GB1586249A

GB1586249A - Aminoalkyl-bicycloheptanes

Info

Publication number: GB1586249A
Application number: GB45628/76A
Authority: GB
Original assignee: Lilly Industries Ltd
Current assignee: Lilly Industries Ltd
Priority date: 1977-11-01
Filing date: 1977-11-01
Publication date: 1981-03-18

Description

(54) AMINOALKYL-BICYCLOHEPTANES (71) We, LILLY INDUSTRIES LIMITED, a British company of Henrietta House, Henrietta Place, London, W.1., do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a novel class of 2-arylbicycloheptane derivatives having useful central nervous system activity, to methods of preparing such derivatives and to pharmaceutical compositions including them.

In the Applicants' W. German Offenlegungsschrift No. 2,354,931 there is described and claimed in class of trans-2-phenylbicyclooctane derivatives which have activity in the central nervous system. United States Patent Specification Nos.

3,308,160 and 3,362,878 also disclose bicyclooctanes having central nervous system activity.

According to the present invention there is provided a cis-arylbicyclo[2,2, 1] heptylamine of formula (I):

or a pharmaceutically-acceptable salt thereof, wherein Ar represents a phenyl group optionally substituted by one or more substituents selected from halogen, trifluoromethyl, nitro C25 alkylamino, amino, mono or di-C1.4 alkylamino, C 1.4 alkyl, C1.4 alkoxy and C1.3 alkylene dioxy,Ar being attached at the 2- or 3- position of the bicyclo[2,2,1] heptyl nucleus, and wherein the(CH2)nNR1R2 group, in which n is an integer from 1 to 3,.R' is C1.4 alkyl and R2 is hydrogen or C14 alkyl, is attached at the 3- or 2- position of the bicyclo[2,2,1] heptyl nucleus. Preferably the optional substituent in Ar is halogen. Advantageously Ar has up to two substituents.

Those skilled in the art will appreciate that the cis-arylbicyclo [2,2,1 ]heptylamines of formula (I) may exist in both the exo-form (atom numbered 7 lying below the plane of the representation of formula (I) above) and the endo-form (atom numbered 7 lying above the plane of the representation of formula (I) above). It will also readily be appreciated that there are two enantiomeric forms of both the exo-and endo-forms of the compounds of formula (I). It is to be clearly understood that the invention extends to the exo- and endo-forms and to mixtures thereof, and to the (+) and (-) forms, and non-racemic mixtures of the (+) and (-) forms, as well as to the racemic mixtures of the exo-and en do-forms.

Compounds of formula (I) may also be designated by the formula II: R(CH2)nNR1R2 (11) wherein R is a group of formula (III)

wherein, Ar, is as defined above and is attached at the 2- or 3- position of the bicyclo[2,2,l]heptyl nucleus, the group (CH2)nNR1R2 in formula (II) being as defined above and being attached at the 3- or 2-position of the group of formula (III).

Preferred compounds of formula (I) are those having one or more of the following features: (a) n is 1; (b) R1 is C13 alkyl and R2 is hydrogen, methyl or ethyl; (c) R1 and R2 are the same or different C13 alkyl groups; (d) R1 and R2 are methyl; (e) Ar is phenyl singly or doubly substituted by halogen; (f) Ar is a p-chlorophenyl group; (g) Ar is 3,4-dichlorophenyl; or (h) the compound of formula (I) is a cis-endo-arylbicyclo [2,2,1] heptylamine.

For the avoidance of doubt, the term "C1~4 alkyl" as used herein, whether explicitly or implicitly, as in the term "C2B alkanoyl amino", is intended to encompass any straight or branched chain alkyl group having from 1 to 4 carbon atoms. Thus R1 and/or R2 may be a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl group. Similarly, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

Presently preferred compounds of the invention are: cis-endo-phenyl-3-N,N-dimethylaminomethyl-bicyclo[2,2,1]heptane; cis-endo-2-p-chlorophenyl-3-N,N-dimethylaminomethyl-bicyclo[2,2,1]heptane cis-endo - 3 - (3,4 - dichlorophenyl) - 2 - N,N dimethylaminomethylbicyclo[2,2, I] heptane; cis - exo - 3 - (3,4 - dichlorophenyl) - 2 - N,N - dimethylamino methylbicyclo[2,2,1]heptane; and their hydrochloride addition salts.

The compounds of formula (I) may be prepared by any of the normal methods for preparing substituted alkyl amines.

