IL40397A - Ethylene diamine derivatives their production and pharmaceutical compositions containing them - Google Patents

Description

MR o»V»3nn nmpn »*»*w:m Novel ethylene diamine derivatives, tneir pi!Qdtio ion and phaimaceutical compositions containing them ALLEN & HAK URyS LIMITED Or 38399 e presen nvent on relates to novel substituted ethylene diamines which have heen found to have pharmacological activity. ^ According to ~the invention, therefore, there are ' provided, as new compounds, .compounds of the general formula ■ ■ . ·· · and non-toxic acid addition salts thereof in which one of the 1 2 groups R and R represents hydrogen or alkyl and the other represents an acyl group RCO- or a benzensulphonyl group, R is H, lower alkyl, lower alkoxy or phenyl and the phenyl group R as well as the phenyl ring of the benzenesulphonyl group may each be substituted by one or more halogen atoms, alkyl, hydroxy, alkoxy, trifluoromethyl , nitro, amino and/or dialkylamino groups; R alkyl, C2_g alkenyl, C2-6 alkvnvl or cycloalkylalkyl or benzyl, the phenyl ring of which may be substituted as defined above for the 3 4 phenyl ring of the benzoyl group and wherein R and R can also together form an alkylene group which may be interrupted by an -NH- or -N-alkyl- group; R5 may represent hydrogen or alkyl 6 7 8 · and represents hydrogen and R and R may be the same or and are each different, /an alkyl group or together form a pentamethylene group except that when R2, R4 , R5 and R6 are hydrogen R3 is 7 8 hydrogen or alkyl and R together with R fqrm a pentamethylene group, R^" -cannot represent alkoxycarbonyl.

- The term acyl as_used herein means the residue -of an organic acid and includes apart from the benzoyl and benzenesulphonyl groups specified above, the formyl group, lower alkanoyl groups, such as acetyl -and also-alkoxycarbonyl-groups^for-example- ^thpxy The invention extends to the non-toxic acid addition salts of the compounds defined above in particular acid addition salts, such as the hydrochloride, sulphate, maleate and tartrate.

Since some of the compounds can exist in optically active form the invention also extends to such isomers and mixtures thereof.

This is particularly the case with the open chain compounds possessing at least one asymmetric carbon atom.

A preferred group of compounds according to the 7 fi invention are those in which the groups R and R together with the adjacent carbon atom form a cyclohexylidene group.

The groups R and R preferably represent alkyl or alkenyl or alkynyl groups containing up to 6 carbon atoms preferably up to 4 carbon atoms in the. case of alkyl and alkynyl such as methyl, allyl, propargyl of dimethylallyl but can represent hydrogen or aralkyl in particular phenethyl or benzyl, or cyclopentyl or together with the adjacent nitrogen atom, form a heterocyclic ring system of which ring systems, piperidino, 4-methyl-rl-piperazinyl and 1-pyrrolidinyl are representative. The 1 2 ' " * groups R and R preferably represent hydrogen, ^ alkyl, in particular methyl, acyl, in particular formyl (HC0-) and benzoyl which may be substituted by fluorine or chlorine in the 5 aryl portion. Preferably the group R represents hydrogen or alkyl in particular methyl. 40397/2 In another speci ic group of compounds R7 and preferably represent alkyl. Particularly preferred 7 8 compounds are those in which R and R both represent C-j^ alkyl in particular methyl and R 5 represents alkyl, in particular methyl, or hydrogen.

A particular sub-class of compounds within this other specific group of compounds are those of the general formula in which R1 represents benzoyl, chloro substituted benzoyl 2 or COOAlk, i which Alk is alkyl group. R represents hydrogen or methyl.

Particularly preferred classes of compounds accordin to the invention are those specified below. 1. Compounds in which ^ represents one of the following aoyl groups, 3,4^dichlorobenzoyl, formyl, benzoyl, 4-fluoro-benzoyl, 4-ehlorobenzoyl, 3,4-dimethoxybenzoyl, 4-methylbenzoyl, 2-chlorobenzoyl, acetyl, tosyl, 3»4,5-trimethoxybenzoyl, 3,4-dichlorobenzene-sulphonyl, ,4-dlchlorobenzoyl 2 R represents a hydrogen or a methyl group.

R represents a methyl group. 4 ^ represents a methyl group or a benzyl group or represents a hydrogen atom. 40397/2 λ , 5 6 ∑r and R represent hydrogen or methyl, 7 8 and together form a cyclohexyl group. 2. Compounds in which R1 represents one of the following acyl groups, formyl, acetyl, 4-fluorobenzoyl, 2-chlorobenzoyl, 3,4-dichlorobenzoyl, 3»4,5-trimethoxybenzoyl, 4-nitrobenzoyl or 4-aminobenzoyl, or represents an ethoxycarbonyl group; R2 represents hydrogen or methyl. 5 represents hydrogen.

R7 and E8 together form a cyclohexylidene group. ^ and together with the adjacent nitrogen atom form a piperidino group. 3. Compounds in which R1 represents one of the following acyl groupa, forrayl, acetyl, 3»4-dichlorobenzoyl, 3,4,5-trimethoxybenzoyl, tosyl, 2, -dichlorobenzoyl; or a methyl or ethyl group; 2 R represents a hydrogen atom or a methyl group 2 1 2 when R is acyl or if R represents methyl or ethyl R represents formyl; R represents a hydrogen atom; ^ represents a hydrogen atom; 3 4 R and R -form, together with the adjacent nitrogen atom a 4-m thyl-l-piperazlnyl group and 1 Ά R and R together form a cyclohexylidene group. 40397/2 Compounds in which R represents one of the following ncyl groups, 3, Ί-dichloro-benzoyl, 2-ehlorobenzoyl or benzoyl; or an cthoxy-j carbonyl group; 2 R represents a hydrogen atom or methyl group; llJ represents a methyl group; ll l represents a hydrogen atom or methyl, benzyl, al lyl, propynyl, dimethylal yl, cyclopropylinethyl , phenethyl; R represents hydrogen or methyl; ' R^ represents hydrogen; R7 represents methyl; and 8 R represents methyl or butyl.

Specific preferred compounds are those the preparation of which is described in the Examples.

The compounds according to the invention may in principle be prepared from an aminonitrile of the formula: 3 4 , R7 ' 8 iii which R , and R have the above stated meanings.

This aminon trile may be prepared from' a parent ketone by the standard Strecker synthesis as exemplified below with reference to cyclohexanone .

In this synthesis the parent ketone is reacted wi.th an amine of the formula R R NH, in which ^ and R have the I ... 'J 40397/2 meanings given above, or an acid addition salt thereof, in the presence of IICN or CN.

The aminonitrile II is then convortcd into of two ways. is reduced lex metal n. Another minium bis me hoxyethoxy hydride. According to the second method the aminonitrilo may first be hydrolysed to the amide,for exumple with concentrated sulphuric acid which amide may then subsequently be reduced to the amine by a chemical reducing agent such as LiAlH^.

The above described process is appropriate for 1 2 ¾ the preparation of compounds in which It and It and Ir and II are hydrogen. These compounds, are acylated ; 1 / 2 to produce compounds in which It and/or I have meaning other than hydrogen. Acylation may bo effected in a ' conventional manner. Thus, for example, whore represents an acyl group the amino may be treated with an acylating · agent providing such a group It1, for example on aoid chloride, or an ar ^sulphonyl chloride where 11 is an aryl sulphonyl group, Acylation, for example formylation inay also bo carried out using formic acid and aoetio anhydride to convert the group = H to R ~ OHC- (formyl) If the resulting formyl compound is reduced for example with LiAlH^ the formyl group is converted to the me thy1 group and in this one obtains a compound in which R is an alkyl group. The monomethylarnino compound can then be formylated once again to give the compound in which R"1" ~ 2 CH-j and R = OHC. The scheme below shows an example of such a reaction.

LiAlH, 40397/2 This reaction is applicable to the other acylat d compounds, and thus for' example the acetylation may ho effected to give the · corresponding acetyl compound which may then bo reduced to convert the acetyl group to the ethyl grou pli-cabi e alkyl.

In an alternative process starting with the 5 nitrile II for the production of compounds in which Hi is an alkyl group, the nitrile may be reacted with a metal alkyl for example a lithium alkyl to givo an intermediate iminc which way then be reduced to tho primary amine by chemical or catalytic reduction, for example with LiΛIII, or ttaney nickel/hydrogen.. .This- 1 2 This results in compounds in which R and R are hydrogen. . This compound is aoylatcd (and alkylated) as described above. Compounds in which' is .alkoxycarbonyl may be prepared by acylat on with a haloacid ester such as chloroformic acid ester and the term acylation extends to such reaction.

The nature of the groups R*5 and ¾ may bo the 40397/2 same as in tho starting moiety providing that moiety of the compound. However, it is possible to convert tho groups tt and It into other groups within tho meanings given after production of a compound according to tho invoiition. Thus, where, either of Ir and R are -hydrogen they may bo aoylatod 1 2 or alkylated as described above for 11 and 11 provided that 1 2 the group Nft ft . is itsolf not capable of being alkylated or aoylatod. Alkylation may also be effected subject to this proviso with a halide such as an alkyl or aralkyl halide to · yiold the group TXJ or ll'* (other thcin hydrogen). Compounds in which ItJ and/or ft are hydrogen are conveniently prepared by debenzylation of those compounds in which these groups are benzyl. Also where an acyl group contains a nitro group e.g. -nitro benzoyl, this may be reduced to an amino group subsequently. 40397/2 The invention therefore further provides a process for the production of compounds according to the 1 2 invention where II is acyl and R is hydrogen which comprises acylating a compound of the formula: with an acylating agent yielding a group R ; o for the production of compounds in which R is 2 alkyl and R is acyl,, reducing the said acyl group to an alkyl group and acylating the resulting luonoalkylamine with a compound yielding said acyl group R2; rt L or for the production of compounds in which R-' or R is hydrogen debenzylating the corresponding compound in which R-^ or R represents a "benzyl group; n. or for the production of compounds in which R^ and R are other than hydrogen alkylating a 1 2 compound of formula I in which the group NR R is • not capable of being · alkylated; and if desired isolating the product as an acid addition salt. 40397/2 The compounds according to the invention show good activity as oral analgesics. They may be formulated for administration in association with any suitable pharmaceutically acceptable carrier. The formulations may be liquid or solid and may be suitable for oral or parenteral admini stration or other route. Preferred formulations include ~ capsules, tablets, which may he coated, injections, liquid oral dosage forms and suppositories. A preferred dosage is parenterally from 10-500 mg. and orally from 8-500 mg.

