GB1575593A - Cycloalkylamines - Google Patents

Description

(54) NEW CYCLOALKYLAMINES (71) We, ASTRA LAKEMEDEL AKTIEBOLAG, a Swedish Body Corporate of Fack, S-151 85 Sodertalie, Sweden, 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: The present invention relates to new compounds of the diphenylcycloalkylamine type having a therapeutic activity in the central nervous system and useful as experimental substances in the study of the central nervous system of animals.

Compounds having the general formula

wherein X and Y, which may be the same or different, each represents a hydrogen or chlorine atom or a methoxy group, n is 0 or 1 and R1 and R2, which may be the same or different, each represents a hydrogen atom or a methyl group, said compounds having psychopharmacological properties, are previously known from British Patent No.

1,372,644.

The present invention provides a compound of the general formula

wherein R and R', which may be the same or different, each represents a hydrogen atom or a methyl group; or a therapeutically acceptable acid addition salt thereof.

The compounds have effects on the central nervous system which will be further discussed below. The effects of the compounds may make them useful for treatment of i.a. depression, anxiety, parkinsonism and obesitas, and as pharmacological tools to investigate the role of catecholamine neurons in the central nervous system.

The compounds of the invention may be prepared by different methods: a) The compound of the invention with the formula

can be obtained according to the reaction scheme

razz rQd, < ; > rev. arent riaw The starting ketone may be obtained by reacting 1,1-diphenyl-ethylene and allene and oxidizing the cycloaddition product or by reaction of diphenylketone with diazomethane.

The oxime group in the intermediate compound may be substituted by other reducible groups and thus a compound of the formula

wherein E is > C=NOR", > C=NOCOR", > C=NOSO2R", > C=NR, > CHNRCOR", > CHNRCOOR", > CHNs, > CHNO2 or I > C=NNHR" wherein R has the meaning given above and R" is a hydrogen atom, an alkyl group, e.g. with 1-3 carbon atoms such as methyl, or an aryl group such as phenyl or tolyl, may be reduced to form a compound of formula I. b) The compounds of the invention can be prepared according to the reaction scheme

0(2 (2 (2 V reducong anent nx wherein R and R' have the meaning given above and R"' is a hydrogen atom, an acyl or sulphonyl group. Alternatively a compound of the formula

wherein M is a reactive ester group, can be used as the Starting material whereby a reducing agent is not required.

Illustrative examples of reactive ester groups are -Cl, -Br, -I or -OSO2R" wherein R" has the meaning given above. Thus, in general a compound of the formula

wherein D is > C=O or > CHM and wherein M is a reactive ester group, may be reacted with a compound of the formula R"'NRR' wherein R, R' and R"' have the meaning given above, whereby rhe reaction is carried out in the presence of a reducing agent when D is > C= O. c) An acid or acid derivative of the formula

wherein Z is a hydroxy group or an acid residue, such as an organic acid residue of the formula R"'COO-, wherein R" has the meaning given above or an inorganic acid residue e.g. Cl, Br or I, may be degraded to form a primary amine of formula II above, in a Schmidt reaction. The degradation requires heating with hydrazoic acid or an inorganic salt thereof, suitably in the presence of a strong mineral acid.

Modifications of the methcd, whereby the primary amine is obtained from an acid amide of the above formula wherein Z is NH2 in a Hofmann reaction or from an acid azide of the above formula wherein Z is N2 in a Curtius reaction or from a hydroxamic acid derivative of the above formula wherein Z is -N±O-CO-R", wherein R" has the meaning given above, in a Lossen reaction, may also be employed. The Hofmann reaction may be carried out by treatment of the amide with Br, or C12 under alkaline conditions. The Curtius reaction may be carried out by heating the azide in an inert solvent and subsequent hydrolysis of the intermediate formed. The Lossen reaction may be carried out by heating the starting compound in an aqueous solution, possibly under alkaline conditions, and, if necessary, hydrolysis of the compound formed.

In the cases where an intermediate acylic derivative is obtained by any of the methods, a)-c) hydrolysis is necessary to obtain the compounds of the formula I.