According to one aspect of the present invention there is provided a method of preparing a compound of formula (I), or an acid-addition salt thereof, which comprises (A) reducing: (i) a compound of formula (V): R(CH2)rnZ (V) where m is 0, 1 or 2 and Z is -CONR1 R2, -CH=NR1 or-C(OR)=NR; or (ii) an olefin of formula (VI):

where R5 and R6 taken together represent a single bond or independently represent hydrogen atoms and R7 and RB taken together represent a single bond or, when R5 and RB taken together represent a single bond, independently represent hydrogen atoms, and where one of R9 and R10 is -(CH2)nNR1R2 and the other of R9 and R10 is Ar: (B) alkylating a compound of formula (VII): R(CH2)nNHR21 (VII) or (C) condensing an amine of formula: HNR1R2 with a compound of formula (VIII): R(CH2)nQ (VIII) where Q is a leaving group; optionally followed by (D) resolution of the product of formula (I) formed in reaction (A), (B) or (C); into its (+) or (-) enantiomeric form.

The preferred methods of preparation according to the present invention involve the use of an intermediate of formula (IX): R(CH2)rnZ' (IX) where m is as defined above, i.e. n-l, and Z' represents Z or -CHO, -CN, COCL, CONH2, -CH2NCO or -COOR11 where R11 is C14 alkyl, which may, if convenient, be reacted in situ in the reaction medium in which it is formed.

Use of the nitrile intermediate is much preferred since the cis-nitrile is thermally stable and the nitrile group is a good activating group in the Diels-Alder reaction by which this class of intermediates is prepared.

The compounds of formula (IX) are readily converted to compounds of formula (I), or primary amino analogues thereof by reduction. In the case of the nitriles and amides of formula (IX), the reduction is preferably carried out using a complex hydride reducing agent such as lithium aluminium hydride or sodium borohydride, whilst in the case of the isocyanates of formula (IX), treatment with a concentrated mineral acid such as hydrochloric acid produces the desired conversion. The aldehydes and esters of formula (IX) may be reductively aminated to the desired compounds of formula (I) by reduction to the corresponding alcohols, for example using a complex hydride reducing agent, conversion of the alcohols to the corresponding alkyl or aryl sulphonates (by reaction with an alkyl or aryl sulphonyl chloride such as methyl sulphonyl chloride or p-toluene sulphonyl chloride) and reaction of the sulphonates with an amine of formula HNR1R2.

Reductive amination of the aldehydes of formula (IX) may also be carried out by catalytic hydrogenation in the presence of ammonia or an amine of formula HNR1 R2.

Alternatively, compounds of formula (IX) where Z' is -CHO may be condensed directly with an amine to give the corresponding Schiffs base which can be reduced with a complex hydride, preferably sodium borohydride, to give a compound of formula (I) in which R2 is hydrogen.

Where Z' is -CN, -CONH2 or CH2NCO, or the above-mentioned reductive amination is carried out in the presence of ammonia, the resultant product is a primary amine of formula R(CH2)n NH2 which can then be alkylated to produce a compound of formula (I) in which R1 and/or R2 is C14 alkyl. The alkylation may be carried out in conventional manner, for example by reductive alkylation reaction with an alkyl halide or sulphate, reaction with an alkyl chloroformate followed by reduction of the resultant urethane or, when methylation is to be carried out, by reaction with formic acid/formaldehyde. Similarly, monoalkylated products of formula (I), i.e. compounds of formula (I) where R2 is hydrogen, can be alkylated to form dialkylated products of formula (I) where R2 is C14 alkyl.

In the case where Z' is CN, the compound of formula (I) in which R1 is hydrogen and R2 is C14 alkyl can be obtained by treatment with the corresponding oxonium salt followed by addition of the corresponding alcohol and reduction with sodium borohydride (see J. Org. Chem. 34, 627 (1969)).

This reaction may be schematically illustrated:

R- (CH2 )CN di C14 alko > :ycarbonium fluoroborate (+) R- ( CH2 ) C=N-R RloH (CH2 )C=N1HR1 OR NaBH4 R-(CH2) NHR1 The above intermediates of formula (IX), are novel.

They may be obtained from the nitrile of formula (X) according to the following reaction sequences, in which R, R1, R2, and R11 are as defined above.

wherein one of R12 and R13 is -CN, the other of R12 and R13 being Ar. Where R5 and R6 are cis-hydrogen atoms, the cis-6-phenylbicyclo[2,2,l]hept-2-ene-5- carbonitrile of formula (X) can be prepared by a Diels-Alder reaction between the appropriate cis-cinnamonitrile and 1 ,3-cyclopentadiene. The cis-cinnamonitrile may be prepared by the route described in J. Pharm. Sci., 54, 1110 (1965) or by decarboxylation of the corresponding benzalcyanoacetic acid.