Examples 1, 15, 27, 30, 40, 44, 50, 53, 54, 56, 60, 62, 64, 68, 75 and 78 describe the preparation of starting materials. Examples 2-14, 16-26, 28, 29, 31-39, 4l,-43, 5-49, 51, 52, 55, 57-59, 61, 63, 65-67, 69-74, 76, 77 and 79 illustrate the invention: EXAMPLE 1 l-(Aminomethyl )-NtN-dimethylcyclohexylamine (a) l-Cyano-N,N-dimethylcyclohexylamine Dimethylammonium chloride (81.5 g, 1.0 mole) dissolved in water (150 ml) was added to cyclohexanone (98.0 g., 1.0 mole), quickly followed by a solution of .. potassium cyanide (68.0 g, 1.045 mole) in water (150 ml) added over a period of five minutes. The reaction mixture was stirred for 24 hours during which time a colourless crystalline solid was JLormecL. The solid was JLiJLt.exed. oJLf_, washed with ice cold water (200 ml), dissolved in benzene (150 ml) and rewashed with water (100 ml). The aqueous layer was extracted with benzene (100 ml), the benzene solutions then being combined, -drLed over anhydrous sodium sulphate and evaporated under reduced pressure. The oily residue (144 g) solidified to give l-cyano-N,N-dimethylcyclo-hexylamine, m.p. 360. (b) l-(Aminomethyl )-N .N-dimethylcyclohexylamine l-Cyano-N,N-dimethylcyclohexylamine (22.7 g, 0.15 mole) was dissolved in dry ether (200 ml) and added drop-wise to a stirred suspension of lithium aluminium hydride (11.37 g, 0.3 mole) in dry ether (300 ml). The suspension 40397/2 decomposed by dropwise addition of water (28 ml.) and 30% sodium hydroxide solution (21 ml.) followed by water (50 ail.). The ether layer was separated, dried ( a2S04) , and evaporated to yield a colourless, mobile oil (21.4 g, 92.5%). Addition of 10% ethanolic HC1 to an ethereal solution of the oil gave a solid which was recrystallised from ethanol/ether as colourless needles of 1- (aiainomethyl) -N,N-dimethylcyclohexyl-amine dihydrochloride m.p. 251-3°.

EXAMPLE 2 1- (3 ,4-Dichlorobenzamidomethyl) -N,N-dimethylcyclohexylamine hydrochloride A mixture of 1- (aminoir^tb¾L) ,N-dimethylcyclohexyl-amine (1.0 g.) , 3 ,4-dichlorofaenzoyl chloride (2 ml) and pyridi (10 ml) Was allowed to stand at room temp, for 1 hr. The pale yellow solid producedwas filtered 'and recrystallised from ethanol/ether to give colourless microneedles of l-(3,4-dichlorobenzaroidomethyl) -N,N-dimeth Ic clohex lamina hydrochloride m.p. 215-16°.

EXAMPLE 3 1- (Formylaminometh l) -N,N~dirttethyIcyclohexylarnine A solution of chloral (4.7 g.) in chloroform (30 ml) was added dropwise to a stirred and cooled solution of l-(aminometh l)-N,N-dimethyIcyclohexylamine (2) (5 g.) in chloroform (30 ml). The mixture was stirred for 64 hrs. and then heated in a steam bath for 0.5 hrs.

The excess chloroform was evaporated under reduced pressure and the oily residue distilled under high vacuum to give l-(fomylaminomethyl)-N,N-dimethylcyclohexyl-amine (6.0 g.) b.p. 120°C at 0.7 mm Ilg. 40397/2 EXAMPLE 4 1- (Benzamidomethyl) -M,N-dimethylcyclohexylamlne hydrochloride A mixture of 1- (aminomethyl) -N,N^dimethylcyclohexyl-amine (1.5 g) , benzoyl chloride (3 ml) and pyridine (10 ml) was allowed to stand at room temperature for 1 hr. The crystalline mass was filtered and recrystalllsed several times from 95% ethanol to give colourless prisms of 1- (benzamidomethyl) -N^M^dimethylcyclohexylamine hydrochloride m.p. 245-6°.

EXAMPLE 5 lr (4»Fluorobenzamidometh 1) -N,N-diroethylcyclOhexylamlne hydrochloride A mixture of 1- (aminomethyl) -N fN-dimethylcyclohexyl-amine (1.0 g) , 4-fluorobenzoyl chloride (2 ml) and pyridine (10 ml) was allowed to stand at room temperature for 1 hr. The crystalline material produced was filtered and recry-stallised several times from ethanol/ether to give colourless needles of 1- (4-fluorobenzamldomethyl) -Ν,Ν-diroethyl·-cyclohexylamine hydrochloride m.p.238-239°.

EXAMPLE 6 1- ( -Chlorobenzamidometh l) -N,N-dimethylcyclohexylantine A solution of 4-chlorobenzoyl chloride (1 g.) and 1- (aminomethyl) -N,N-dimethylcyclohexylamine (1.8 g.) in benzene (100 ml.) Was heated under reflux for 0.5 hours on a steam bath. Th excess benzene was removed under reduced pressure and the oily residue was dissolved in water and 3 extracted with chloroform ( 40 cm ) . The chloroform extracts were dried (anhyd. sodium sulphate) and the chloroform removed under reduced pressure to give a white solid (1.6 g. m.p. 97-99°). 40397/2 The solid was dissolved in chloroform (60 ml.) ^ and washed with 2N sodium carbonate (2 x 40 ml) . The chloroform extract was dried (anhyd. sodium sulphate) and the chloroform evaporated under reduced pressure. The solid residue was crystallised from petroleum ether (60r-80°C) to give 1- (4-chlorobenzamldome h 1) -M,N-dimethylcyclohexyl-amine (1.5 g.) m.p. 105-7°.

EXAMPLE 7 1- (3 ,4-Dimethoxybenzamidomethyl) -N,N-dimethylcyclohexylamine hydrochloride A solution of 3,4-dimethoxybenzoyl chloride (1.28 g.) and 1- (aminomethyl)-NN-dimethylcyclohexylamine (1 g.) in benzene (100 ml.) were heated under reflux for 1.5 hours. The excess benzene was evaporated under reduced pressure and the residue dissolved in water and made alkaline. The aqueous solution was extracted with chloroform (4 x 40 ml) , the chloroform solution was extracted with 2N hydrochloric acid (2 x 15 ml) and the excess water was evaporated under reduced pressure. The solid residue was crystallised from ethanol to give 1- (3 #4-dimethoxybengamldomethyl) - fN-dimethyl-cyclohexylamine hydrochloride (0.5 g.) m.p. 227-229°.

EXAMPLE 8 1- (4- ethylbenzamidomethyl) -N,N-dimethylcyclohexylamine hydrochloride A solution o g-toluoyl chloride (1 g.) 1-(amino-methyl)-NrN-dimethylcyclohexylamine (1 g.) and triethylamine (0.65 g.) in benzene (60 ml.) was heated under reflux for 1.5 hrs. The excess benzene was evaporated under reduced pressure, the residue dissolved in water and extracted with chloroform. The extracts were dried (anhyd. sodium sulphate) and the chloroform evaporated under reduced pressure to give 40397/2 an oil which solidified on cooling. Excess ethereal hydrochloric acid was added to an ethereal solution of the solid and the excess ether removed under reduced pressure. The solid residue was crystallised from isopropanol/petroleum ether (80-100) to give 1- (4-methylben2amidomethyl) -N^N-dimethylcyclohexylaroine hydrochloride cup. 199-201° (0.7 g.). EXAMPLE 9 IT (3-Chlorobenzamidomethyl) -N , -dimethylcyclohexy1amine hydrochloride A siution of l-(aminomethyl)-N,N-dimethylcyclohexyl amine (1 g.) and m-chlorobenzoyl chloride (1.12 g.) in benzene (60 ml.) was heated under reflux for three hours.

The precipitate was filtered and crystallised from ethanol/ isopropanol to give 1-» (3-chlorobenzamidomethyl) - ,H-dimethylcyclohexylamine hydrochloride (2.0 g.) m.p. 233-235®.

EXAMPLE 10 1- (2-Chlorobenzamidomethyl) -N/N-dimethylcyclohexylamine hydrochloride A solution of 1- (amlnomethyl) -N,N-dimethyIcyclohexyl-amine (1 g.) and o-chlorobenzoyl chloride (1.12 g.) in benzene (60 ml.) was heated under reflux for 3 hrs. The precipitate was filtered and crystallised from isopropanol to give 1- (2^chlorobenzamidomethyl)^ hydrochloride (1.3 g.) m.p. 229-231·.

EXAMPLE 11 1- (Acetamidomethyl)-N N-dlmethylcyclohex lamine A mixture of acetic anhydride (50 ml.) and , l-(aminomethyl)-NfN-dimethylcyclohexylamine (6 g.) was heated on a steam bath for one hour. The excess acetic anhydride was evaporated under reduced pressure. Ether (75 ml) 5N sodium hydroxide (10 ml) and sodium hydroxide (1 g. ) was added to 40397/2 mixture was filtered after 60 mins. The excess ether was ( evaporated under reduced pressure to give an oily residue (7.1 g. ). 3 g. of this oil was distilled under high vacuum to give 1- (acetamidomethyl) -N,N-dimethylcyclohexylamine (2.6 g) b.p. 120°C at 0.1 mm Hg.

EXAMPLE 12 (%-Toluenesulphonamidomethyl) -N,N-dimethy1cyclohexylamine hydrochloride A solution of toluene-4-sulphonyl chloride (1.22 g) and 1- (amino methyl) - N-dimethylcyclohexylamine (1 g.) in benzene (60 ml) was heated under reflux for 45 mins. The precipitate was filtered and crystallised from ethanol to give 1-(p-toluene sulphonamldomethyl) cyclohexyldimethylamlne hydrochloride (1.9 g) m.p. 226-228eC.

EXAMPLE 13 1- (3 , ,5-Trimethoxybenzamidomethy1) -N,N-dlmethylcyclohexyl-amine hydrochloride Solutions of 3,4,5-trimethoxybenzoylchloride (1.5 g.) in benzene (25 ml.) and 1- cyclohexylamlne (1.0 g.) in benzene (25 ml.) were mixed and heated unde reflux for 1½ hrs. The solid which separated was filtered, washed with benzene and crystallised from isopropanol to give 1- (3 ,4 ,5-trimethoxybenzanddomethyl)-Nf13-dimethyicyclohexylamine hydrochloride (1.6 g. 65%) m.p. 198-9°. EXAMPLE 14 3 r4-Dichloro-N- [1- (dimethylamino) cyclohexanemethy1)benzene-sulphonamide hydrochloride Solutions c 1- (aminomethylJ-N , rdimethylcyclohexylamine (1.0 g. ) in dry benzene (15 ml. ) and 3 ,4-dichlorobenzene-sulphonyl chloride (1.57 g. ) in dry benzene (15 ml.) were 40397/2 mixed .and heated under reflux on a steam batch for one hour. i The reaction mixture was cooled, filtered and the residue was washed with benzene and dried. This solid was crystallised from isopropanol to give 3 4-dichl0ro-N- [1- (dimethylamino) -cyclohexanemethyl]benzenesulphonamlde hydrochloride (1.9 g. 74%) m.p. 206·.

