NO144957B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW TERBAPEUTIC EFFECTIVE CYCLOAL CYLAMINES - Google Patents

Description

The present invention relates to the production of new compounds of the diphenylcycloalkylamine type, which compounds have effects on the central nervous system and this makes them useful in the treatment of, among other things, depression, anxiety, parkinsonism and obesity, and as pharmacological agents for investigating the role catecholamine neurons have in the central nervous system.

The new compounds have the general formula:

where R and R<1>, which may be the same or different, each is a hydrogen atom or a methyl group, as well as therapeutic accept-

table acid addition salts thereof.

Compounds with the general formula:

where X and Y, which may be the same or different, are each a hydrogen or chlorine atom or a methoxy group, n is 0 or 1

1 2

and R and R , which may be the same or different, each being a hydrogen atom or a methyl group, and which compounds have psychopharmacological properties, are described in British Patent No. 1,372,644.

The compounds of formula I are prepared according to the invention by

a) a compound with the formula:

where E is ^C=NOR", r=C=NOCOR", ^=C=NOS02R", ^=C=NR,

Z^CHNRCOR", r^CHNRCOOR", :rrCHN3,' ^CHN02 or I==C=NNHR",

where R has the meaning given above and R" is a hydrogen atom, an alkyl group or an aryl group, is reduced to form a compound of formula I, or

b) a compound of the formula:

where D is ^;C=0 or ^CHM and where M is a reactive ester group,

is reacted with a compound with the formula:

R'" NRR'

where R and R<1> have the meaning given above, and R'" is a hydrogen atom, an acyl or a sulfonyl group, the reaction being carried out in the presence of a reducing agent when D is

C=0,

and, if desired, preparation from a primary/secondary amine prepared according to any of the methods set forth above.

of the secondary/tertiary amine by methylation in a manner known per se.

The starting ketone compound under method b) can be obtained

by reacting 1,1-diphenylethylene with allene and oxidizing the cycloaddition product or by reacting diphenylketone with diazomethane. Illustrative examples of reactive ester groups M are -Cl, -Br, -I or -OSO 2 R", where R" has the meaning indicated above.

In cases where an acyl intermediate or the like is obtained by any of the methods a) and b), it is necessary to carry out hydrolysis to obtain compounds of formula I. Suitable reducing agents in the methods are: nascent hydrogen (sodium and some alcohol ; zinc and'acetic acid), catalytically activated hydrogen gas (Pb, Pd, Ni are suitable catalysts) and hydrides such as LiAlH4.

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

Both organic and inorganic acids can be used for the formation of non-toxic pharmaceutically acceptable acid addition salts of the compounds of formula I. Examples of acids are sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, citric acid, acetic acid, lactic acid, tartaric acid, pamoic acid, ethanedisulfonic acid, sulfamic acid, succinic acid, cyclohexylsulfamic acid, fumaric acid, maleic acid and benzoic acid. These salts are easily prepared in a known manner.

In clinical use, the compounds of formula I 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, the lactate, the acetate, the sulfamate, and the like, in conjunction with a pharmaceutically acceptable carrier. The new compounds shall both generally and in particular include both the free amine base and the acid addition salts of the free amine base, unless the context in which these designations are used, e.g. in the particular examples, would be inconsistent with the concept of the invention. The carrier can be a solid, semi-solid or liquid diluent or capsule. The active substance will usually make up between 0.1 and 95% by weight of the preparation, more particularly between 0.5 and 20% by weight for preparations intended for injection and between 2 and 50% by weight for preparations suitable for oral administration.

The following examples, in which the chemical syntheses follow the reaction schemes below, shall further illustrate the invention.

In the examples, the melting points are uncorrected and were determined

in open capillary tubes. Elemental analyzes are indicated by the symbols of the elements. The analytical results obtained were within ±0.4% of the theoretical values, if nothing else is stated. IR, NMR

and MS data were consistent with the reported structures. Example 1

3^3-diphenyl c<ykl>obutanone

A thermal cycloaddition reaction was carried out by heating a mixture of 160 g of 1,1-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 113-120°C/2.5 Pa was highly enriched in 1-methylene-3,3-diphenylcyclobutane as shown by NMR. A solution of this crude product (13 g) in 50 mL (CH3)2CO was added to a stirred solution of 107 g NaI04 in 600 mL H2<D and 300 mL (CH3)2CO and then a solution of 1.3 g KMnO^ in 50 ml H20, added dropwise at 25°C. After continued stirring for 16 hours, the solvent was removed in vacuo and the residue extracted with ether. ^Drying (MgSO^) and evaporation of the solvent gave.