When R5 and RB represent a single bond, the nitrile of formula (X) may be prepared from the corresponding aldehyde of formula (XI):

where one of R14 and R'5 is -CHO, the other of R14 and Rls being Ar, by reaction with hydroxylamine followed by dehydration of the oxime thus formed with any suitable dehydrating agent, for example P2Os or cyanuric chloride.

Alternatively, and preferably, the aldehyde of formula (XI) is directly converted to the acid of formula RCOOH by selective hydrogenation followed by the treatment of the partially reduced aldehyde with Jones Reagent (Na2Cr2O7/H2SO4).

The aldehyde of formula (XI) may be prepared by a Diels-Alder reaction between the appropriate phenyl propargyl aldehyde and 1,3-cyclopentadiene.

Reaction A above involves the reduction of the compound of formula (X) using, for example, hydrogen in the presence of a suitable catalyst such as palladium on charcoal, to produce the nitrile of formula (IX) in which m is 0.

Clearly, when R5 and R6 represent a single bond, selective hydrogenation must be employed, the reaction being stopped after uptake of one mole of hydrogen.

Reaction B is accomplished by hydrolysis as is well known in the art and the resultant carboxylic acid may then be converted to the corresponding acid chloride reaction D--in conventional manner, for example, by reaction with thionyl chloride. The latter may then be converted by the Arndt-Eistert synthesisreaction F-to a substituted acetic acid and, by repetition of reactions D and F, the correspondingly substituted propionic and butyric acid may be obtained. The aforementioned substituted propionic acid may also be prepared from the aldehyde R-CHO by reactions I and J, reaction I being the well-known Knoevenagel reaction to produce a 3-substituted acrylic acid and reaction J involving the reduction of the acrylic acid using, for example, hydrogen over a palladium catalyst to produce the desired propionic acid.

By reaction C, the aforementioned carboxylic acid, substituted acetic acid or substituted propionic acid may be converted to the corresponding nitriles of formula (IX) in which m is 0, 1 or 2. Reaction C may be carried out by treatment of the acid with ammonia at elevated temperatures in the presence of alumina.

The acid chlorides produced by reaction D above are readily converted reaction E-to the desired amides of formula (IX) by reaction with the appropriate amine of formula HNR'R2. Additionally, by reduction of substituted acetyl and propionyl chlorides produced above-reaction G--the required aldehydes of formula (IX) in which m is 1 or 2 may be obtained. The well known Rosenmund reaction provides one means of accomplishing this reduction.

The above-mentioned substituted acetic, propionic and butyric acids may also be converted-reaction H-to the desired isocyanates of formula (IX) in which m is 0, 1 or 2. This conversion may be accomplished by forming the corresponding acid azide either by treatment of the corresponding acid chloride with sodium azide or by formation of the corresponding acid hydrazide and treatment of the latter with nitrous acid, and then heating the acid azide in benzene or chloroform solution.

Reaction K involves the conventional esterification of the corresponding acid, for example, by reaction with an alcohol R11-OH. The esters of formula (IX) in which m is 0 can also be prepared by the following reaction sequence:

where one of R16 and R17 is -COOR11, the other of R16 and R17 being Ar, wherein reaction A is as described above, the compound of formula (IX) being obtained by a Diels-Alder reaction between the appropriate cis-cinnamonitrile and 1,3cyclopentadiene, followed by hydrolysis and subsequent esterification. The resultant ester may then be hydrolysed-reaction L-to yield the corresponding acid.

Reaction M can be accomplished by the well-known Rosenmund reduction.

As stated above, reaction A involves reduction, for example by means of catalytic hydrogenation, and it will therefore be appreciated by those skilled in the art that, if Ar is substituted with a nitro group, the latter may be partially or entirely reduced to the corresponding amino substituted product. Accordingly, if a nitro substituted end product is desired, the appropriate intermediate of formula (IX) is preferably obtained by nitration after reaction A has been carried out and the subsequent conversion of the nitrated intermediate to the desired compound of formula (I) carried out under conditions which will not reduce the nitro substituent.

The compounds of formula (I) may also be prepared by the reduction of an olefin of formula VI as hereinbefore defined.