EXAMPLE 15 M,N-Dimethyl-1- (methylaminomethyl) cyclohexylamine 1- (Formylaminoraethy1) ~W,N-dimethylcyclohexylamine prepared as in Example 3 (9.0 g. 0.05 mole) was dissolved in dry ether (100 ml) and added dropwise to a stirred suspension of lithium aluminium hydride (3.8 g. 0.1 mole) in dry ether (200 ml). The suspension was refluxed for 24 hr. and excess lithium aluminium hydride decomposed by dropwise addition of water (8 ml) , 30% sodium hydroxide solution (6 ml) , and water (28 ml) . The ether layer was separated, dried (Na2SQ4) , and evaporated to give a colourless mobile oil (7.8 g. 94.2%). An aliquot of this oil was treated with 10% ethanolic hydrochloric acid to give colourless needles of Ν,Ν-dlmethyl- (methylaminomethyl)-cyclohexylamine dihydrochloride , m.p. 232-233° (from ethanol/ ether). 40397/2 EXAMPLE 16 H,N-Dimethyl-1- (N-formyl-N-methylaminomethyl) cyclohexylamine Formic acid (6.9 g,Q.15 mole) and acetic anhydride (15.3 g, 0.15 mole) were mixed without cooling and kept at room temperature for 1 hr. 1-methylaminomethyl-N,N-dimethylcyclohexylamine (5.9 g, 0.034 mole) was dissolved in formic acid (12 ml) and the formylating mixture (16 ml) added slowly. This produced vigorous effervescence and a temperature rise to 75°. The mixture was then left at room temperature for 2 hr. and then heated on a water bath at 55° for 0.75 hr. The solvents were removed under reduced pressure to give an amber oil (5.32 g, 77.7%) which crystallised as colourless prisms of Ν,Ν-dimethyl-l- (N-formyl-N-methylaminomethy1) cyclohexylamin from light petroleum (b.p. 60-80·), m.p. 59-60°. 40397/2 EXAMPLE 17 -→ ( N,N-Dimetfoy1-1-N~methylacetamldomethy1) eyclohexanylamine 3 5N sodium hydroxide (5 cm ) was added to a solution of N,N-dimethyl-l-(methylaminomethyl)cyclohexylamino-dihydrochloride prepared as in Example 15 (2 g.) in water (2 ml) . Benzene (50 cm ) and excess anhyd. sodium sulphate were added and the mixture was filtered* Acetic anhydride (40 ml) was added to the benzene solution and the mixture was heated under reflux for one hour. The excess acetic anhydride and benzene were evaporated under reduced pressure to give a solid residue. This was made alkaline with excess of a saturated solution of sodium carbonate, ether (50 ml) was added followed by excess anhydrous sodium carbonate to remove the water. The mixture was filtered and the excess ether evaporated under reduced pressure to give an oily residue which was crystallised from petroleum ether (80-100eC) to give N,N-dimethyl-l- (N-methylacetamidomethyl) cyclohexan=-yiami¾e (0.45 g.) m.p. (69-71°). 40397/2 I EXAMPLE 18 l-(3,4-Dlchloro N-met^ cyclohexylamine hydrochloride 5N sodium hydroxide (3 ml) was added to a solution of N,N-dimethyl-l- (methylaminomethyl)cyclohexylamine dihydrochloride (1.16 g) in water (1 ml). Benzene (50 ml) and excess anhyd. sodium sulphate were added, the mixture was filtered and the benzene solution added to a solution of 3,4-dichlorobenzoyl chloride (1 g.) in benzene (20 ml).

The solution was heated under reflux for 45 mins. and left to stand fo 2 days. The crystalline solid which appeared was filtered to give 1·» (3,4-dlchloro-N-methylben2amidometh l) «· N,N-dimethylcyclohexylamine hydrochloride (1.1 g.) m.p. 189 -192eC.

EXAMPLE 19 3,4,,S-Trimethoxy-N-methyi-N^ |l- (dimethylamine) cyclohexylmethyl j benzamide hydrochloride N,N-Dimeth 1-1- (methylaminomethyl) cyclohexylamine dihydrochloride (1.5 g) was made alkaline with 5N NaOH (5.0 ml). Benzene (20 ml) was added and the basic solution dried (anhyd. Na2C03) . The solution was filtered and the sodium carbonate residue washed with benzene and 3,4,5-trimethoxybenzoyl chloride (1.42 g.) in dry benzene (25 ml) was added. The mixture was heated under reflux for 1 1/4 hrs. The solid which separated was filtered, and washed 40397/2 with benzene and crystallised from benzene to give 3 4,5-trimethoxy-N-methyl-N- [ [1-dlmethylamine)cyclohexylmethyl) benzamide hydrochloride (1.5 g. 61%) m.p. 197*0.

EXAMPLE 20 3 4-Dlchloro-N- [1- (1-dimethylaminocyclohexyl)ethyl]-benzamide To N,N-dimethyl-l- (1-iminoethyl) cyclohexylamine (35.8 g) was added a suspension of lithium aluminium hydride (12 g.) in dry dioxan (ca. 40 ml) and the mixture was heated under reflu for 5½ hrs. The excess lithium aluminium hydride was neutralised with water and the residue was filtered (Hyflo. Hyflo is a Registered Trade Mark). The filtrate was extracted with 2N HCX (50 ml) and the acid extract evaporated to dryness. The residue was dissolved in water (10 ml) the solution was made alkaline with 5N NaOH (10 ml) and ether (30 ml) was added followed by excess anhyd. NajCO^. The solution was filtered, the filtrate was dried (anhyd. Na2S04) and evaporated to an oil which was distilled to give 1-(1-amihoethyl)-N,N-dimethylcyclohexylamine b.p. 12 mm 105-115° (10.70 g. 30%) .

To a solutio of l-(l-aminoethyl) -N,N-dimethyl-cyclohexylamine (1 g.) in dry benzene (15 ml) was added a solution of 3 ,4-dichloro-benzoylchloride (1.23 g.) in dry benzene (15 ml) and the mixture was heated under reflux on a steam bath for 1 nr. The benzene was evaporated, the residue was made alkaline with 2N NaOH and extracted with 40397/2 chloroform (x3) . The combined chloroform extracts were dried (anhyd. Na2S04) and evaporated to an oil which was dissolved in hot light petroleum (60-80°) , decolourised with charcoal and on cooling gave 3,4-dichloro-N-ll- (1-dimethylaminocyclohexyl)ethyl]benzamide. (1.25 g. 62%) m.p. 111-114·.

EXAMPLE 21 2 , 4-DichlorO'-N~ [1- (1-dimethylaminocyclohexyl)ethyl] -benzamide To a solution of l-(l-aminoethyl) -N,N-dimethyl cyclohexylamine (1 g.) in dry benzene (15 ml) was added a solution of 2,4-dichlorobenzoylchloride (1.23 g.) in dry benzene (15 ml) and the mixture was heated under reflux for 1 hr. The benzene was evaporated, the residue was made alkaline with 2N NaOH and extracted with chloroform (x3) . The combined chloroform extracts were dried (anhyd. Na2S04) and evaporated to an oil which was dissolved in hot light petroleum (60-80°), decolourised with charcoal and on cooling gave 2 ,4-Dichloro-N- II- (1-dimethylaminocyclohexyl) -ethyl] -benzamide (0.9 g. 44%) m.p. 123-126°.

EXAMPLE 22 3,4÷Dichloro-N- [i-(l-Qijmethylaminocyclohexyl) ethyl] r sulphonamide To a solution of 1- (l-aminoethyl)-N,N-dimethyl-cyclohex lamina (1 g. ) in dry benzene (15 ml) was added a solution of 3,4-dichlbrbbenzenesulphonyl chloride (1.23 g.) in dry benzene (15 ml) and the mixture was heated under reflux on a steam bath for 1 nr. The benzene was evaporated, the residue was made alkaline with 2N NaOH and extracted with chloroform (x3) · The combined chloroform extracts 40397/2 was dissolved in ho light petroelum (80-100*) , decolourised with charcoal and on cooling gave 3 ,4-Dichloro-N- [1~ (l^dimet-hylaminocyclohe«yl)ethyl3-sulph (0.88 g. 40%) m.p. 111-115°.

EXAMPLE 23 2-Chloro-N- £1- (l-dlmethylaiainocyclohexyl) ethyl] benaanylde hydrochloride A solution o ^ l-ll-aminoethylJ-NiN^dimethylcyclo-hexylamine (1 g.) in dry benzene (15 ml) and a aiution of 2-chlorobenzoyl chloride (1.03 g) in dry benzene (15 ml) wee mixed and heated under reflux for 1 hr. The solid which separated on cooling was iltered and crystallised f om isopropanol to give 2-chloro-N- [1- (l-dimethylamino-cyclohexylethyl3faenzamlde hydrochloride (0.9 g 45%) m.p. 227-228·.