12.5 g of a viscous oil which was chromatographed on silica ("Merck kieselgel", 30-70 mesh, 1.2 kg) with toluene as eluent. 4.7 g of the impure desired ketone was obtained and recrystallized from CH 3 OH, yield 4.3 g, m.p. 82-83°C.

Example 2

3Z3-diphenylcyclobutanone

The above 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 of diazomethane without filtration. No gradient-

elution was found to be necessary in the isolation. The desired ketone was isolated by chromatography as described in example 1. yield 14.4 g, m.p. 82-83°C.

Example 3

3^3-diphenyl c<ykl>obutanone oxime

A solution of 3,3-diphenylcyclobutanone (5.0 g, 22.5 mmol) and NH 2 OH-HCl (5.0 g, 71.9 mmol) in 50 mL of pyridine was heated under reflux for 4 h. The mixture was poured into ice-water and stirred for 1 hour. The white precipitate was collected and washed with cold water and dried. Recrystallization from ethanol gave 4.4 g (82%) of the oxime, m.p. 133-134°C. Elementary analysis: '

(C16H15NO) C, H, N, O.

Example 4

^i^idiphenylcyclobutylamine (method a)

A solution of the oxime obtained in Example 3 (4.0 g, 16.8 mmol) in 100 mL of dry ethyl acetate was added dropwise to a

slurry of LiAlH^ (3.0 g, 79.0 mmol) in 100 mL of dry ether in an amount sufficient to maintain a gentle reflux. The mixture was then heated under reflux for 16 hours. After cooling, excess hydride was decomposed by wood

addition, of 3 ml H2O, 3 ml 15% NaOH solution. and 9 ml of H 2 O.

The precipitate was filtered off, washed with ether and the filtrate dried (MgSO4). The solvent was evaporated in vacuo to give 3.6 g of a colorless oil which crystallized on standing.

Temp. 43-47°C, recrystallization of the hydrochloride from H 2 and 3.5 g (80%) of the amine hydrochloride, m.p. 273-274°C.

Elemental analysis: (C^gH^NCl) C, H, N, Cl.

Example 5

Ethyl chloroformate (2.2 g, 20 mmol) was added dropwise over 15 min to a stirred mixture of 3,3-diphenyl-,cyclobutylamine (3.3 g, 12.7 mmol) in 30 mL CHCl 3 and 10 mL 2 M NaOH solution at 0°C. Stirring was continued for an additional 15 minutes and then the organic layer was washed with 1^0

and dried (MgSO4). The solvent was removed in vacuo to give 4.2 g of a colorless oil which crystallized on cooling. Recrystallization from CH 2 OH gave 2.8 g (75%) of the desired compound, m.p. 130-131 C.

Elemental analysis: (CigH21N02) C, H, N, 0.

Example 6

NlmetYl33i3-dif§DYic.Y3sl2!?y£Y.i5miD (method a)

A mixture of the carbamate obtained in Example 5 (2.75 g, 7.6 mmol) and LiAlH 2 (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 colorless oil. Recrystallization of the hydrochloride from etariol gave 1.7 g

(82%) of the amine hydrochloride, m.p. 260-262°C.

Elemental analysis: (C,'7H NC1) C, H, N, Cl.

Example 7

^i5z^im§tYil3i3l^i£§DYi£Y?Si25^£Yi§miD (method b)

A solution of 3,3-diphenylcyclobutahone (1.1 g, 4.9 mmol) in 5 mL of dimethylformamide was added to dimethylammonium formate (from HCOOH (0.46 g, 10 mmol)) and dimethylamine (1.6 g, 3 5 mmol ) at -10°C) and the mixture was heated under reflux for 5 h. 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 MgSO 4 . The solvent was evaporated in vacuo and the resulting crude base (1.1 g) had a melting point of 57-58°C. The amine was converted to its hydrochloride and recrystallized from ethanol/di-isopropyl ether, yielding 0.9 g (64%) of the desired amine hydrochloride, m.p. 222-224°C.

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

Pharmacological methods

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

Inhibition of accumulation of NA, DA and 5-HT was measured

in brain slices both in vitro and in vivo by simultaneous recording

3 3 3

of accumulation of H-norepinephrine (H-NA) or H-dopamine

3 14 14

( H-DA) and of C-5-hydroxytryptamine ( C-5-HT), (Eur. J. Pharmacol. _17 107 (1972) and Acta Pharmacol. Toxicol. 39 152

(1976)). In the in vivo measurements, the test compounds were injected 0.5 hours before the animals were killed. The EC5q and ED5Q values were calculated from log-dose response curves by linear regression analysis and based on four concentrations or dosage levels including four determinations per dosage level.

The determination of 5-HTP potentiation was performed as described in the above-mentioned Acta Pharmacol. Toxicol. article. The EDj-Q values were determined by probit analysis and are based on at least four doses with five animals per dosage level.

