amino group, phthalimido group, acetamido group and the like . 958-FTE-9 SK-cm For the preparation of those compounds having an etherlfled hydroxy group in position 2, the compounds of formula II obtained above are subjected to an etherification reaction. This reaction may often be, carried out simply by dissolving the hydroxy compound in the appropriate alcohol and allowing the ether to crystallize.

The starting compounds of the general formula VIII may be prepared according to the following reaction scheme: VII wherein Rp is lower alkyl.

The conversion of the Schiff base VII into the aldehyde is effected by means of an acid, preferably a Lewis acid such as BF-, . 3 958-FTE-10 SK-cm The starting compounds of formula VIII may also be obtained by a reaction according to the following reaction scheme: The compounds of this invention may also be prepared by reacting a benzodiazapine-4-oxide of the general formula wherein R^, R^ and X are as previously defined except that R^ is desirably other than hydrogen, with a Grignard reagent of the general formula XII R^-MgHal (XII), wherein ^ is as previously defined and Hal represents a halogen atom. By hydrolysis and dehydration of the so-formed complex a compound of the general formula I is obtained.

This process may for example be performed analogously to the process described in the Belgian Patent No. 711 09· 19 9-0CT-20 958-FTE-12 SK-cm The following examples illustrate the preparation of representative compounds of this invention: Example 1 Preparation of 7-chloro-l- (2, 2, 2-trifluoroethyl) -2 hydroxy-2, ~dihydro-5-phenyl-lH-l, 4-benzodiazeplne 0.64 Grams (0.017 moles) lithium aluminium hydride are added to a stirred solution of 5.6 grams (0.016 mole) of 7-chloro-l-- (2 2, 2-trifluoroethyl) -1,3-dihydro-2-oxo-5-phenyl--2H-l, 4-benzodiazeplne in 80 ml. of dry tetrahydrofuran cooled to 0°C. After the addition is completed, the mixture is stirred a further 5 minutes, and then quenched with wet ether. The solution is filtered, dried over sodium sulfate, and concentrated under reduced pressure. triturated with a small amount of hexane and J.O grams of the title compound in the form of white needles (m.p. 130-131°C.) are collected.

If in the above Example 1- (2, 2, 2-trifluoroethyl) -1,3-dihydro-2-oxo~5-phenyl-2H~l 4-benzodiazepine is used as a starting compound the 1- (2, 2, 2-trifluoroethyl) -2-hydroxy-2,3-dihydro-5-pheny1-1H-1, 4-benzodiazepine is obtained. (M.p. 123°C.-125°C . ) 958-FTE-13 SK-cm Example 2 Preparation of 7-chloro-l- (2, 2, 2-trifluoroethyl) -2- methoxy-2,3--^ihydro-»5-phenyi-lH-l,^benzodiazepine 2.5 Grams (0.0071 moles) of 7-chloro-l- (2, 2, 2-tri-fluoroethyl) -2-hydroxy-2J3-dlhydro-5-phenyl-lH-l54-benzodiazepine are dissolved In 10 ml. methanol and allowed to stand at 0°C. until crystallization occurs. 2.2 Grams of the title compound (m.p. l45°C-146°C.) are collected.

If in the above Example the methanol is replaced by ethanolj, the corresponding 2-ethoxy compound is obtained (m.p. 135°C-136°C . ) Example 3 Preparation of 7-chlor6-l~methyl-2-hydroxy-2,3- dihydro-5-phenyl-lH-l, 4-benzodiazepine 1.2 Grams (0.032 mole) of lithium aluminium hydride are added to a stirred solution of 7-0 grams (0.025 mole) of 7-chloro-l>3-dihydro-l-methyl-2-oxo-5-phenyl-2H-li -benzodiazepine in 150 ml. of dry tetrahydrofuran cooled to 0°C. After the addition is completed, the mixture is stirred a further 5 minutes, and then quenched 953-FTE-14 SK~cm with wet ether. The solution is filtered, dried over sodium sulfate, and concentrated under reduced pressure. The mixture is then triturated with e'ther-petroleum ether and 2.8 grams of the title compound (m.p. 125°C . -126°C . ) are collected.