EXAMPLE 24 3 ,4-Pichloro-Kt-methyl-N- [1- (1-dimethylaminocyclohexyl) ethyl3benzamide hydrochloride Solutions o l-(l-me hylaminoethyl) rN H-dim thyl-cyclbhexylamine (1 g.) in benzene (15 ml) arid 3#4-dichloro-benzoyl chloride (1.14 g.) in benzene (15 ml) were mixed and heated under reflux for 1 hr. The solid which separated on cooling was filtered, dried and crystallised from isopropanol to give 3 ,4-dichioro-N-methyl-M- [1- (1-dijethylaminocyclohexyl) ethyUbenzamide hydrochloride (0.5 g. 24%) m.p. 212°. 40397/2 EXAMPLE 25 2~Cfaloro*N-MetihyX-»N-» [1- (dimethylamino) -cyclohexylethyl] benzamide hydrochloride A solution of l-(l-methylaminoethyl)-N,N-dimethyl-cyclohexylamine (1 g.) in benzene and a solution of 2-chlorobenzoyl chloride: (0.97 g.) was mixed and heated under reflux or 1 hr. The solid which separated on cooling was filtered to give a deliquescent solid which was dissolved in water (50 ml) and made alkaline with 5 NaOH. The suspension was extracted with chloroform (3 x 50 ml) , the combined chloroform extracts washed with water (50 ml) and dried (anhyd. Na2S04) . The chloroform was evaporated, the residue was dissolved in hot light-petroleum (b.p. 80-100°) , treated with decol. C. and evaporated to dryness. A solution of the residue in ethyl acetate was eluted through an alumina/ ethylacetate column. To a suspension of the oil in dry ether was added ethereal HCi. dropwise until the solution was acid. The supernatant liquid was decanted and the solid residue triturated and washed with dry ether to give a white powder. The residue was crystallised from ethanol-ether to give 2-chloro-N-methyl-N- [1- (l-dimethylaminpT-" cyclohexyl)e hyl]benzamide hydrochloride (0.24 g. 13%) , m.p. 214°. 40397/2 EXAMPLE 26 1- [3,4-Dochlorobenzoylaminomethyl] -N-methyl-N-benzylcyclo- hexylamine A solution of 3,4-dichlorobenzoyl chloride (2.095 g. ) in benzene (50 ml) was added to a solution of l-aminome hyl-N-me hyl-N~benzylcyclohexylamine (2.32 g.) in "' " } benzene (50 ml) and the mixture heated under reflux for 1 r. The solution was allowed to cool, washed with 2M sodium hydroxide solution (3 x 50 ml), water (4 x 100 ml), dried ) graphed on a column of silica (50 x 4.4 cms) eluting with benzene/ether 1:1 and fractions (4 x 250 ml) were collected. Fractions (2) and (3) were combined, evaporated and rechroma- tographed on a column of silica (50 x 4.4 cms) eluting with • 40397/2 benzene/ether 4:1. Fractions (8 x 100 ml) were collected. Fractions ( 3-6 ) were combined and evaporated to give a colourless -oil ( 7.0 g.). The remaining oil (10.4 g) was purified similarly giving 1-cyano-N-methyl-N-benzylcyclo- hexylaraine (14 g. 6l ) as a colourless oil. 1-Cyano-N-methyl-N-benzylcyclohexylamine ( 57.0 g) in ether ( 50. ml) was added dropwise to a stirred suspension of lithium aluminium hydride (12.7 g) in ether ( 500 ml) cooled in an ice-water bath. The mixture was stirred overnight and excess water added dropwise, with ice-water cooling, to destroy the excess lithium aluminium hydride. The mixture was filtered on hyfl'o, the layers separated and -the-aqueous layer-extracted with ether "( 3 x 200 ml).; The combined ether extracts were washed with water (4 x 200 ml), dried (Na2S0^) and evaporated to leave a colourless oil ( 52.6 g). The residual oil was distilled to give 1-Aminomethyl-N-methyl-N-benzylcyclohexylamine b.p. 116-141° 0.05 - 0.5 mm.

EXAMPLE 28 , .

N- [1- (N-benzyl , N-methy1amino) cyclohexyl] methyljbenzamide and hydrochloride A solution of benzoyl chloride (2.108 g., 1.73 ml) in dry benzene ( 75 ml) was added to a solution of 1-aminomethyl-N-methyl-N-benzylcyclohexylamine ( 3.142 g) in dry benzene ( 75 nil) and the solution refluxed for one hour. The solution was allowed to cool, washed with 2N sodium hydroxide ( 2 x 100 ml), water (4 x 200 ml), dried (Na^SO^) and evaporated yielding a white crystalline solid ( 5. 2 g). Recrystallisation from cyclohexane/40-60 petrol 1:1 afforded N- [1- (N-benzyl, N-methylamino) cyclohexyl] methyl 40397/2 N- ^ [1- (Benzylmethylamino) cyclohexyl] methyl {benzamide 1 hydrochloride N- [ [1- (Benzylmethylamino) cyclohexyl] methyl ] - benzamide (0.673 g.).was dissolved in absolute ethanol (5 ml) and ethereal hydrogen chloride (5 ml) was added.

The resulting solution was evaporated to give a white semi- crystalline solid which was dissolved in the minimum of ethanol. Dropwise addition of ether with scratching., and ice-water cooling, precipitated a white crystalline solid whic was filtered. Recrystallisation from ethanol (addition -,of ether) afforded N- { [l-benzy,lmethylamino) cyclohexyl] methyl] - benzamide hydrochloride - as white powder (0.895 g. 93%; m.p. 195-200°C.

EXAMPLE 29 N- [ ( 1-methylaminocyclohexyl ) methyl ] Benzamide and hydrochloride N- [1- (Benzylmethylamino) cyclohexyl] methyl] -benzamide prepared as in Example 28 (3.365 g) was dissolved in acetic acid (50 ml), palladium black (0.200 g) was added, and the atmosphere saturated with hydrogen at atmospheric pressure with vigorous' stirring over four hrs. The catalyst was filtered on celite, the filtrates diluted with water and basified with 5N sodium hydroxide solution. The cloudy solution was extracted with ether (k x 200 ml) the ether' extracts washed with water (4 x 200 ml), dried and evaporated to leave a colourless oil (2.4 g). The oil was dissolved in ether (10 ml) and chroraatographed on a column of alumina (30 x 3.0 cms) eluting initially with ether (5 x 100 ml)fractions) and finally methanol (5 x 100 ml. fractions). Fractions 7-9 were combined and, on evaporation 40397/2 afforded M- [ (1-methylaminocyclohexyl)methyl]benzamide 1 as a pale yellow oil (2.253 g. 91%).

N- [ (l^meth laminocyclohexyl)methyl3benzamide (0.493 g.) was dissolved in absolute ethanol (2 ml) and ethereal hydrogen chloride (1 ml) was added. The resulting solution was evaporated and the oil dissolved in the minimum of absolute ethanol. Dropwise addition of ether, with scratching, precipitated a white crystalline solid which was filtered. Recrystallisation from absolute ethanol (addition of ether) afforded M- [ (Ι-τ-methylaminocyclohexyl) -methylIbenzamide hydrochloride (0.427 g. 75%) as white prisms m.p. 152-154°.

EXAMPLE 30 1- [1- (Aminomethyl) cyclohexyl1 iperidine l-(l-cyanocyclohexyl) piperidine (1.92 g. 0.01 mole) was dissolved in dry ether (50 ml) and added dropwise to a stirred suspension of LiAlH^ (0.76 g. 0.02 mole) in dry ether (100 ml) . The suspension was stirred overnight and worked up as in (lb) to give a colourless oil (1.4 g 74.4%) which on treatment with ethanolic HCl gave colourless needles of 1- [1- (amlnomethyl) cyclohexyl] iperidine dihydro-chloride m.p. 256-7°. 40397/2 1 - —*.

The l-(l-cyanocyclohexyl)piperidine was prepared as follows: . .

; . ) Piperidine hydrochloride (24.J. g... 0.2. mole) and KCN (13.O g. 0.2 mole) were dissolved in water (80 ml) and ethanpl (l60 ml). To this stirred solution was added drop-wise a solution of cyclohexanone (19.6 g., 0.2 mole) in ethanol ( O ml), the mixture refluxed for 2k hr. Ethanol was then removed under reduced pressure and the residue extracted with chloroform. The extract was washed with water, dried (NaoS0, ) and evaporated under reduced pressure to give a pale* amber oil (27.0 g. 68.8$) which crystallised on standing. Recrystallisation from vethanol afforded colourless plates of l-(l-cyanocyclohexyl )piperidine m.p. 67-8°. . ." EXAMPLE 31, " ' l-['l-CForrnyiaminomethyl) cyclohexyl] piperidine Chloral (4.65 g.).was added dropwise to a cooled solution of l-[l-(aminometh l )cyclohexyl]piperidine (5.9 g) in dry chloroform (30 ml). The mixture was stirred at room temperature for 16 hrs . and then heated under reflux for 30 iiins. """.The solution was evaporated to dryness and the oily residue re-evaporated with ether. This residual brown oil (7..9 g) was distilled under high vacuum to give a viscous pale yellow oil of 1- [1- (formylaminomethy1) cyclohexyl) piperidine (5.1 g.) b.p. 170-2°C at 1.7 mm. 40397/2 l-[l-(Amino]_iethyl)cyclohexyl]piperidine (9.8 g) vas added dropvise to ice-cold acetic anhydride ed e 10 EXAMPLE 33 "1- [1- (4-Fluorobenzamidomethyl) cyclohexyl] iperidine hydrochloride A mixture of 1- [ (1-aminomethyl) cyclohexyl] - piperidine. (1.5 g.), Ί-fluorobenzoyl chloride (2 ml) and pyridine (lO ml) vas allowed to stand at room temperature for 1 hr. The crystalline material produced was filtered 40397/2 (2.35 g. 86.6%) and afforded pale lemon rosettes of 1-[1- (4-fluorobenzamidomethyl) cyclohexyll iperidine, hydrochloride m.p. 243-5° (Decomp.).

EXAMPLE 34 1- LI- (2-Chlorobenzamidomethyl) cyclohexyl]piperidine hydrochloride A mixture of 1- 11- (aminomethyl) cyclohexyll iperidine (1.5 g.), 2-chlorobenzoyl chloride (2 ml) and pyridine (10 ml) was allowed to stand at room temperature for 1 hr. with no apparent effect. The mixture was therefore refluxed for 1 hr. , cooled, diluted with wate , baslfied with ammonia and extracted with chloroform. This chloroform extract was washed with water, dried (NajSC^) , and evaporated to give a viscous, brown oil (3.0 g. 79.2%). On dissolving in ether and bubbling dry HC1 gas into the solution pale buff rosettes of 1- [1- (2-chlorobenzamidomethyl) cyclohexylIpiperidine hydrochloride, m.p. 234-6° were obtained (from ethanol/ether).

EXAMPLE 35 1- [1- (3 ,4-Dichl0robenzamidomethy1) cyclohexyl) iperidine A mixture of 1-[1- (aminomethyl) cyclohexyllpiperidine (1.5 g. ) , 3,4-dichlorobenzoyl chloride (2 g.) and pyridine (10 ml) was allowed to stand at room temperature for 1 hr. when the whole mass solidified. Recapstallisation from ethanol/ether several times gave small colourless needles of 1- [1- (3,,4-dichlorobenzamidomethyl) cyclohexyll iperidine hydrochloride (1.7 g. 54.8%), m.p. 235-236° (decomp.).