Some of the methods above are reductive methods. Suitable reducing agents to be used at these methods are: hydrogen in status nascendi (sodium and some alcohol; zinc and acetic acid), catalytically activated hydrogen gas (Pb, Pd, Ni are appropriate catalysts) and hydrides such as LiAlH4.

From a primary/secondary amine prepared according to any of the methods described above the secondary/tertiary amine may be prepared by methylation by ways well known in the art. Thus, a primary amine may be reacted with formamide and formic acid in an Eschweiler-Clarke reaction.

Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids being sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic and benzoic. These salts are readily prepared by methods known in the art.

In clinical practice, the compounds of the present invention will normally be administered orally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, lactate, acetate or sulfamate, in association with a pharmaceutically acceptable carrier. Accordingly, terms relating to the novel compounds of this invention, whether generically or specifically, are intended to cover both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific Examples, would be inconsistent with the broad concept. The carrier may be a solid, semisolid or liquid diluent or capsule. These pharmaceutical preparations constitute a further aspect of this invention. Usually the active substance will constitute 0.1 to 95% by weight of the preparation, more specifically 0.5 to 20% by weight for preparations intended for injection and 2 to 50% by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid fine grain carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, com starch or amylopectin, cellulose derivatives, or gelatin and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol waxes, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatin, talcum or titanium dioxide. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volative organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order readily to distinguish between tablets containing different active substances or different amounts of the active compound.

For the preparation of soft gelatin capsules (pearl-shaped closed capsules) consisting of gelatin and, for example, glycerol or similar closed capsules, the active substances may be admixed with a vegetable oil. Hard gelatin capsules may contain granulates of the active substance in combination with solid, fine grain carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from 0.2% to 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol and propyleneglycol. Optionally such liquid preparations may contain colouring agents, flavourings agents, saccharine and carboxymethyl-cellulose as a thickening agent.

Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from 0.5% to 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

In therapeutical treatment the suitable diurnal doses of the compounds of the invention are 5-500 mg for oral application, preferentially 50 250 mg, and 1-100 mg for parenteral application, preferentially 1050 mg. The following Examples, in which the chemical syntheses follow the reaction schemes below, will further illustrate the invention.

r.mple o P'(CYJ)2 |E x at 3 Exmplc- ;9 NOH / NH, /Examp le 5 C x qnp l e 6 fX ) NFICOOC,sis 9cq3 In the Examples, the melting points are uncorrected and were determined in open capillary tubes. Elemental analyses are indicated by symbols of the elements.

The analytical results obtained were within #0.4% of the theoretical values if not otherwise stated. IR, NMR and MS data were consistent with the assigned structures.

Example 1.

3,3 -diphenylcyclobutanone.

A thermal cycloaddition reaction was performed by heating a mixture of 160 g of l,l-diphenylethylene, 20 g of allene, 1 g of hydroquinone and 50 ml of toluene at 200 C for 16 hours. The complex mixture of products was distilled in vacuo.

A fraction, 13 g, boiling at 113120 C/2.5 Pa ways highly enriched in l-methylene3,3-diphenyl-cyclobutane as shown by NMR. A solution of this crude product (13 g) in 50 ml of (CHS)2CO was added to a stirred solution of 107 g of NaIO4 in 600 ml of H2O and 300 ml of (CH3)2CO and then a solution of 1.3 g of KMnO4 in 50 ml of H20 was added dropwise at 250 C. After continued stirring for 16 hours the solvent was removed in vacuo and the residue extracted with ether. Drying (MgSO4) and evaporation of the solvent gave 12.5 g of a viscous oil which was chromatographed on silica (Merck Kieselgel 3070 mesh, 1.2 kg) with toluene as eluent. 4.7 g of the crude ketone desired was obtained and recrystallized from CH,OH. Yield 4.3 g, mp. 8283 C.

Example 2.

3,3 -diphenylcyclobutanone.

The title compound was prepared from 115 g of diphenylacetyl chloride, which was reduced to diphenylketene. The crude solution of diphenylketene was added to a solution of 2 equivalents diazomethane without filtration. No gradient elution was found to be necessary in the isolation procedure. The desired ketone was isolated by chromatography as described in Example 1. Yield 14.4 g, mp 8283 C.

Example 3.

3,3-diphenylcyclobutanone oxime.