Similarly, one can prepare other compounds of this invention by substituting the corresponding 1, -dihydro 2-oxo-5-aryl-2H-l, ^-benzodiazepine of formula IV to produce the desired 2-hydroxy-2, -dihydro-5-aryl-lH-1, 4-benzodiazepine, as for example: 1- (2, 2, 2-trifluoroethyl) -2-hydroxy-2,3- dihydro-5-phenyl-lH-l, 4-benzodiazeplne-; 7-chloro-l~ (2, 2, 2-trifluoroethyl) -2-hydroxy~ 2,3-dihydro-5- (2-pyrryl) -lH-1, 4-benzodiazepine; 7-chloro-l-diethylaminoeth l-2-hydroxy-5- ( ο-ί' luoi ophenyl) (¾KxiHaKapk3QX^ik) -2,3-dihydro-lH-l, ^-benzodiazepine 6-trifluoromethyl-1- (2-isopentenyl) -2,3-dihydro- 2-hydroxy-3-methyl-5- p_-chlorophenyl) -lH-1, 4- benzodiazepine ; 7-nitro-l-trifluoromethyl-2-hydroxy-2,3- dihydro-5- (p_-tolyl) -lH-1, 4-benzodiazepine; 1- (2, 2, 2-trifluoroethyl) -2-hydroxy-2,3- dihydro-5-phenyl-lH-l, 4-benzodiazepine; 7-hydroxy-1-isopropyl-2-hydroxy-2,3-dihydro- p-hydroxyphenyl - (jo phono1) -lH-1, 4-benzodiazepine; - SK-cm 7-methoxy-l-allyl-2-hydroxy-2,3-dihydro- 5- (1-naphthyl) -1H-.1, 4-benzodiazepine; 8-bromo-l- (1, 2, 2, 2-tetrafluoroethyl) -2- hydroxy-2J3-dihydro-3-acetoxy-5- (2-thienyl) - lH-1, 4-benzodiazepine; 9-fluoro-l-pheneth l-2-hydroxy-2i3-dihydro- 5- (m-nitrophenyl) -lH-1, 4-benzodiazepine; By reaction with the appropriate alcohol (e.g. methanol, ethanol, dimethylaminoethanol etc.) one can similarly produce the corresponding ethers, as for example: 7-chloro-l-cyclopropylmethyl-2-methoxy-2,3- dihydro-5-phenyl-lH-l, 4-benzodiazepine; 7-chloro-l-methyl-2-methoxy-2,3-dihydro-5- phenyl-lH-1, -benzodiazepine; 7-chloro^l-methyl-2-ethoxy-3-acetoxy-2i3- dihydro-5-phenyl-lH-l, -benzodiazepine; 7-chloro-l-methyl-2- (2-N,N-dimethylaminoethoxy) - 2,3-dihydro~5-phenyl-.lH-li 4-benzodiazepine; o-metho y heny1 1, 8-dimethyl-2-ethoxy-2,3-dihydro-5- (^-aiiisole) - lH-1, 4-benzodiazepine; 8-isopropoxy-l-methyl-3-Pr>opionyloxy-2J,3- -phenyl dihydro-5- (jD-trifluoromethyl)-lH-l, 4-benzodiazepine; l-methyl-2- ( -aminopropoxy) -2, 3-dihydro-5- (o- fluorophenyl) -lH-1, 4-benzodiazepine . - - 958-FTE-16 SK-cm Example 4 Preparation of 7-chloro-l- (2, 2, 2-trlfluoroethyl) -2- hydroxy-2,3-dihydro-5-phenyl-lH-l, 4-benzodiazepine A mixture of 3.1 grams (0.01 mole) of 2- (2, , 2-tri- fluoroethylamino) -5-chlorobenzophenone and 25 ml. of arninoacetaldehyde dimethyl acetal is refluxed for 3 hours. The mixture is cooled,, poured onto water, and the material that separates is collected. This material is added to 50 ml. of 0.1N hydrochloric acid and the mixture is basified with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform layer is dried and evaporated almost to dryness. It is then triturated with a small amount of hexane and the product collected, m.p. 130°C . -131°C . - - 958-FTE-17 SK-cm The tangible embodiments of this invention exert an effect on the mammalian central nervous system as determined by standard pharmacological evaluation aid as such are useful as tranquillizer or anti- 958-FTE-18 SK-cm anxiety agents. Additionally they exhibit valuable anti-convulsant and muscle relaxant properties. In pharmacological testing there has been observed significant differentials between tranquillizing and muscle-relaxing doses and doses which cause neurological impairment, e.g. ataxia. The therapeutic ratio, is generally higher in the compounds of this invention than that observed in analogous compounds presently known in the art. By way of further advantage, it has been found that test animals do not develop a tolerance to the tangible embodiments on repeated treatment in anti-convulsant evaluation.