EXAMPLE 36 1-I1- (3, ,5-trimethoxybenzamldomathyl) cyclohexyl1piperidine hydrochloride A solution of 3,4 ,5-trimethoxybenzoyl chloride (1,2 g.) and 1-[1- (aminomethyl) cyclohexyllpiperidine (1.0 g) 40397/2 40397/2 EXAMPLE 39 1- Il~ (p-Aminobenzamidomethyl) cyclohexyllpiperidine A solution of l-[l-(g_-nitrobenzamidomethy1) -cyclohexyllpiperidine hydrochloride (2 g.) in water (20 ml) was made alkaline with 5N NaOH and the suspension extracted with chloroform (3 x 30 ml.). The combined chloroform extracts were dried (anhyd. NajSO^) and evaporated to give a yellow solid (1.7 g.). To a stirred solution of this in ethanol (100 ml) containing Raney Nickel in suspension was added dropwise a solution of hydrazine hydrate (5 ml) in ethanol (5 ml) over 30 mins. The suspension was stirred for a further 3¾ hrs., the suspension was heated to boiling for 30 mins. and filtered through Hyflo. The filtrate was evaporated to dryness and the white solid which formed was crystallised from benzene to give 1- [1- (p-aminobenzamido-methyl) cyclohexy11piperidine (0.95 g. 50%), m.p. 160-163°. EXAMPLE 40 1- [1- (M thylaminomethyl) cyclohexyl)piperidine dihydrochloride 1-I1- (Pormylaminomethyl) cyclohexyl] iperidine (4.48 g. 0.02 mole) was reduced with LlAlH^ (1.52 g. 0.04 mole) and the suspension worked up as in (lb) to give an amber, mobile oil (4.1 g. 93.0%) which on treatment with ethanolic HC1 gave colourless needles of 1- [l-raet&ylamlno-» methyl) cyclohexyllpiperidine dihydrochloride m.p. 259^-60°. ¾. ' · 40397/2 EXAMPLE 41 1- [1- (N-roethylfo:raylagftinome h l cyclohexyl]piperidine Formic acid 98/100% (13.8 g. 0.3 mole) and acetic anhydride (30.6 g. 0.3 mole) were mixed without cooling and kept at room temp, for 1 hr. 1- 11- (methylaminomethyl) -cyclohexyUpiperidine (4.2 g. 0.02 mole) was dissolved in formic acid (15 ml) and the formylating agent (25 ml) added slowly. This produced effervescence and a rise in temp, to 60°. The mixture was allowed to stand at room temp, overnight and the solvents then evaporated under reduced pressure to yield a viscous, amber oil (3.79 g. 80%) which crystallised on cooling and gave colourless prisms of 1-[1-(H-me hyl ormylaminomethyl) cyclohexyHpiperidine m. . 94· (fi-pm light petroleum b.p. 60-80°) . 40397/2 EXAMPLE 42 N-methyl-N- [(l-piperidinocyclphexyl)methyl]acetamide A mixture of l-ll-(methylaminomethyl)cyclohexyl]-piperidine (1.0 g. , 0.005 mole) and acetic anhydride (10 ml) was heated on a steam-bath: fo 30 mins.

The solution was evaporated to dryness and water (5 ml) was added to the residue. A saturated solution of sodium carbonate (10 ml) was added and the alkaline solutio was extracted with chloroform (50 ml x 3) and dried (anhyd. Na2S04) . The chloroform solution was evaporated to dryness and the oily residue re-evaporated with ether, This was dissolved in petroleum ether (60-80°C) , treated with decol. charcoal, and filtered (Hyflo) . The combined filtrates were evaporated to dryness to give N-methyl-N- [ -piperidlno cyclohexyl)methyl] -acetamide (1.3 g.).

EXA,MPLE^43 3 ,4-Dichloro-N-methyl-N- [ (l-piperidinocyclohexyi)iaathyl] benzamide hydrochloride Solutions of 1- tl- (m thylarainome hy1) cyclohexyl] piperidine (1.1 g. , 0.005 mole) in dry benzene (25 ml) and 3,4-dichlorobenzoylchloride (1.0 g. , 0.005 mole) in dry benzene (50 ml) were mixed and heated under reflux (steam bath) for 1 hr. The precipitate was filtered, washed with benzene and dried. (1. 6 g.) m.p. 222° (dec.) Crystallisation from isopropanol gave 3 ,4-dichloro-N-methyl-N- [ (l-piperidinocyclohexyl)methyl] -benzamide hydrochloride (0.9 g.,) m.p. 239° (dec).

EXAMPLE 44 1- [1- (Aminomethyl) cyclohexyl] -4-methylpiperazine 1- (l-Cyanocyclohexyl)-4-methylpiperazine (4.1 gr 0.02 mole) was dissolved in dry ether (100 ml) and added dropwise to a stirred suspension of lithium aluminium hydride (1.52 g, 0.04 mole) in dry ether (200 ml.). The suspension was stirred overnight and excess lithium aluminium hydride decomposed by dropwise addition of water (4 ml. ) , 30% sodium hydroxide solution (3 ml), and water (14 ml) . The ether layer was separated, dried (Na2S04) , and evaporated to yield a colourless mobile oil (3.48 g, 82.9%). An aliquot was refluxed with ethanol (10 ml.) and excess methyl iodide for 0.5 hr. to give yellow needles of 1- .11- (aminomethyl) cyclohexyl] -4-methyl piperazine dimethiodide which was recrystallised from methanol/ether as pale yellow needles, m.p. 243-5°.

EXAMPLE 45 1~Il~ (ForroylaiBinpme hyl)cyclohexy Formic acid (6.9 g, 0.15 mole) and; acetic anhydride (15.3 g, 0.15 mole) were mixed without cooling and kept at room temperature for 1 nr. 1- [1- (amiriomethyl) cyclohexylj -4-methylpiperazine (8.4 g, d ch formed was recrystallised from . petroleum ether (b.p. ..·. . 80-100° ) to give l-[ l-(acetainidomethyl)cyclohexyl] -4- methylpiperazine (8. 3 g; 65/ m.p. 110-111° .

EXAMPLE! 47 1-Γΐ- ( 3 , 4 Dichlorobenzamidomethyl )cyclohexyl] -4-methyl- piperazine ·...

A solution of 3 i 4-dichlorohenzoyl chloride (1.05 g.,) in benzene (.10.ml) was added d'ropwise over 40 mins. to a stirred solution of l-[ l-|(aminomethyl)cyclohexyl] - 4-methylpiperazine (I.06 gv,) in benzene ( 15 ml). The' mixture was heated under reflux for 1 hr^ on a steam bath and the solution was evaporated. The solid residue was dissolved in ethanol, acidified with ethereal HC1 and . evaporated to give a white solid.. This solid was suspended in water, made alkaline with 5NNa0H and extracted with chloroform (x2). The combined chloroform The solid residue was dissolved in hot petroleum ether (80°-100°) decolourised with charcoal and crystallised from petroleum ether (80-100·) to give l-[l- (3 , 4 diehloro-benzamidomethyl) cyclohexyll -4-methylpiperazine (0.95 g; 49%) m.p. 143° -146° .

EXAMPLE 48 1- [1- (3 ,4 ,5-Trimethoxybenzamidomethyl) cyclohexyl- -methyl-pipera'zine hydrochloride A solutio of 3 ,4 ,5-trimethoxybenzoyl chloride (2.2 g;) in dry benzene (25 ml) and a solution of 1- [1- (aminomethyl) cyclohexyl] -4-methylpiperazine (2.0 g;) in dry benzene (25 ml) were mixed and heated under reflux for 1 hr. Th solid which formed wa filtered, washed with benzene and was crystallised from isopropanol-ether to give 1- [1- (3 ,4 , 5-trimethoxybenz-amidomethyl) cyclohexyl] -4-methylpiperazine hydrochloride (1.9 g., 45.4ft) m.p. 208-9eC.

EXAMPLE 49 1- [l-(Tosylaminomethyl)cyclohexyll-4-methylpiperazlne 1- II- (Aminomethyl) cyclohexyl] -4-methylpiperazine (0.5 g) was added to 10% sodium hydroxide solution (10 ml) and p_-toluenesulphonyi chloride (0.5 g) , and the mixture shaken vigorously. The solid was filtered, washed with water and recrystallised from 95% ethanol to give colourless needles (0.4 g, 46.2%) of l-[l-(tosyl-aminomethyl) cyclohexyl] -4-methylpiperazine, m.p. 128-130·. 40397/2 EXAMPLE 50 - 1- [1- (Methylaminomethyl) cyclohexyl] -4-methylpiperazine 1- [1- (Formylaminomethyl) cyclohexyl] -4-methylpiperazine (5.97 g, 0.025 mole) was dissolved in dry benzene (100 ml) and added dropwise to a stirred suspension of lithium aluminium hydride (.3.8 g; 0.1 mole) in dry ether (200 ml). The suspension was refluxed for four days and excess lithium aluminium hydride decomposed' hy the dropwise addition of water (8 ml), 30$ sodium hydroxide solution (6 ml) and water (28 ml). The ether/benzene layer was separated, dried (Na2S0^) and evaporated to yield an amher, mobile oil (5.2 g, 93.0 ) which failed to crystallise or produce stahle salts. Distillation of this oil in vacuo gave 1- [1- (methylaminomethyl) cyclohexyl] - -methyl i erazine as a colourless oil. . .. . 40397/2 EXAMPLE 51 4ft " ' ' ' .-' 1- [1- (M-Methylfoaaaylapvinometh l) cyclohexyll -4-gethyl-piperazine Formic acid (3.45 g, 0.07 mole) and acetic anhydride (7.65 g, 0.07 mole) were mixed without cooling and kep at room temperature for 1 hr. 1- [1- (Methylamino-methyl)cyclohexyll-4-methylpiperaaine (2.25 g, 0.01 mole) was dissolved in formic acid (6 ml) and the formylating mixture (8 ml) added. This produced vigorous effervescence and a temperature rise to 60°. The mixture was left at room temperature for 2 hr. and then heated on a water bath at 55° for 0.75 hr. The solvents were removed under reduced pressure to give a viscous reddish-brown oil (2.13 g, 83.3%) which crystallised as colourless needles of 1- [1- (N-methylformylaminomethyl) cyclohexyll-4»Hfethylpiperazine from ligh petroleum (b.p. 80-100·) , ro.p. 107-108° .

EXAMPLE 52 cyclohexyl]methyl}benzamide 40397/2 A solution of 3, ^-dichlorooenzoylj chloride (0.61 g.,) in benzene (lO.ml) ias added dropwise over 25 mins. to a stirred solution of. l-[ l-(methylaiuinomethyl)cyclohexyl] -4-methylpiperazine (l) (0.65 g.,). The mixture was then heated on a steamhath for 1 hr. and the mixture was evaporated to dryness. The residue was dissolved in hot light petroleum (60-80°) and decolourised with charcoal. The solid which separated was crys tallised from light petroleum (60-80°) to give 3 , -Dichloro-N-methyl-N- [|" l-( -methyl-l-piperazinyl)cyclohexyll methylIbonzamide (0.27 g. 23%) m.p. 126-129°. I 40397/2 . 40397/2 rcfltixed for 16 hrs. and then water was added to decompose the excess lithium aluminium hydride. The mixture was dried (anhyd. sodium sulphate) and extracted with ether. The ether extracts were extracted with 2N hydrochloric acid (3 x 15 ml.) and the excess water evaporated under reduced pressure to give a solid residue which was crystallised from methanol to give 2-di]nethylamino-2-methylpropylaminedihydrochloride (2 g. 56#) m.p. 254-256°C.