This reduction may be effected using hydrogen over a catalyst such as a group VIII metal, for example, platinum or palladium. The catalyst may be supported on an inert carrier, for example charcoal. To carry out the reaction the unsaturated compound of formula (VI) may be dissolved in a suitable inert solvent, for example ethanol or ethyl acetate. When it is desired to form a compound of formula (I) in which R5 and RB represent a single bond, selective hydrogenation of the R7/R8 olefinic group must be accomplished.

Compounds of formula (VI) are novel. They may be prepared from compounds of formula (XIII):

where one of RIB and R'9 is Z' and the other of R'8 and R19 is Ar, where R7 and R8 are as defined for formula. (VI) and wherein Z' is -CHO, CO2 H, CO2R11 or CN by any of the methods described above for converting the same Z' groups, in the compound of formula (IX) to -NR1R2, provided, of course, that such manipulations do not destroy the unsaturated nature of the bicycloheptene moiety.

Compounds of formula (XIII) in which R5 and R6 taken together represent a single bond, R7 and RB represent hydrogen atom and Z' represents an aldehyde group may be prepared: 1. By a Diels-Alder reaction between the appropriate trans-cinnamaldehyde and 1,3-cyclopentadiene followed by catalytic reduction, bromination with cupric bromide, and subsequent dehydrobromination, preferably with a lithium chloridelithium carbonate mixture; or 2. By a Diels-Alder reaction between the appropriate phenyl propargyl aldehyde and 1,3-cyclopentadiene followed by catalytic reduction.

Compounds of formula (XIII) where R7 and R8 taken together represent a single bond and Z' is CHO may be prepared by a Dield-Alder reaction between 1,3cyclopentadiene and an aldehyde of formula ArR4C=CR3CHO.

The acid, acid chloride, ester and nitrile analogues may be similarly prepared using appropriate modifications of the above synthetic procedures. Preparation of the compounds of formula (XIII) in which R7 and R8 represent a single bond, R5 and R6 represent cis-hydrogen atoms and Z' is nitrile, has already been described hereinabove. Such compounds can be converted into the corresponding acid, ester derivatives, etc., by the methods indicated previously for the compound of formula (X) except, of course, that the reduction step A should be omitted.

A further method of preparing the amines of formula (I) involves the condensation of a compound of formula (VIII): R(CH2)nQ (VIII) where Q is a leaving group, being a reactive atom such as a halogen atom, e.g. an iodine atom, or a reactive group such as a sulphonate, e.g. mesyl or tosyl, group, with an amine of formula: HNR'R2 where R, R' and R2 are as defined above.

The above type of reaction is well-known in the art and any skilled art worker will immediately appreciate the nature of the reaction conditions necessary to effect the reaction and the identity of suitable Q radicals. However, in passing, it may be mentioned that since the reaction proceeds with elimination of HQ, presence of a proton acceptor such as a base is advisable. If desired, the reaction may be carried out in the presence of a suitable solvent such as methylenedichloride or dimethyl sulphoxide.

The compounds of formula (VIII) may be derived from the corresponding alcohols of formula (XIV): R(CH2)nOH (XIV) For example, to obtain a compound of formula (VIII) is which Q is chlorine, the above alcohol may be reacted with phosphorous pentachloride or oxychloride, and to obtain such a compound in which Q is tosyl or mesyl, the alcohol may be reacted with p-toluene sulphonyl chloride or methyl sulphonyl chloride.

The alcohols of formula (XIV) may be derived from aldehydes of formula: R(CH2)mCHO by reduction using an alkali metal borohydride such a sodium borohydride or lithium aluminium hydride.

The intermediates of formula (VIII) and (XIV) are novel compounds.

It will also be appreciated by those skilled in the art that a resultant compound of formula (I) in which Ar is substituted by an amino group can be converted to other compounds of formula (I) is conventional manner. Thus, the amino susbsituted compound may be acylated to produce a desired product of formula (I) in which Ar is substituted by a C2B alkanoylamino group, or mono- or di-alkylated to produce a desired compound in which Ar is substituted by a mono- or di-C14 alkylamino group. Further the amino substituted product may be diazotized and the resultant diazonium salt converted to a variety of other products, for example by decomposition in an alcohol to yield the corresponding C14 alkoxy substituted compound or by reaction with a cuprous halide to yield the corresponding halo substituted compound of formula (I).

The compounds of formula (I) produced by the foregoing processes may be isolated per se or in acid-addition salt form.