A solution of 3,3-diphenylcyclobutanone (5.0 g, 22.5 mmol) and NH2IH . HC1 (5.0 g, 71.9 mmol) in 50 ml of pyridine was heated under reflux for 4 hours. The mixture was poured into ice-water and stirred for 1 hour. The white precipitate was collected and washed with cold H2O and dried. Recrystallization from ethanol gave 4.4 g (82%) of the oxime, mp 133134 C. Elemental analysis: (Cl6H,SNO) C, H, N, O.

Example 4.

3,3-diphenylcyclobutylamine (Method a).

A solution of the oxime obtained according to Example 3 (4,0 g, 16.8 mmol) in 100 ml of dry ethyl acetate was added dropwise to a slurry of LiAIH4 (3.0 g, 79.0 mmol) in 100 ml of dry ether at a rate sufficient to maintain gentle reflux. The mixture was then heated under reflux for 16 hours. After cooling the excess of hydride was destroyed by adding 3 ml of H2O, 3 ml of 15% NaOH solution and 9 ml of H2O. The precipitate was filtered off, washed with ether and the filtrate was dried (MgSO4). The solvent was evaporated in vacuo yielding 3.6 g of a colourless oil, which crystallized on standing. Mp 4347 C. Recrystallization of the hydrochloride from H2O afforded 3.5 g (80%) of the amine hydrochloride, mp 273-274@ C.

Elemental analysis: (SlsH,8NCl) C, H, N, Cl.

Example 5.

N-ethoxycarbonyl-3,3 diphenylcyclobutylamine.

Ethyl chloroformate (2.2 g, 20 mmol) was added dropwise during 15 min. to a stirred mixture of 3,3-diphenylcyclobutylamine (3.3 g, 12.7 mmol) in 30 ml of CHCI, and 10 ml of 2 M NaOH solution at 0 C. Stirring was continued for a further 15 min. and then the organic layer was washed with H2O and dried (MgSO4).

The solvent was removed in vacuo giving 4.2 g of a colourless oil, which crystallized on cooling. Recrystallization from CH3OH gave 2.8 g (75%) of the desired compound, mp 130131 C. Elemental analysis: (Cl9H2lNO2) C, H, N, O.

Example 6.

N-methyl-3,3-diphenylcyclobutylamine (Method a).

A mixture of the carbamate obtained according to Example 5 (2.75 g, 7.5 mmol) and LiAIH4 (1.0 g, 26 mmol) in 50 ml of dry ethyl acetate was heated under reflux for 4 hours. Isolation as described for 3,3-diphenylcyclobutylamine gave 1.0 g of a colourless oil. Recrystallization of the hydrochloride from ethanol afforded 1.7 g (82%) of the amine hydrochloride, mp 260262 C. Elemental analysis: (ClXH20NCl C, H, N, Cl.

Example 7.

N,N-dimethyl-3,3-diphenylcyclobutylamine (Method b).

A solution of the 3,3-diphenylcyclobutanone (1'2 g, 4.9 mmol) in 5 ml of dimethyl formamide was added to dimethylammonium formate [from HCOOH (0.46 g, 10 mmol) and dimethylamine (1.6 g, 35 mmol) at - 100 C] and the mixture was heated under reflux for 5 hours. Ether was added to the cooled reaction mixture, and the solution was extracted with 2 M HCl solution. The acidic extracts were made alkaline with a 50% NaOH solution and extracted with ether. The ether extracts were combined and dried over MgSO4. The solvent was evaporated in vacuo and the resulting crude base (1.1 g) had a m.p. 57-58 C. The amine was converted to its hydrochloride and recrystallized from ethanol/di-isopropyl ether to give 0.9 g (64%) of the desired amine hydrochloride, mp 222224 C. Elemental analysis: (C,8H22NCI) C, H, N, Cl.

Example 8.

Preparation of tablets. a) Each tablet contains: 3,3-diphenylcyclobutylamine-HC1 10 mg Lactose 60 Starch 29 Magnesium stearate 1 The powders are mixed and directly compressed to tablets with a diameter of 6 mm.