EXAMPLE 55 ' 3, ^-Dichloro-Ν-Γ2-dimethylamino-'2-methyl-propyll -benzamide hydrochloride monohydrate 2-Dimethylamino-2-methylpropylaminedihydrochloride (I.65 g.) was dissolved in water (2 ml.) and made alkaline (5N aOH) . Benzene (l50 ml.) was added and the mixture dried (anhyd. sodium sulphate). The suspension was filtered, and. the benzene solution added to a solution of 3, 4-dichlorobenzoyl chloride (1.8 g. ) in benze (50 ml.). The mixture was refluxed for ½5 mins. and the solid which separated was crystallised from methanol/isopropanol to give 3., ^-dichloro-Ν-Γ 2-dimethyl-aitiino-2-methylpropyl] benzamide hydrochloride monohydrate (1.6 g. 59%) m.p. 192-194°C.

EXAMPLE 56 2-Dimethylamino-l .2-dimethy propylamine dihydrochlqride " ■ ; ; : r A solution of methyl iodide (15.5 g.) in ether (5 ml.) was added dropwise to a stirred suspension of lithium turnings . (l." g.) in ether (lOO ml.) at -10°C. in an atmosphere of nitrogen. The mixture was stirred for one hour whilst the temperature rose from -10°C to 10°C. The methyl lithium was filtered under nitrogen and a solution of 2-(dimethylamino)~2~methy3 A solution of the imine in ether was added dropwise to a stirred and cooled suspension of lithium aluminium hydride (5.9 g.) in ether (100 ml.). The mixture was heated under reflux overnight and the excess lithium aluminium hydride was decomposed with water (5 ml.). The suspension was dried over anhydrous sodium sulphate and filtered. The ethereal solution was extracted with 2N hydrochloric acid (3 x 15 ml.) and the acid extract was evaporated under reduced pressure to give a solid residue which was crystallised from ethanol/methanol to give 2-dimethylamino-l , 2-dimethyl-pro y1amine dih drochior1de ( 8.5 g . ) in. p · 252-4° EXAMPLE JfT 5 , t-Dichloro-N-[ 1 ? 2-dimethyl--2-"dimethylamiiio¾- ropyl] -henzamide hydroch1oride 2-Dimethylamino~l , 2-dimeth ^propylamine dihydrochloride (1.6 g.) was dissolved in sodium, hydroxide (5 ml.). Benzene (50 ml.) and anhydrous sodium sulphate was added and the mixture was filtered of 3> -dichlorobenzoylchloride (1.6 g.) in benzene (30 ml.) and the mixture was refluxed for 45 mins. on a steam bath. . The precipitate which- formed was filtered (2.0 g., m.p. 248-250°C ) and crystallised from methanol to give 3» 4-dichloro N-[ 1 , 2-dimethyl-2-dlmethylaniino-propyl] benzamide hydrochloride (1. 34 g.) m.p. 252~4°C. EXAMPLE -66 5"? benzamide hydx·och1or1de 2-Dimethylamino-.l , 2-dimethylpropylamine dihydrochloride (1.5 g.) was dissolved in water (3 ml.) and made alkaline with 5 sodium hydroxide. Benzene (lOO ml.) was added and the mixture dried (anhyd. agSO^) and filtered. The benzene solution was added to a solution of O-chloro benzoyl chloride (1.3 g.) in benzene (50 ml.), the mixtiire refluxed for 1.5 hrs. and allowed to stand overnight. The crystals were filtered and recrystallised from isopropanol to give benzamide hydrochloride (1.9 g.) m.p. 245-47°C .

EXAMPLE fr ζΟ N-[ 1 , 2-Dimethy1-2- ( dimethylamino ) ropyl] carbamic acid ethyl ester hydrochloride 2-Dimethylamino-l , 2r-dimethylpropylamine dihydrochloride ( 2 g.) was dissolved in water (3 ml.) and made alkaline with 5 NaOH. Benzene (lOO ml.) was added and the mixture dried (anhyd. NagSO^).

A solution of ethyl chloroformate (l.07 g.) in ben ene (30 ml.) was added dropwise to the benzene to stand overnight. Crystals formed which were filtered to give N-[ 1 , 2-Dimethyl-2"( dlinethylamlno )propyl] carbamic acid ethyl ester hydrochloride (1.5 g«) m.p. 1 - 6°C. EXAMPLE ?Q QO N-methy1-2-dimethy1amino-2-met yl^ ropy1amine d1 droch1oride 2-Dimethylamino-2-methyl-propylamine dihydrochloride (2 g.) was dissolved in water (2 ml.) and the solution made alkaline with 5 sodium hydroxide. Chloroform (100 ml.) was added and the mixture was dried (anhyd.

Na2S0j!±) and filtered. A solution of chloral (1. g.) in chloroform (50 ml.) was added to the stirred and cooled chloroform solution. The mixture was heated under reflux for 40 hrs., and the excess chloroform evaporated under reduced pressure to give an oily residue (0.9 g.)« This was dissolved in ether (50ml.), the solution was added dropwise to a cooled and stirred suspension, of lithium aluminium hydride (0.43 £·) in ether (100 ml) and the mixture was heated under reflux for 16 hrs. On cooling, the excess lithium aluminium hydride was decomposed by the addition of water, and the mixture dried (anhydrous NagSO^) , and extracted with ether. The ether extracts were extracted with 2N HC1 (2 x 20 ml. and 0 ml.), the excess water was evaporated under reduced pressure and the liquid residue dried by re-evaporation with ethanol/benzene mixture to give a solid residue. This was crystallised from ethanol to give N-methy1-2-d1methy1amino-2-methyi^ ro y1am1ne dihydroch1o ide (0.9 . ) 40397/2 EXAMPLE 61 3, -Dichloro-N- [2- (dimethylamino) -2-methylpropyl.i--N-methylbenzamide hydrochloride N-methyl-2-dimethylamino-2-methylpropylamine dihydrochloride (0.5 g.) was dissolved in water (2 ml.) and the solution was made alkaline with 5N sodium hydroxide. Benzene (100 ml.) was added and the mixture dried (anhyd. Na2S04) , filtered, and added to a solution of 3,4-dichlorobenzoyl chloride (0.5 g.) in benzene (50 ml.). The mixture was heated under reflux for one hour, and the solid which separated was filtered and washed with benzene to give 3 ,4-dichloro-N- [2- (dimethylamlno) -2-methylpropyl] -H-methylbenzamide hydrochloride (0.95 g.) m.p. 163-165°C.

EXAMPLE 62 2-Benzyliiethylaii no"2~ineth lpropylamine (a) 2~Benzylmethylamino-2-meth lpropionitrile A solutio of sodium cyanide (9.8 g.) in water (50 ml.) was added dropwise to a stirred mixture of N-benzylmethylamlne hydrochloride (30 g.) in water (100 ml.) and acetone (11 g.)f cooled to 0°C. The mixture was stirred for 20 hrs. extracted with ether (4 x 100 ml.) the ether extracts washed with water (1 x 100 ml.) dried (anhyd. Na2SG4 and filtered (hyflo) . The excess ether was removed under reduced pressure to give a solid residue (28 g. ).

The solid was purified by column chromatography (Silica column with ethyl acetate as eluent) to give 2«benzylmethylaiaino-2-methylproplonitrile (18 g.) 40397/2 (b) 2-Bcnzylme hy amino-2-methylpropylamine A solution of 2-benzylmethylainino-2-methyl- propionitrile (6.7 g.) n ether (100 ml.) was added dropwise to a stirred solution of sodium dihydro bis[ 2-metlioxyethoxy] aluminate (28.5 g.) n ether (150 ml.), kept at 0°C. The mixture was then gently refluxed for .20 hrs.'and then excess reducing agent was decomposed hy the dropwise addition of water to the cooled suspension. The mixture was dried , filtered (hyflo) and the excess ether evaporated under reduced pressure. Tha residual liquid. as distilled under water pump vacuum to give 2-benzyituethyl- amino-2-methylpropylamine (3.8 g.) b.p. 138-140°C.

EXAMPLE 63 3 ,4-Dichloro-N- [2-benzylmethylamino-2-methylpropyl] benzamide hydrochloride A solution of 2-benzylmethylamino-2-methyl-propylamine (0.5 g.) in henzene (25 ml) was added dropwise to a solution of 3 , 4-dichlorobenzoyl chloride (0. ^ g.) in benzene' (25 ml.) and the mixture was heated on a steam bath for two hours. OJI cooling a precipitate appeared which was filtered and recrystallised from ethanol to give 3 ,- -dichloro-N- [ 2-hcnzylinethylami o-2-methyIpropyl] benzamide hydrochlorid (0.7 g) in. p. 192-193?. · EXAMPLE 64 2-Benzylmethylamino-l , 2-dimethylpropylamine Methyl -iodide (21.3 g.,) in ether (25 ml.) was added dropwise to a suspension of lithium (2.1 g.,) in 40397/2 Ν -. -When- all the lithium hacUdissolved a solution 2-benzyl-methylamino-2-methylpropionitrile (9.4 g.,) in ether (50 ml.) was added dropwise to the stirred methyl lithium solution at -10°C. The mixture was 'allowed to stir for 20 hrs. The excess methyl lithium was decomposed hy the dropwisc addition of water to the ice cold mixture. The mixture was dried (anhyd. NagSO^) , filtered (hyflo) and the dry ethereal i ine solution added dropwise to an ice cooled,, stirred suspension of lithium aluminium hydride (lO g.) in ether (200 ml.).

The mixture was gently refluxed for 16 hrs.

The excess LiAlII^ was decomposed hy the dropwise addition of water to the ice-cold mixture. The mixture was dried (anhyd. NagSO^), filtered (hyflo) and the excess ether evaporated under reduced pressure to give a residue liquid. This was distilled under water pump vacuum to give 2-behzylmethylamino-l , 2-dimethyl- ropy1amine (4.1 g.) b.p. 151°C.

EXAMPLE 65 3 ,4-Dichloro-N-|2-benzylmethylamino-l , 2-dimethylpropyl ] -benzamide hydrochloride A solution of 2-benzylmethylamino-l , 2-dimethyl-prcpylaminc (0.5 g., 0.0024 mole) in benzene ( 5 ml.), was added dropwise to a solution of 3, ^t-dichlorohcnzoyl^ chloride (0.51 g., 0.0024 mole) in benzene (25 ml.).