The acid-addition salts are preferably the pharmaceutically acceptable, nontoxic addition salts with suitable acids, such as those with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, nicotinic or isonicotinic acid, or organic sulphonic acids for example methane sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid. Apart from pharmaceutically acceptable acidaddition salts, other salts are also included within the scope of acid-addition salts such as, for example, those with picric or oxalic acid; they may serve as intermediates in the purification of the compounds or in the preparation of other, for example pharmaceutically acceptable, acid-addition salts, or are useful for identification, characterization or purification of the bases.

A resulting acid-addition salt may be converted into the free compound according to known methods, for example by treating it with a base, such as with a metal hydroxide or alkoxide, for example an alkali metal or alkaline earth metal hydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; with a metal carbonate, such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate, for example sodium, potassium or calcium carbonate or hydrogen carbonate; with ammonia; or with a hydroxyl ion exchange preparation, or with any other suitable reagent.

A resulting acid-addition salt may also be converted into another acid-addition salt according to known methods; for example, a salt with an inorganic acid may be treated with a metal salt, for example a sodium, barium or silver salt, of an acid in a suitable diluent, in which a resulting inorganic salt is insoluble and is thus removed from the reaction medium. An acid-addition salt may also be converted into another acid-addition salt by treatment with an anion exchange preparation.

As stated previously, when R5 and RB represent cis-hydrogen atoms, the compounds of formula (I) may exist in two enantiomeric forms. Although the racemate possesses antidepressant activity in its own right, in certain circumstances it may be desirable to resolve the racemate into its dextrorotatory (+) and laevorotatory (-) forms. The resolution may be effected by any method conventionally used in the resolution of optically active bases, such as by reaction with optically active acids of known stereochemistry, followed by fracfional crystallisation of the salts formed. Suitable optically active acids which may be mentioned are (+) or (-) tartaric, malic, mandelic or camphor sulphonic acid, use of the latter acid being preferred.

The compounds of formula (I), and pharmaceutically-acceptable acid-addition salts thereof, possess antidepressant activity and hence are useful for the treatment of various depressive states in mammals. Their usefulness has been demonstrated in well-known test procedures such as antagonism of reserpine hypothermia in mice and inhibition of re-uptake of noradrenaline (NA) and 5-hydroxytryptamine (5HT) in mouse brain synaptosomes. They have low toxicity.

As noted above, the active compounds of the present invention form acidaddition salts and, where such salts are pharmaceutically-acceptable, they are equally useful for the treatments mentioned herein. The active compounds and the pharmaceutically-acceptable acid-addition salts thereof of this invention are effective over a wide dosage range, the actual dose administered being dependent on such factors as the particular compound being used, the condition being treated and the type and size of mammal being treated. However, the dosage per day required will normally fall within the range of 1 to 20 mg/Kg., for example in the treatment of adult humans, single dosages of from 0.5 to 5 mg/Kg. may be used whilst, in the treatment of test animals such as mice and rats, single dosages of from 10 to 50 mg/Kg, may be employed.

The active compounds and salts of the present invention will normally be administered orally or by injection and, for this purpose, said compounds and salts will usually be utilised in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound or salt of the invention in association with a pharmaceutically-acceptable carrier therefor. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoate, talc, magnesium stearate or mineral oil. The compositions of the invention may, as is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

Depending on the route of administration, the foregoing compositions may be formulated as tablets, capsules or suspensions for oral use and injection solutions for parenteral use. Preferably the compositions are formulated in a dosage unit form, each dosage containing from 1 to 500 mg., more usually 5 to 250 mg., of the active ingredient.

Accordingly, in one aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically-acceptable acid-addition salt thereof, associated with a pharmaceutically-acceptable carrier therefor.

In a further aspect of the invention there is provided a method of preparing a pharmaceutical composition as described above which comprises admixing a compound of formula (I), or a pharmaceutically-acceptable acid-addition salt thereof, with a pharmaceutically-acceptable carrier therefor.

The compounds of the invention may be used to treat depressive states in mammals, particularly humans, by a method which comprises administering a chemotherapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to the afflicted mammal.

It is to be clearly understood that the preferred features set out below the initial discussion of the compounds of formula (I) hereinbefore, apply mutatis mutandis to all other aspects of the invention.

The invention will now be illustrated with references to the following Examples.

EXAMPLE 1 Cis-endo-2-p-chlorophenyl-3-N,N-dimethylaminomethyl-bicyclo[2,2, 1 ]heptane (a) Cis-endo-2-p-chlorophenyl-3-cyano-bicyclo[2,2, 1 ]hept-5-ene Cis-p-chlorocinnamonitrile (10.0 g) (D. B. Roll and A. C. Huitric, J. Pharm, Sci., 54, 1110, (1965)) was dissolved in 70 ml of o-dichlorobenzene, and a few crystals of hydroquinone were added. Freshly cracked cyclopentadiene (40 g) was added and the solution was heated at 1400C for two days in a glass bomb. The resultant solution was evaporated and the residue triturated to give the title product which was a white solid. A small portion of the crude product was recrystallised from ethanol and had a m.p. of 131--133"C.