The compounds of this invention have greater water solubility than their corresponding 2-oxo-precursors . They have a more favourable distribution constant between organic and aqueous layers. This factor is important in effecting greater absorption into the mammalian blood stream when orally administered.

Based upon standard laboratory investigative procedures such as the Antagonism of Pentylene Tetrazole, Everett and Richard, J. Pharm. and Exp. Ther., Vol. 8l, pg. 402 (19 ) and Antagonism of Maximal Electro-Shock-Induced seizures in Mice Synward, E. A. et al., 958-FTE-19 SK-cm J. Pharm. and Exp. Ther., Vol. 106, pg. 519 (1952) for anti-convulsant activity, the Central Nervous System Activity and Acute Toxicity, Irwin, Science 136, pg. 123 (1962) for muscle relaxant and sedative-hypnotic activities, and Antagonism of Foot-Shock Induced Fighting in Mice, Tedeschi, et al., J. Pharm. and Exp. Ther., Vol. 125, pg. 28 (1959) and Taming Activity in Monkeys, Randall, Diseases of the Nervous System, Vol. 21, pg. 7 (I960) for anti-anxiety activity, it is found that when used as an antianxiety agent the dosage range is about 0.1-5 mg/kg. of body weight per day, preferably administered orally in divided dosages. When used as an anticonvulsant the dosage range is about 2-30 mg/kg. of body weight per day, preferably orally administered in divided doses. When used as a muscle relaxant the dosage range is about 0.1-1.5 mg/kg. of body weight per day, preferably orally administered in divided doses. When used as a sedative-hypnotic the dosage range is about 3-10 mg/kg. of body weight preferably orally administered in a single dose.

The compounds of this invention may be administered aloie or combined with other medicaments. In any event, a suitable pharmaceutically acceptable carrier is generally employed. A carrier is selected accord - - 958~FTE-aO SK-cm as according to the physical properties of the compounds and standard pharmaceutical practice. It should not react chemically with the compound to be administered. In a preferred embodiment the compositions of this invention are administered orally, although parenteral and topical administration are also contemplated. The preparations containing the active ingredients of this invention may be in the form of tablets, capsules, syrups, elixirs, suspensions, ointments, creams and the like.

In the formulations of pharmaceutical preparations there can be employed such pharmaceutically acceptable diluents, as for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, gums and petroleum jelly.

The following examples show typical tablet and capsule formulations incorporating the tangible embodiments of this invention. The formulations are illustrative merely and no limitation is intended. 958-FTE-21 SK-cm Tablet Formulations I. Formula and Method of Manufacture for 7-chloro 1- (2, 2, 2-trifluoroethyl) -2-hydroxy-2,3-dihydro-5-phenyl lH-1, 4-benzodiazepine Coated Tablets; mg/core fluoroethyl) - -5-phenyl-- 100.0 lH-lj, ^-benzodiazepine Lactose, USP 123-0 Dicalcium Phosphate 70.0 Sodium Lauryl Sulfate 15.0 Polyvinylpyrrolidone 15.0 Water 50 ml/1000 cores Corn Starch 30.0 Dry_ Sodium Lauryl Sulfate -0 Magnesium Stearate 3.0 Tablet Weight 359-0 Procedure ; The 7~chloro~l- (2, 2, 2-trifluoroethyl) -2-hydroxy-2J> dihydro-5-phenyl-lH-l, -benzodiazepine is mixed with the lactose, dicalcium phosphate, and sodium lauryl SK-cm sulfate. The above mixture Is screened through a No. 60 screen and granulated with an aqueous solution containing polyvinylpyrrolidone. Add additional water, if necessary, to bring powders to a pasty mass. Add corn starch and continue mixing until uniform granules are formed. Pass through a No. 10 screen, tray and dry in oven at 100°C. for 12 to 1 hours. Reduce dried granulation through a No . 16 screen, add sodium lauryl sulfate and magnesium sulfate, mix and compress into desired shape on a table machine.