The active substance shown above may be replaced by other pharmaceutically acceptable acid addition salts according to the invention. b) 3,3 -diphenylcyclobutylamine 50 mg Aerosil (Registered Trade Mark) (silicium dioxide) 20 Lactose 100 3tarch 30 Magnesium stearate 2 The active principle is mixed with the Aerosil. This mixture is added to the other powders. Tablets are compressed with a diameter of 10 morn.

The active substance shown above may be replaced by other pharmaceutically acceptable acid addition salts according to the invention.

Example 9.

Prepararion of capsules. a) N-methyl-3 ,3 diphenylcydobutylamine 20 mg Peanut oil 60 The solution is filled into soft gelatine capsules, each capsule containing 20 mg of the active principle.

The active substance shown above may be replaced by other pharmaceutically acceptable acid addition salts according to the invention. b) N-methyl-3,3 -diphenylcyclobutylamine 10 mg Polyoxyethylene sorbitan monoleate 100 The capsules are made as described above.

The active substance shown above may be replaced by other pharmaceutically acceptable acid addition salts according to the invention.

Pharmacological methods.

The compounds were administered as salts intraperitoneally (i. p. ) or intravenously (i.v.) to male albino mice (the NMRI strain) weighing 18-22 g.

Inhibition of the accumulation of NA, DA and 5 HT was measured in brain slices both in vitro and in vivo by simultaneously recording the accumulation of 3H-noradrenaline ('H-NA) or SH-dopamfine (3H-DA) and of '4C-5-hydroxy- tryptamine (14S-HT), (Eur. J. Elharmacol. 17 107 (1972) and Acta Pharmacol. Toxicol. 39 152 (1976) j. In the in vivo measurements the test compounds were injected 0.5 hours before the sacrifice of the animals. The EC,, and ED,, values were calculated from log dose response curves by linear regression analysis and based on four concentrations or dose levels including four determinations per dose level.

The assessment of 5-HTP potentiation was performed as described in the above cited Acta Pharmacol. Toxicol. article. The EDso values were estimated by probit analysis, and are based on at least four doses with five animals per dose level.

The motor activity was measured in electronic activity cages (Activity Meter type DO, Farad Electronics, Sweden). The animals were tested individually and controls with saline were run simultaneously. The activity was recorded 20 min. after administration of the test compounds or saline. The animals were pretreated with the following compounds (compound, dose mg/kg i.p. and time before test compound is given): Reserpine, 2.5, 24 h; Phenoxybenzamine, 5, 15 min; Pimozade, 1, 2 h; DL-tr-methyltyrosine methyl ester hydrochloride 200, 2 h; Methergoline, 2.5, 30 min.; The mydriatic effect was estimated by observing the pupil diameter after i.v. injection.

Acute.toxicity (24 hours) was determined (J. Med. Chem., 17, 65 (1974)).

The results of the pharmacological studies are given in Table 1 and in the enclosed diagrams which illustrate: Fig. 1.

Locomotor activity in mice after giving the test compounds i.p. Each value represents the mean activity for groups of 6-8 mice. One-way analysis of variance was used over the total observation period (2 h), followed by Student's t-test, (twotailed), Control

3,3 -diphenylcyclobutylamine

N-methyl-3,3-di-phenylcyclobutylamine

N,N-dimethyl-3 -diphenylcyclobutylamine

D-amphetamine

Fig. 2.

Hyperactivity induced by N,N-dimethyl-3,3-diphenylcyclobutyl-amine. Effects of pretreatment with phenoxybenzamine 15 min. and with reserpine 24 hours before said test compound. Each column represents the mean total locomotion (counts/2 hrs) for groups of W8 mice. The extensions to the columns stand for s.e.m. Statistical analysis as described in Fig. 1. xxxp < 001, compared with N,N-dimethyl-3,3-diphenylcydobutylamine alone (Student's t-test).

Fig. 3.

Hyperactivity induced by N,N-dimethyl-3,3-diphenylcyclobutylamine and Damphetamine. Effects of pretreatment with pimozide 2 h and &alpha;-methyltyrosine 2 hours before said test compound and D-amphetamine. Each column represents the mean total activity (counts/2 hrs) for groups of 68 mice. The extensions to the columns represent s.e.m. Statistical analysis as described in Fig. 1 xxp < 0.01; xxx p < 0.001, compared with N,N-dimethyl-3,3-diphenylcyclobutylamine or D-amphetamine alone (Student's t-test).