(b) Cis-endo-2-p-chlorophenyl-3-cyano-bicyclo[2,2, 1] heptane The total crude product of step (a) was dissolved in 50 ml of ethanol and hydrogenated at atmospheric pressure over 500 mg of palladium on charcoal. The resultant solution was filtered and evaporated to dryness in vacuo to give the desired product as a white powder (8.6 g).

(c) Cis-endo-2-p-chlorophenyl-3-aminomethyl-bicyclo-[2,2, 1 ]heptane The product from step (b) (2.0 g) was dissolved in 25 ml of ether and the resultant solution was added dropwise to a stirred suspension of lithium aluminium hydride (1.5 g resultant solution was added dropwise to a stirred suspension of lithium aluminium hydride (3.0 g) in ether (50 ml) with cooling (ice-water bath). The solution was stirred for a further 20 minutes, cooled, and 50 ml of 2N sodium hydroxide solution was added dropwise. The solution was diluted with 100 ml of water and extracted with four 20 ml portions of ether. The combined ether extracts were evaporated to dryness to yield the title product as a light yellow oil (9.7 g). On dissolution in ether and addition of excess ethereal HCI the hydrochloride salt of the title product was obtained as a white crystalline solid (m.p. 2500 C).

(d) Cis-endo-2-phenyl-3-dimethylaminomethyl-bicyclo[2,2, I] heptane The title product from step (c) in the form of the free base (4.0 g) was treated by method of Example I (d) above, and the hydrochloride salt of the title product was obtained in the form of white plates in a yield of 2.0 g, m.p. 208--2100C.

EXAMPLE 3 Endo- and exo-cis-3-(3,4-dichlorophenyl)-2-N,N-dimethyl- aminomethylbicyclo [2,2,l]heptane hydrochloride (a) Endo-and-exo-cis-3-cyano-2-(3 ,4-dichlorophenyl)bicyclo[2,2, 1] hept-5-ene Cis-3,4-dichlorocinnamonitrile (5 g), several crystals of hydroquinone, and freshly cracked cyclopentadiene (17 g) were heated together in a glass bomb for 12 hours at 1400C. After cooling, the residue obtained thereby was washed with cold petrol (b.p, 40--600C) and the washings were discarded. The washed residue was then digested twice with boiling petrol (b.p. 8e100"C). The petrol extracts were evaporated to dryness to yield a mixture of endo-and exo-title products as a yellow oil (4.4 g.).

(b) Endo- and exo-cis-3-cyano-2-(3,4-dichlorophenyl)bicyclo[2,2,1]heptane The mixture of endo- and exo- products from step (a) (4.2 g) was hydrogenated at atmospheric pressure over 5% palladium on charcoal (400 mg) in ethanol (100 ml) for 30 minutes. Upon filtration and evaporation a mixture of the endo- and exotitle products was obtained in the form of a yellow oil (4.1 g).

(c) Endo- and exo-cis-3-(3,4-dichlorophenyl)-2-aminomethylbicyclo- [2,2,l]heptane hydrochloride The mixture of endo- and exo- products from step (b) (4.0 g) was dissolved in dry ether (50 ml). The ether solution was added dropwise to a stirred suspension of LiAIH4 (3 g) in ether (20 ml) maintained at OOC by an ice-water bath. The resulting solution was refluxed for 5 hours and cooled to OOC, followed by addition of 2 ml of water, 5 ml of 10% W/V sodium hydroxide solution and 100 ml of water.

The mixture obtained thereby was filtered, and the solid residue and aqueous fraction were extracted with five portions of ether. The combined ether extracts were evaporated to dryness, yielding a mixture of the endo- and exo- title products as a yellow oil (3.2 g).