Coating: The above cores are treated with a lacquer and dusted with talc to prevent moisture absorption. Sub-coat layers are added to round out the core. A sufficient number of lacquer coats are applied to make the core enteric. Additional sub-coa.ts and smoothing coats are applied to completely round out and smooth the tablet. Colour coats are applied until desired shade is obtained. After drying the coated tablets are polished to give the tablets an even gloss. 958-FTE-23 SK-cra II. Capsule Formulations Formula: mg/capsule 7- Chloro-1- (2, 2, 2-trifluoroethyl) - 2-hydroxy-2,3-dihydro-5-phenyl-lH- 100.0 1, -benzodiazepine Sodium Lauryl Sulfate 20.0 Lactose 279.0 Magnesium Stearate 101.0 Capsule Weight 500.0 Procedure : Mix together 7~chloro-l- (2, 2, 2-trifluoroethyl) -2-hydrpxy-2, 3-dihydro-5-phenyl-lH-l, - enzodiazepine, sodium lauryl sulfate and lactose. Pass through a No. 8o screen. Add magnesium stearate, mix and encapsulate into the proper size 2 piece gelatin capsule .

III· Suppository Formula; mg/2 gs. 7-Chloro-l- (2, , 2-trifluoroethyl) - 2-hydroxy-2J,-3-dihydro-5-phenyl-lH- 100 1, -benzodiazepine, microriized Theobroma Oil, Pharm. Grade to c* make Method of Preparation; J Prepare a slurry of the 7-chloro-l- (2, 2, 2-tri luoroethyl) -2-hydroxy-2,3-dihydro-5-phenyl-lH~lji -benzo- - - SK-cm In particular, other active ingredients within the definition*) to bring the batch to final weight./ Pour the melted mix, while maintaining uniformity, into appropriately prepared molds and allow to cool. j Numerous variations of the above compositions of matter and processes for the manufacture will be apparent to one skilled in the art within the spirit of the present invention. *)of the invention may be substituted for the active ingredients specified in formulations I to III. 33394 Prior Art Acknowledgement "In Dutch Patent Application No. 6,6l ,92j5 there are disclosed specified l-unsubstituted-2, 3-dihydro-5-aryl-lH-l, -benzodiazepines substituted in the 2-position by a range of substituents including, inter alia, 2-hydroxy and 2-etherified hydroxy substituents The specified compounds are stated therein to be useful as anticonvulsant agents and muscle relaxants. 2&

Claims (2)

1. 33394 958 Israel August- 50, 1972 ED/jrn We claim: 1. 1, -Benzodiazepines of the general formula I the ^-oxidee /and pharmaceutically ' acceptable salts thereof wherein X is hydrogen, halogen, trifluoromethyl, nitro, lower alkyl, hydroxy or lower alkoxy; is lower alkyl, polyfluoro-lower alkyl, phenyl-lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, lower alkenyl or amirio-low,er alkyl the amino group of which may be mono- or disubstituted by lower alkyl groups; Rg is hydrogen, lower alkyl, hydroxy or lower alkanoyloxy; R, is phenyl, X-substituted phenyl, naphthyl, thienyl 0r pyrryl; and R^ is hydrogen, lower alkyl, or the grouping -OT2.C¾.(OT2)n.N 3 n ±s Q qv ± R6 and Rp. and Rg are hydrogen or lower alkyl.