TABLE 1 Some pharmacological effects of 3,3-diphenylcyclobutylamines

Inhibition of Accumulation a Potentiation Mydriatic Acute in vitro, IC50 M invivo ED50 mol/kg i.p. of 5-HTPb Effectc Toxicityd ED50 mol/kg PD200 mol/kg LD50 mol/kg Compound NA 5-HT NA 5-HT DA i.p. i.v. i.v.

3,3-diphenylcyclo- 2,2 2,8 103 162 > 154e > 38 15 192 butylamine (1,0-3,9) (1,4-5,1) (78-151) (116-309) (7%) N-methyl-3,3-diphenyl- 0,8 3,0 31 95 91 9 9 128 cyclobutylamine (0,4-1,6) (1,3-6,4) (15-55) (61-194) (5-14) N,N.dimethyl-3,3-di- 0,8 0,9 32 48 104 17 24 104 phenylcyclobutylamine (0,4-1,4) (0,6-1,4) (22-44) (34-72) (9-30) Desipramine 1,6 9,3 34 > 66e > 100e > 170 63 116 (0,7-5,1) (4,9-16) (25-51) (23%) (0%) Chlorimipramine 0,9 0,07 109 20 > 113e 8 6 142 (0,6-1,8) (0,04-0,10) (75-439) (16-25) (9%) (5-11) DL-Amphetamine 1,0 45 44 > 100e 60 > 27 (0,7-1,3) (33-72) (20-56) (0%) a Inhibition of five minutes accumulation of the labelled transmitter amines in slices of mouse hypthalamus (NA) and (5-HT) or striatum (DA) expressed as the dose producing 50% inhibition, 95% confidence limits in brackets. The mice were killed half an hour after the i.p. injections b The dose of the test compound producing head-twitching in 50% of the animals when given 1 h prior to 5-hydroxytryptophane (5-HTP) 90 mg/kg i.v., 95% confidence limits in brackets. c PD200. is the dose which increases the pupil diameter by 200%. d Lethality within 24 h after administration. e Per cent inhibition at the highest dose tested is given in brackets.

Comments to the pharmacological tests.

Inhibition of the NA accumulation in vitro and in vivo.

The 3,3-diphenylcyclobutylamines decreased the accumulation of 3H-NA within the same concentration range as the tricyclic antidepressants desipramine and chlorimipramine.

The secondary amine and the tertiary amine were more active than the corresponding primary amine. The compounds of the invention also reduced NA accumulation after i.p. administration in the same ormer of potency as in the in vitro studies. The secondary and tertiary amines were equipotent with desipramine and amphetamine.

Inhibition of the 5-HT accumulation in vitro and in vvo.

The cyclobutylamines interfere with the accumulation of 5-HT in the order of potency: tertiary > secondary primary.

Inhibition of DA accumulation in vivo.

The secondary amine and the tertiary amine reduced DA accumulation in striatal slices after i.p. administration, whereas the primary amine had only a weak effect. However, the compounds of the invention were weaker inhibitors of the DA accumulation than of the NA and 5-HT accumulation.

Potentiation of 5-HTP in mce.

Pretreatment with inhibitors of 5-HT accumulation potentiates the behavioural effects of 5-HTP e.g. head-twitching. The secondary and tertiary amines which decreased 5-HT accumulation in vivo also potentiated the behavioural effects of 5-HTP. Said two test compounds were as potent as chlorimipramine.

Mydriatic effects and acute toxicity.

The new compounds had weaker mydriatic effects than chlorimipramine. The order of potency of the mydriatic effects was secondary amine > primary > tertiary.

The i.v. toxicities of the new compounds was in the same range as those of the reference compounds.

Motor activity.

The cyclobutylamines were found to cause motor stimulation and behavioural effects rather similar to those of amphetamine, characterized by motor excitation, irritability, sniffing, tremor, rearing and stereotype like behaviour such as circling and repetirive movements of the head. Animals receiving the three cyclobutylamines showed significantly increased locomotion compared with the control animals during especially the later phase of the observation period (Fig. 1). The tertiary amine (N,N-dimethyl3,3-diphenylcyclobutyl amine) was most potent and its effect on locomotion was therefore further studied.