The mixture was gently refluxed for 2 hrs. and the benzene evaporated under reduced pressure to give a residual solid. This was recrystallised from isopropanol/ ether to give 3 ,4-dichloro-N- [2-benzylmethylamino-l , 2- 40397/2 EXAMPLE ,66 N-[ 2-Bon ylmcthyl amlno-2- ctny]jpropyl] benzamide A solution of 2-benz lmethYlauiino-2-me h l added . 8 g.,) in , n a erai solid kaline with (3 50 ml.). filtered (hyflo), and the excess ether evaporated under reduced pressure to give a solid residue which was rccrystallised from cyclohexane to give N-[ 2-Benzyliiiethy1amino-2-methyl propyl] benzamide ( . ) . ■·. .- .

EXAMPLE 67 N-[ 2-Mcthylaiiiino-2-methylpropyl] benzamide N-[ 2-benzylmethylamino-2-methylpropyl] benzamide (3.55 g.j) was dissolved in glacial acetic acid (30 ml.) and hydrogenated over palladium chloride (140 mg.) 320 ml of H2 was taken up. The catalyst was filtered and the filtrate washed with ether (2 x 100 ml.).

The filtrate was then made allcaline with 5 sodium •7. hydroxide and extracted wii;h ether (3 x 60 cm ) . The ether extracts were dried (anhyd. Na2S02j(), filtered arid the excess ether evaporated under reduced pressure to give a liquid residue (2.7 g.) the liquid was dissolved in ether (30 ml.). To this was added ethereal nCl in a dropwise manner. The excess ether was evaporated under reduced pressure to give a sticky solid which was refluxed with ethyl acetate for two hours. On EXAMPLE -9S G? 2-Al 1y1met y1am:i.no~2-inethy1propy1amine (a) 2-Methylamino-2-methy],propioni tri1e • A solution of. sodium cyanide (51.5 g. , ) in water (150 ml.) was added dropwise over a period of 1 hr. to a cooled mixture of methylamine hydrochloride (67.5 g.j) acetone (58 g.,) and water (150 ml). The mixture was stirred overnight at room temperature and then made alkaline to litmus by the addition of dilute sodium hydroxide solution and extracted with ether (3 x 100 ml.). The ether extract was washed with water (2 x 0 ml.) dried (MgSO^) and the solvent was removed in vacuo to give a colourless liquid (71.6 g.). This was distilled at 5½-7°/22 mm to give 2-methy1ami11o-2- ethy1propioni tri1e as a colourless liquid (65.8 g., 67 ) (h) A mixture of 2-methylamino-2-methylpropionltrile (l .7 g., 0.15. mole) allyl bromide (18. Og. , Q .15 mole), sodium carbonate (15·9 g., 0.15 mole), sodium iodide (0.2 g., 0.001 mole) and methyl ethyl ketone (200 ml.) was heated under reflux for 40 hrs. The sodium carbonate was filtered off and the solvent was removed from the filtrate in vacuo to give a yellow oil, T.L.C. (Silica, ether), three components RF 0.8, 0.4 and 0.0. 4 The oil was passed through a column of silica 40 x 3.5 cm. using ether as an eluent to give 2-a11y1methy1amino-2-methylpro ionitrl1e (lO.O g., 48$) (c) 2-Allylmethylamino-2-methylpropionitrile (1.3 g.>) in benzene (20 ml., dry) was added dropwise to a stirred solution of sodium dihydro-bis [ 2-mctlioxy-ethoxy] aluminatc of nitrogen and stirred overnight. The excess reducing agent was decomposed by the addition of water. The phases were separated, the organic phase was washed with water, the aqueous phase was washed with benzene and the combined organic extract was dried (MgSO^) and the solvent was removed in vacuo to give a pale yellow liquid (1.8 g.). Distillation at 80-90°/l5 mm. gave 2-allylmeth lamino-2-meth lpropylamine as a colourless liquid (0.8 g. , * 60%) .

EXAMPLE -6η , ~Dichloro-N-( 2-allylmethylamino-2-methylpropyl )benzamide A mixture of 2-allylmethylamino-2-methylpropylamine (1.3 g.,) and 3, ½-dichlorobenzoyl chloride (3.15 g.,) was heated under reflux in dry benzene (150 ml.); for 1 hrs. The cooled mixture was washed w th dilute sodium hydroxide solution (2 x 30 ml.), water (2 x 0 ml.), dried (MgSO^) and the solvent was removed in vacuo to give a yellow oil (3.9 g.)« The oil was passed through a column of alumina kO x 2.5 cm. using ethyl acetate as an eluent to give 5i ^-dichloro-N-( 2-allylmethyl-amino-2-methylpropyl )-benzamide as a pale yellow liquid (2.25 g., 71/ -EXAMPLE io N-[ 2-Methyl-2~[ methyl (2-propyn)fl ) amino] propyl] benzamide A solution of N-[ 2~methylamino-2-methylpropyl] benzamide (l g., 0.0053 mole) in methyl ethyl ketone (25 ml.) was added dropwise to a mixture of propargyl bromide (0.58 g., 0.052 mole), sodium carbonate (0.55 g., Ο.ΟΟ52 mole) and a few crystals of sodium iodide in gently under reflux for hrs .

The inorganic solids were filtered off and the excess MEK evaporated under reduced pressure to give a liquid residue traces of solid. Water was added to the residue, the mixture made alkaline with 5 sodium hydroxide and extracted with ether (3 x 50 ml.).

The ether extracts were dried (anhyd. Na2S0;)s filtered (hyflo) and the excess ether evaporated at atmospheric pressure to give a liquid residue. The residue was loaded onto an alumina column (30 3-5 cm.) and eluted with ethyl acetate. Fractions of 25 ml. were collected once t.l.c. spotting had determined that the first of the compounds was leaving the column. Fractions 1 to 7 were combined and the excess ethyl acetate evaporated under reduced pressure to give Ν-Γ 2-methyl--2-[ methyl (2-propyngfl )amino ] propyl] benzamide ( 1.0 g . ) EXAMPLE m N-[ 2-methyl-2[ methyl ( 5-mcthyl-2-butenyl ) amino] ropyl] henzamide A solution of NC2-methylamino-2-methylpropyl] henzamide (l g., 0.0052 mole) in methylethyl ketone (MEK) (25 ml.) was added to a solution of l~hromo-3-riLethyl h'ut~ 2-eiie (0.78 g., 0.0052 mole) in MEK (hO ml.) containing sodium carbonate (0.55 g., 0.0052 mole) and a few crystals of sodium iodide. The mixture was heated under reflux for 30 hrs. The inorganic solids were filtered off and the filtrant concentrated by evaporation under reduced pressure to give a liquid collected and concentrated to give ( 3~met y 1 - 2-buteny 1 ) amino J propy 1] benzamide (1.2 . ) .

The oxalate was prepared as follows :- A solution of anhyd. oxalic acid (0.26 g. mole) in ethyl acetate (20 ml.) was added dropwise to a solution of the base (0.8 g., 0.0029 mole) in ethyl acetate (20 ml.). A sticky ppt. was thrown out. A little methanol was added to the hot mixture to dissolve the ppt. on cooling this gave crystals of . N-[ 2-methyl-2-,' ( -methyl-2-'buteny 1 ) mino] propyl] benzamide oxalate EXAMPLE -8-2 SL ' N-[ 2-| (cycloprop7lmethyl )methylamino] -2-methylpropyl] benzamide A solution of N-[ 2-methylamino-.2-methyl^propyl] -benzamide ( 1 g., 0.0052 mole) in MEK (50 ml.) was added to a solution of cyclopropyl e-ea' no-l bromide (0.66 g. in MEK (30 ml.) containing sodium carbonate (0.55 g.>) and a few crystals of sodium iodide. The mixture was refluxed for 2 hrs. and then filtered and the excess MEK evaporated under reduced pressure to give a liquid residue. This was passed down an alumina column, eluting with ethyl acetate to give -Γ 2-[ (cyclopropylmc-thyl ) methylamino-2-methylpropyl henzamide (0.9 g- ) A solution of oxalic acid (0.31 g.>) n ethyl acetate was added dropwise to the base (0.9 g.>) in ethyl acetate to give a sticky precipitate. A few drops of methanol were added to the hot mixture to dissolve the ppt.

On cooling crystals of N-[ 2-[ (cyclopropylmethyl )meth l-amino] -2-»methyl propyl] henzamide oxalate were obtained, m. . l 2~l EXAMPLE Θ - 3> N-[ 2-( al lylmethylamino )--2-methyl propyl] benzamide oxalate & A solution of N-[ 2-methylamino-2-metliylpropyl] - . benzamide (l. g.,) in MEK (25 ml.) was added to a solution of ally! bromide (0.58 g.,) in MEK (25 ml.) containing sodium carbonate (0.5 g.>) and .a few crystals of sodium iodide. The mixture was refluxed for 24 hrs. The inorganic solids were filtered off and the filtrant concentrated by evaporation under reduced pressure. The liquid residue was eluted down an alumina column with ethyl acetate to give N-[ 2-(allylmethyl mino )-2~methylpropyl] benzamide 1.1 g .

A solution of oxalic acid (0.4 g., 0.0045 mole) in ethyl acetate (20 ml.) was added dropwise to solution of the base (l g., 0.0045 mole) in ethyl acetate (20 ml.) to give a sticky precipitate. A few drops of methanol were added to the hot mixture to dissolve the precipitate, on cooling crystals of N-[ 2-( al1ylinethy1amino )-2-methy1propy1 )benzamide oxalate were obtained ni.p. (137-139°C).

EXAMPLE -0 ^ N-[ 2-methy1-2-(methylphenethy!amino) ropyl] benzamide A solution of N-[ 2-methylamino-2-methylpropyl] benzamide (l g.,) in methyl ethyl ketone (25 ml) was added dropwise to a mixture of 2-phenylethyl bromide (0.97 g.,) in methyl ethyl ketone (25 ml), sodium carbonate (0.55 g.) and a few crystals of sodium iodide. The mixture was refluxed for 30 hrs.

The inorganic solids were fi tered off and the filtrant ethyl acetate. Fractions (15 ml.) were collected and the first 7 fractions were combined and the excess ethyl acetate evaporated under reduced pressure to give Ν-Γ 2-methyl--2-(methylphenethylaruino ) ropyl | benzamide (0.5. g.).

N-[ 2-methyl-2-(methylphenethylamino ) ropyl] benzaniide oxalate The base (0.4 g.,) was dissolved in ethyl acetate (20 ml) and to it was added dropwise a solution of oxalic acid (0.12 g.) in ethyl acetate (.10 ml).

A sticky precipitate was thrown out which was crystallised from ethyl acetate/methanol to give N-[ 2-methyl-2~(methylphenethylamlno )propyl] benzamide oxalate (0.25 g. ) m.p. (l50-152°C).