2. Compounds according to claim 1, wherein R^ is polyfluoro-lower alkyl. Compounds according to claim 1 or 2, wherein Rn is 2,2,2-trifluoroethyl. 4. Compounds according to claim 1, wherein is methyl. 5. Compounds according to any one of claims 1 to , wherein X is a 7-chloro-substituent . 6. Compounds according to any one of- claims 1 to 5* wherein is phenyl. 7. Compounds according to any one of claims 1 to 6, wherein is methyl. 8. 7-Chloro-l- [2, 2, 2-trifluoroethyl )-2-hydroxy-2, 3-dihydro-5-phenyl-lH-l, 4-benzodiazepine. 9. 7-Chloro-l-methyl-2-hydroxy-2, 3-dihydro-5~ phenyl-lH-1, 4-benzodiazepine. 10. 7-Chloro-l-(2,2,2-trifluoroethyl-2-methoxy-2, 3-dihydro-5-phenyl-lH-l, -benzodiazepine. 11. 7-Chloro-l-methyl-2-methoxy-2J3-»dihydro-5-phenyl-lH-l,4-benzodiazepine. 12. Process for the preparation of the 1, -benzodiazepine compounds claimed in claim 1 characterised in that a compound of the general formula VIII wherein R^, Rg, R^ and X are as defined in claim 1, is treated with a base whereby the ring is closed and a 2-hydroxy compound of formula I is obtained; that for the preparation of those compounds of for¬ compound obtained by any of the previous steps is transformed into a pharmaceutically acceptable salt. 15· Process for the preparation of the 1, -benzo-diazepine compounds claimed in claim 1, characterised a in that/ compound of the general formula X wherein R^, R2, R · and X are as defined in claim 1, and L is a free or protected amino group, is subjected to an intramolecular condensation whereby a 2-hydroxy compound of formula I is obtained; that for the preparation of those compounds of formula I in which the 2-hydroxy compound is etherified accordingly; and that, if desired, a compound obtained by any of the previous steps is transformed into a pharmaceutically acceptable salt. 14. Process for the preparation of the 1, -benzo-diazepine compounds claimed in claim 1, characterised in that a compound of the general formula IV wherein R, , R , R-. and X are as defined in claim 1, 1 2 ^ is reduced at the keto group:, whereby a 2-hydroxy compound of formula I is obtained; that for the preparation of those compounds of formula I in which Rj. is lower alkyl or the grouping -CH .CHp. (CH ) .N< 33394-2 the 2-hydroxy compound is etherified accordingly, and that, if desired, the compound obtained by any of the previous steps is transformed into a pharmaceutically acceptable salt. 15. Process according to claim 14, characterised in that the reduction is performed by means of a complex metal hydride. 16. Process according to claim 15, characterised in that the reduction is performed by means of a complex rnetal hydride with the general formula wherein is lower alkyl and m is 0, 1, 2 or 3* 17. · Process according to claim 1β, characterised in that the reduction is performed by means of LiAlH^, in a suitable inert solvent and added to the 2-keto compound at reduced temperature. 18. Process according to claim 14, characterised in that the reduction is performed electrolyticaily. 19. Process according to claim 14, characterised in that the reduction is performed by means of an amalgam. 20. Process according to claim 1 , characterised in that the reduction is performed by means of sodium amalgam. 21. Process for the preparation of the 1, -benzo-diazepine compounds claimed in claim 1, characterised in that a compound of the general formula XI wherein R-^, g, R^ and X are as defined in claim 1, is reacted with a Grlgnard reagent of the general formula XII R^-MgHal (XII), wherein R, is as defined in claim 1 and Hal represents a halogen atom; that the so-formed complex is hydrolysed and dehydrated to a compound of general formula I; and that, if desired, the compound obtained is transformed into a pharmaceutically acceptable salt. 22. 1, -Benzodiazepines having the general formula I and the salts thereof, when prepared by a process according to any one of claims 12 to 21. 25. A therapeutical composition comprising a compound as defined in any one of claims 1 to 11 and 22, as an active ingredient in admixture with a suitable therapeutical carrier. 24. A composition according to claim 2j5> in the form of a solid shaped dosage unit. 25. A composition according to claim 24, wherein the dosage unit is a tablet. 26. A composition according to claim 24, wherein the dosage unit is a capsule. 27. A composition according to claim 25 in the form of a liquid solution or suspension. 28. A composition according to claim 27, wherein the liquid is sterile, for use as an injectable. 29. Process for the preparation of a therapeutical composition- characterised in that a compound as defined in any one of claims 1 to 11 and 22 is brought into a form suitable for therapeutical administration. oo 4~2> JO. Process according to claim 29, characterised in that a compound as defined in any one of claims 1 to 11 and 22 is admixed with a suitable therapeutical carrier. 31. A therapeutical composition when prepared by the process of claim 29 or claim >0, Attorneys for Applicant