Pretreatment with the NA receptor blocker phenoxybenzamine (Fig. 2) did not antagonize the hyperactivity caused by the tertiary amine nor that caused by amphetamine. The 5-HT receptor blocker methergoline did not prevent the hyperactivity caused by the tertiary amine. These results with phenoxybenzamine and methergoline demonstrate that the tertiary amine does not directly interact with central NA and 5-HT receptors.

Pretreatment with the DA receptor blocker pimozide reduced the activity caused by the tertiary amine and almost completely suppressed amphetamine-caused hyperactivity (Fig. 3). After treatment with the tyrosine hydroxylase inhibitor, a-methyltyrosine, which reduced both NA and DA levels in the brain, amphetamine-induced hyperactivity was significantly reduced but not the hyperactivity caused by the tertiary amine (Fig. 3). Reserpine treatment, which results in a lowering of both NA, DA as well as 3-HT levels in the brain by impairment of the granula binding of monoamines reduced the activity of the tertiary amine strongly (Fig. 2) but did not reduced amphetamine-induced hyperactivity.

The finding that the hyperactivity induced by the compounds of the invention is not blocked by the tyrosine-hydroxylase inhibitor a-methyltyrosine, in contrast to the hyperactivity induced by D-amphetamine, indicates that the increase in activity of the compounds of the invention is resistant to catecholamine synthesis inhibition. This indicates that the compounds could be of special value in treatment of diseases characterized by a lowered catecholamine synthesis in the brain such as depressions and parkinsonian disease.

Claims (12)

1. WHAT WE CLAIM IS:1. A compound of the general formula

   wherein R and R', which may be the same or different, each represents a hydrogen atom or a methyl group; or a therapeutically acceptable acid addition salt thereof.
2. 2. A compound or salt according to Claim 1 hereinbefore specifically mentioned.
3. 3. A process for preparing a compound as defined in Claim 1 wherein a compound of the formula

   wherein E is > C=NOR", > C=NOCOR", > C=NOSO2R", > C=NR, > CHNRCOR", > CHNRCOOR", > CHN3, > CHNO2 or > C=NNHR", wherein R is as defined in Claim 1 and R" is a hydrogen atom, an alkyl group or an aryl group, is reduced.
4. 4. A process for preparing a compound as defined in Claim 1, wherein a compound of the formula

   wherein D is > C=O or > CHM and wherein M is a reactive ester group, is reacted with a compound of the formula R"' NRR' wherein R and R' are as defined in Claim 1, R"' is a hydrogen atom, an acyl or a sulphonyl group, the reaction being carried out in the presence of a reducing agent when D is > C=O.
5. 5. A process for preparing a compound as defined in Claim 1 wherein an acid or acid derivative of the formula

   wherein Z is a hydroxy group or an acid residue, is degraded to form a primary amine of the formula

   in a Schmidt reaction or via an acid amide in a Hofmann reaction, via an acid azide in a Curtius reaction or a hydroxamic acid derivative in a Lossen reaction.
6. 6. A process according to any one of Claims 3-5, wherein a compound which is a primary or secondary amine is prepared and the primary or secondary amine group is converted to a secondary or tertiary amine group respectively by methylation.
7. 7. A process according to any one of Claims 3-6, wherein the compound is prepared in the form of a free base and the free base is converted to a therapeutically acceptable acid addition salt by reaction with a therapeutically acceptable acid.
8. 8. A process according to any one of Claims 3-5, substantially as hereinbefore described with reference to any one of the Examples.
9. 9. A compound or salt obtained by a process according to any one of Claims 3-8.
10. 10. A pharmaceutical preparation comprising, as an active ingredient, a compound or salt according to Claim 1, 2 or 9 in combination with a pharmaceutically acceptable carrier.
11. 11. A composition according to Claim 10 substantially as hereinbefore described with reference to any one of the Examples.
12. 12. A method for treatment of disorders of the central nervous system which comprises. administering to a host, excluding man, suffering from such disorders a compound or salt according to Claim 1 or 2 or 9 or a composition according to Claim 10 or 11.