EXAMPLE 8-5 fj~ 2-Methy1-2-$iniethy1amino-ijfexy1amine (a) 2-Methy1-2-dimethy1amino-Zh.cxanenitri1e A solutio of potassium cyanide (34.20 g.,) in water (75 ml.) was added dropwise to ft stirred solution of dimethylamine hydrochloride (40.8 g.,) (50 g., 0.5 mole) in water (60 ml.) cooled in an : ice-water bath. The mixture was vigorously stirred for 24 hrs., diluted with water (200 ml.) and extracted w th ether. (4 x 200 ml.). The combined ether extracts were washed with water (4 x 200 ml.), dried (NagSO^) and evaporated to leave a colourless oil which was distilled at 12 mm. to give a colourless oil which when distilled gave 2~methy1~2^i i^hylamino^hexanenitri1e as a colourless oil ( 1. 7 g., 67$, b^p. 92°/l2 nun). (7.70 g.,) in dry ether (100 ml.) was added dropwise to a stirred solution of sodium dih'ydro-bis(2-uiethoxy~ e thoxy)alumi.nate (43.3 g., 70 solution in benzene, 25$ excess) in dry ether (lOO ml.) under nitrogen with ice water cooling. The solution was refluxed overnight under nitrogen and allowed to cool. Ether (200 ml . ) was added, followed, b dropwise addition of excess water with ice-water cooling to destroy excess reducing reagent. The mixture was filtered on hyflo and the. filtrates- extracted with ether (4 x 100 ml.).

The combined ether extracts were washed with water (4 x 200 ml.), dried (Na^SO^) and evaporated leaving a colourless oil. Distillation of the oil afforded 2-methyl-2-dimethylainino-hexylamine as a colourless liquid (4.808 g., 61$) b.p. 86-88/12 mm..

EXAMPLE «86 3, 4-Dichloro-Ν-Γ 2-niethyl-2~dimethylamino-hexyl1 ben amide A solution of 3 , 4~dichlorobenzoyl chloride (2.1 g.,) in dry benzene (25 ml.) was added to a solution of 2-methyl-2-dimethylamino-hexylamine (1.58 g.,) in dry benzene (25 ml.) and the mixture heated under reflux for 1.5 hrs.. The mixture was diluted with water, basified with 2.N sodium hydroxide solution, and extracted with benzene (.4 x 100 ml.). The combined benzene extracts were washed with water (4 x 50 ml.), dried (NapS02j) and evaporated affording 3 , 4--dichloro~N-12-methy1--2-d.imethy1amino exy1J benzamide s a colourless oil (3.6 g., ca 100$) which slowl crystallised.

EXAMPLE s N-[ 2-Methy1-2-JLimethy."I.amino-hexy1]†rormamid.e To a solution of acetic formic anhydride (2.9 mis., 20 mrnole) (prepared by stirring acetic anhydride [2. Oh ml.] and formic acid [O.S6 ml.] on a water hath 5 at 50-60° for two hrs. and cooling) , was added dropwise, . with stirring, 2-methyl-2-dimethylamino^iexylamine (2.37 g.,) at such a rate that the temperature never rose above ½0°C. The solution was stirred for 30 mills, ether (6 ml) was added, and stirring continued at |0 room temperature overnight. The mixture was diluted with ether (50 ml.), basified with 2N sodium hydroxide solution and extracted with ether (! x 100 ml.).

Evaporation of the washed (2 x 100 ml.), dried (NagSO^) extracts gave a colourless oil (2.2 g.). T.L.C. (silica, methanol) showed two. spots: RF 0.5 and RF 0.0. j The oil was chromatographed on a column of silica (20.x 3.0 cm.) eluting with methanol and fractions (6 x 100 ml.) were collected. Fractions 2-5 were combined and evaporated affording N-[ 2-methyl~2-0 dimethylamino|hexyl] formamide as a colourless oil (l.¾27 g EXAMPLE - N-Methy1-2-metliy1-2~dimethy1amino4 exy1amine ■ A solution of N-[ 2-methyl-2-dimethylamino-hexyl] 5 formamide (1.395 g., 7.5mmole) in dry tetrahydrofuran (25 ml.) was added dropwise with stirring to an ice-cold suspension of lithium aluminium hydride (0.51 g.») in dry tetrahydrofuran (25 ml.).. After addition, the mixture was heated under reflux overnight and allowed to decompose excess reducing agent. The mixture was filtered on hyflo, the filtrates washed with 2N sodium hydroxide solution (2 x 50 ml.), water (4 100 ml.), dried (NagS02 ) and evaporated to give a pale yellow oil.

The oil was dissolved in benzene and extracted with 2N hydrochloric acid (4 x 0 ml.). The acid extracts were basified with 5N sodium hydroxide and extracted with ether (4 x 100 ml.). The ether extracts were washed with water (4 x 100 ml.) dried ( agSO^), and evaporated affording N-methyl-2-methyl-2-dimethyl~ amino-hexylamine as a pale yellow oil (0.800 g., 62%) EXAMPLE -89 4 3, 4~Dichloro-N-methyl- --[ 2-methyl-2-dimethylamino hexyl1 benzamide A solution of 3> 4-dichlorobenzoyl chloride (1.048 g., 5 mmole) in dry benzene (25 ml.) was added to a solution of N-methyl-2-methyl-2-dimethylamino hexylamine (0.752* g.» mmole) in dry benzene (25 ml.) and the solution heated under reflux for 1 hr.. The cooled solution was washed with 2N sodium hydroxide solution (4 x 100 ml.), water (4 x 100 ml.), dried ( agSO^) and evaporated to a colourless oil (1.6.12 g.). The oil was dissolved in benzene, chroraatographed on a column of alumina (25 x 3.Q cm.) eluting with benzene/ ether 1:1, and fractions (9 x 100 ml.) were collected.

Fractions 2-8 were combined and, on evaporation, afforded 3 » 4-d:i.chloro-N-methyl-N-[ 2-me.thyl~-2-dimethylaraino~ hex l benzami e as a colourless oil 1.282 . 84 . 40397/2 3,4-pichloro--N--methyl~N- [2"methyl-2~dAn¾ ylamino^hea¾ll benzamide oxalat A solution of oxalic acid (0.180 g. , 2 mmole) in ethyl acetate (5 ml.) was added to a aiution of 3,4-dichloro-N-methyl-U-I2-methyl-2^dinietJiylaniinohexyl]benzamide (0.69 g. , 2 mmole) in ethyl acetate (5 ml.) and the solution boiled for two rains. The solution was allowed to cool, then reduced in volume to ca. 5 ml. , when a colourless oil began to separate. On leaving overnight, hit crystals appeared, which wer filtered, washed with ethyl acetate and dried to afford 3,4-dichloro-N-methyl-N- -methyl-2-dimethylaminohexyl]ben2amide oxalate (0.644 g., 76%), ra.p. 13Q-135°C. 40397/ 6

Claims (1)

1. CLAIMS of the general N C C N arid acid addition salts thereof in which one of the 1 2 groups R and R represents hydrogen or alkyl and the other represents an acyl group or a benzenesulphonyl R is lower lower alkoxy or phenyl and the phenyl group R as well as the phenyl ring of the benzenesulphonyl group may each be substituted by one or more halogen trifluoromethyl amino dialkylamino groups R alkynyl or cycloalkylalkyl or the phenyl ring of which may be substituted as defined above for the 3 4 phenyl of the benzoyl group and wherein R and R can also together an alkylene group which may be interrupted by an or R5 may represent hydrogen or alkyl fi 7 8 and R represents hydrogen and R and R may be the same or and are each an alkyl group or together form a pentamethylene group except that when R5 and R6 are hydrogen R3 is hydrogen or alkyl and R7 together with R8 form a pentamethylene cannot represent 7 Compounds as claimed in claim 1 in which R and R8 together with the adjacent carbon atom for a cyclohexylidene η as claimed in claim 1 in which and represent alkyl containing from 1 to carbon Compounds as claimed in claim 1 of the general i in which R represents chloro substituted benzoyl or in which Alk is alkyl R represents hydrogen or Compounds as claimed in claim 1 in which R represents one of the following acyl sulphonyl and 2 2 R represents a hydrogen atom or a methyl represents a methyl R represents a methyl group or a benzyl group represents a hydrogen represents hydrogen or and together form a Compounds as claimed in claim 1 in which represents one of the following acyl or or represents an ethoxycarbonyl R represents hydrogen or 5 represents 7 8 idene and R together form a 3 and R together the adjacent Compounds as in claim 1 in which represents one of the following acyl tosyl or or a methyl ethyl 2 represents a hydrogen a formyl group or 2 a methyl group when R is acyl or if represents methyl or represents R5 represents a hydrogen represents a hydrogen and R together with the adjacent nitrogen atom a and 7 8 and R together form a cyclohexylidene Compounds as claimed in claim 1 in which represents one of the following acyl groups or or an ethoxycarbonyl group 2 R represents a hydrogen atom or a methyl group represents a methyl group R represents a hydrogen atom or dimethylallyl R represents hydrogen or represents 7 R represents and represents methyl or cyclohexylamine mino hydrochloride enzamidomethy1 hexylamine cyclohexylamine hydrochloride 3 ethyl 32 3 33 dimethy1amino cyclohexylmethyl 34 benzylcyclohexylamine 35 and 36 and piperidine 3 3 hexyl ethyl cyclohexyl 46 cyclohexyl hexyl cyclohexyl methylpiperazine hydrochloride cyclohexyl 56 3 benzaraide hydrochloride 3 1 benzamide acid ethyl 3 benzamide 63 6 prop 68 A process for the production of compounds as claimed in claim 1 where is acyl and R2 is hydrogen which comprises acylating a of the 4 7 ft R R R R and R have the a ove stated acylating agent yielding a group or for the production of compounds in which R is 2 alkyl and R reducing the said acyl group to an alkyl group and acylating the resulting monoalkylainino with a compound yielding said acyl group or for the production of compounds in which or is hydrogen the corresponding compound n which or R represents a benzyl or for the production of compounds in which 4 R are other than hydrogen alkylating a 1 2 compound of formula I in whic the group NR is not capable of and if desired isolating the product as an acid addition process as claimed in claim 74 substantially as herein described with reference to Examples 77 and Compounds as claimed in claim 1 when prepared by a process as claimed in claim 7 or claim A therapeutic composition comprising a compound as claimed in claim or claim 76 in association with a pharmaceutically acceptable A composition as claimed in claim 77 in which the formulation is liquid or solid and is adapted oral administration or parenteral A composition as claimed in claim 78 in the form of a which may be and liquid oral dosage A composition as claimed in claim 78 in dosage unit form suitable for oral each dosage containing from 8 500 A composition as claimed i claim 78 in dosage unit form suitable for parenteral administration each dosage unit containing from 10 500 Applicants 7 PART insufficientOCRQuality