(d) Endo and exo-cis-3-(3,4-dichlorophenyl)-2-N,N,-dimethylaminomethyl bicyclo[2,2,1]heptane hydrochloride The mixture of endo- and exo- primary amines from step (c) (3 g) was dissolved in a mixture of acetic acid (20 ml) and ethanol (40 ml). To the solution obtained thereby was added 30 ml of a 40 V/V aqueous solution of formaldehyde and 1 g. of 5% palladium on charcoal. The mixture was hydrogenated overnight at a pressure of 60 p.s.i. in a Parr apparatus. The resulting solution was filtered and evaporated to dryness. The residue was dissolved in ether (100 ml) and extracted with four 20 ml portions of SN hydrochloric acid. The combined aqueous extract were made alkaline with 2N sodium hydroxide solution and extracted with four 25 ml portions of ether. The combined ether extracts were washed with two 10 ml volumes of water, dried over anhydrous MgSO4, and filtered. On addition of ethereal HCI solution a white solid precipitated out. The ether was evaporated off and the solid residue was recrystallised from isopropyl alcohol to yield the mixture of endo- and exo- title products in the form of white crystals (750 mg, mp 218--220"C).

The following Examples illustrate pharmaceutical formulations containing compounds of formula (I). The active ingredient used was cis-endo-2-p chlorophenyl-3-N,N-dimethylaminomethylbicyclo[2,2, 1] heptane, hydrochloride; however, this compound may be replaced by other active solid compounds of the invention.

EXAMPLE 4 Tablets each containing 5 mg. of active ingredient were made up as follows:- Active ingredient 5 mg.

Potato starch 20 mg.

Lactose 20 mg.

Polyvinylpyrrolidone (as 10% solution in water) 2 mg.

Sodium starch glycolate 2 mg.

Magnesium stearate 0.5 mg.

Talc 0.5 mg.

Total 50 mg.

The starch, lactose and active ingredient were passed through a sieve and thoroughly mixed. The solution of polyvinylpyrrolidone was mixed with the resultant mixture and the combination passed through a No. 12 mesh B.S. sieve.

The granules so produced were dried at approximately 550C. and passed through a No. 16 mesh B.S. sieve. The magnesium stearate, sodium starch glycolate and talc, previously passed through a No. 60 mesh B.S. sieve, were then added to the granules which, after mixing, were compressed on a tablet machine to yield tablets each weighing 50 mg.

EXAMPLE 5 Capsules each containing 10 mg of medicament were made as follows:- Active ingredient 610 mg.

Starch 44 mg.

Lactose 45 mg.

Magnesium stearate I mg.

Total 200 mg.

The lactose, starch, magnesium stearate and active ingredient were passed through a No. 44 mesh B.S. sieve and filled into hard gelatin capsules in 100 mg.

quantities.

EXAMPLE 6 Suppositories each containing 25 mg. of active ingredient were made as follows: Active ingredient 25 mg.

Saturated fatty acid glycerides to 2,000 mg.

The active ingredient was passed through a No. 60 mesh B.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture was then poured into a suppository mould of nominal 2 g. capacity and allowed to cool.

WHAT WE CLAIM IS: 1. A cis-arylbicyclo[2,2,1]heptylamine compound of formula (I):

or a pharmaceutically-acceptable salt thereof, wherein Ar represents a phenyl group optionally substituted by one or more substituents selected from halogen, trifluoromethyl, nitro, amino, C25 alkanoylamino, mono-or di-C1~4 alkylamino, C14 alkyl, C14 alkoxy and C12 alkylenedioxy, Ar being attached at the 2- or 3position of the bicyclo[2,2,1]heptyl nucleus, and wherein the ACH2)nNR'R2 group, in which n is an integer from 1 to 3, R' is C14 alkyl and R2 is hydrogen or C14 alkyl, is attached at the 3- or 2- position of the bicyclo [2,2,1] heptyl nucleus.

2. A compound according to claim 1 wherein Ar represents a phenyl group optionally substituted by one or more halogen atoms.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. EXAMPLE 4 Tablets each containing 5 mg. of active ingredient were made up as follows:- Active ingredient 5 mg. Potato starch 20 mg. Lactose 20 mg. Polyvinylpyrrolidone (as 10% solution in water) 2 mg. Sodium starch glycolate 2 mg. Magnesium stearate 0.5 mg. Talc 0.5 mg. Total 50 mg. The starch, lactose and active ingredient were passed through a sieve and thoroughly mixed. The solution of polyvinylpyrrolidone was mixed with the resultant mixture and the combination passed through a No. 12 mesh B.S. sieve. The granules so produced were dried at approximately 550C. and passed through a No. 16 mesh B.S. sieve. The magnesium stearate, sodium starch glycolate and talc, previously passed through a No. 60 mesh B.S. sieve, were then added to the granules which, after mixing, were compressed on a tablet machine to yield tablets each weighing 50 mg. EXAMPLE 5 Capsules each containing 10 mg of medicament were made as follows:- Active ingredient 610 mg. Starch 44 mg. Lactose 45 mg. Magnesium stearate I mg. Total 200 mg. The lactose, starch, magnesium stearate and active ingredient were passed through a No. 44 mesh B.S. sieve and filled into hard gelatin capsules in 100 mg. quantities. EXAMPLE 6 Suppositories each containing 25 mg. of active ingredient were made as follows: Active ingredient 25 mg. Saturated fatty acid glycerides to 2,000 mg. The active ingredient was passed through a No. 60 mesh B.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture was then poured into a suppository mould of nominal 2 g. capacity and allowed to cool. WHAT WE CLAIM IS:

1. A cis-arylbicyclo[2,2,1]heptylamine compound of formula (I):

3. A compound according to Claim 1 or 2 wherein the phenyl group has up to

two substituents.

4. A compound according to any one of Claims 1 to 3 wherein Ar is pchlorophenyl.

5. A compound according to any one of Claims 1 to 3 wherein Ar is 3,4dichlorophenyl.

6. A compound according to any one of Claims I to 5 wherein n is 1.

7. A compound according to any one of Claims 1 to 6 wherein R' is C14 alkyl and R2 is hydrogen, methyl or ethyl.

8. A compound according to any one of Claims 1 to 7 wherein R' and R2 are both methyl.

9. A compound according to any one of Claims 1 to 8 being a cis-endo arylbicyclo[2,2, l]heptylamtne.

10. Cis.endo.2-phenyl-3-N,N-dimethylaminomethylbicyclo[2,2, 1 ]heptane or its hydrochloride.

11. Cisendo-2-p-chlorophenyl-3-N,N-dimethylaminomethyl- bicyclo[2,2,l]heptane or its hydrochloride.

12. Cis-endo-3-(3,4-dichlorophenyl)-2-N,N-dimethylamino methylbicyclo[2,2,l]heptane or its hydrochloride.

13. Cis-exo-3-(3,4-dichlorophenyl)-2-N,N-dimethylaminomethylbicyclo[2,2,1]heptane or its hydrochloride.

14. A compound of formula (I) as defined in Claim I substantially as hereinbefore described in any one of Examples 1 to 3.

15. A method of preparing a compound of formula (I) as defined in any one of Claims 1 to 14 which comprises (A) reducing (i) a compound of formula (V): R-(CH2)m-Z (V) where m is 0, 1 or 2, Z is -CONR1R2, -CH--NR1 or or-C(OR)=NR, wherein R' and R2 are as defined in Claim I and R is a group of formula (III)

where Ar is as defined in Claim 1 and is attached at the 2- or 3- position of the bicyclo[2,2,1]heptyl nucleus, the group (CH2)rnZ being attached at the 3- or 2position of the bicyclo[2,2,l]heptyl nucleus; or (ii) an olefin of formula (VI)

where R5 and RB taken together represent a single bond or independently represent hydrogen atoms and R7 and RB taken together represent a single bond or, when R5 and R6 taken together represent a single bond, independently represent hydrogen atoms, and where one of R9 and R10 is (CH2)NR1R2 and the other of R9 and R10 is Ar, wherein R', R2 and Ar are as defined in Claim 1; (B) alkylating a compound of formula (VII): R4CH2)nNHR2 (VII) wherein R2 is as defined in Claim 1 and R is as defined above or (C) condensing an amine of formula HNR1R2 wherein R' and R2 are as defined in Claim 1 with a compound of formula (VII I): R--(CH,),Q (VIII) where Q is a leaving group and R is as defined above; optionally followed by (D) resolution of the produce of formula (I) formed in reaction (A), (B) or (C), into its (+) or (-) enantiomeric form.

16. A method of preparing a compound of formula (I) as defined in Claim 1 substantially as hereinbefore described in any one of Examples 1 to 3.

17. A compound of formula (I) as defined in Claim 1 whenever prepared by a method according to Claim 15 or 16.

18. A pharmaceutical formulation comprising a compound according to any one of Claims 1 to 14 and 17 in association with a pharmaceutically-acceptable carrier therefor.

19. A method of preparing a pharmaceutical formulation comprising bringing a compound according to any one of Claims 1 to 14 and 17 into association with a pharmaceutically-acceptable carrier therefor.

20. A pharmaceutical formulation substantially as hereinbefore described in any one of Examples 4 to 6.

21. A method of preparing a pharmaceutical formulation substantially as hereinbefore described in any one of Examples 4 to 6.