Motor activity was measured in electronic activity cages (Activity Meter type DO, Farad Electronics, Sweden). The animals were tested individually and control experiments with saline solution were carried out at the same time. The activity was recorded 20 minutes after administration of the test compounds or the saline solution. The animals were pretreated with the following compounds (compound, dose mg/kg i.p. and time before administration of test compound): reserpine, 2.5, 24 h; phenoxybenzamine, 5, 15 min.; pimozide, 1, 2 h; DL-o-methyltyrosine methyl ester hydrochloride 200, 2 h; metergolin, 2.5, 30 min.; the mydriatic effect was determined by observing the pupil diameter. after i.v. injection. Acute toxicity (24 hours) was determined

(J. Med. Chem., 17, 65 (1974)).

The results from the pharmacological studies are indicated in table 1 and in the accompanying diagrams which illustrate:

Fig. 1

Locomotor activity in mice after administration of the compounds i.p. Each value represents the mean activity for groups of 6-8 mice. One-way analysis of variance was used over the entire observation period (2 hours), followed by Studenf's t-test ("two-tailed").

Control •- ■ , 3,3-diphenylcyclobutylamine o—; o, N-methyl-3,3-diphenylcyclobutylamine □ , N,N-dimethyl-3,3-diphenylcyclobutylamine A A ,. D-amphetamine ■ M .

Fig; 2

Hyperactivity induced with N,N-dimethyl-3,3-diphenylcyclobutylamine. Effects of pretreatment with phenoxybenzamine 15 min. and with reserpine 24 hours before said test compound. Each column represents the mean total movement (counts/2 hours) for groups of 6-8 mice. The extensions of the columns stand for s.e.m. Statistical analysis as described in fig. 1. mm p < 0.01, compared to N,N-dimethyl-3, 3-diphenyl-cyclobutylamine alone (Studenf's t-test).

Fig. 3

Hyperactivity induced by N,N-dimethyl-3,3-diphenylcyclobutylamine and D-amphetamine. Effects of. pretreatment with pimozide 2 hours and α-methyltyrosine 2 hours before said test compound and D-amphetamine. Each column represents the mean total activity (counts/2 hours) for groups of 6-8 mice. The extensions of the columns represent s.e.m. Statistical analysis as described in fig. 1st p < 0.01; aaa p < 0.001, compared to N,N-dimethyl-3,3-diphenylcyclobutylamine or D-amphetamine alone (Studenf's t-test).

a Inhibition of five min.'s accumulation of the labeled transmitter amines in slices of mouse hyptalamus (NA) and (5-HT) or striatum (DA) expressed as the dose giving 50% inhibition, 95% confidence limits in parentheses . The mice were killed half an hour after i.p. the injections.

k The dose of the test compound that causes head twitching in 50% of the animals when administered 1 hour before 5-hydroxy-tryptophan (5-HTP) 90 mg/kg i.v., 95% confidence limits in parentheses.

P°200 is the dose that increases the pupil diameter by 200%.

Mortality within 24 hours of administration.

e Percent inhibition at the highest tested dose is given in parentheses.

Comments on the pharmacological trials

lDhik§£i22_5Y_NA;ak^umule^in^<e>^_<in_v>itro_og_in_yiyo

The 3,3-diphenylcyclobutylamines reduced the accumulation of 3H-NA in 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 formula I also reduced NA accumulation after i.p. administration to the same degree of effect as in the in vitro studies. The secondary and tertiary amines were as effective as desipramine and amphetamine.

lDi2i5§EiS2_5Y_ål5Tlå!sJSHmiii§EiS2_iD_Yi£E2_22_iD_YiY2

The cyclobutylamines affect the accumulation of 5-HT

in the following degree of effect: tertiary > secondary = primary.

iD^i2£Ei£2_5Y_5dl§ySHmHi§EiD2_il?_YiY2

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

Potentierin2_of_53HTP_in_mouse

Pretreatment with inhibitors of 5-HT accumulation potentiates the behavioral effects of 5-HTP, e.g. head jerking.

The secondary and tertiary amines that decreased 5-HT accumulation in vivo also potentiated the behavioral effects of 5-HTP. The two test compounds mentioned were as effective as chlorimipramine.

MYdriatic_effects_o2_acute_toxicity

The new compounds had weaker mydriatic effects than chlorimipramine. The degree of strength of the mydriatic effects was secondary amine > primary > tertiary. The i.v. toxicities of the new compounds were in the same range as those of the reference compounds.

It was found that the cyclobutylamines caused motor stimulation and behavioral effects that were quite similar to those of amphetamine, characterized by motor excitation, irritability, sniffing, tremors, withdrawal and stereotypic behaviour, such as circling and repetitive head movements. Animals receiving the three cyclobutylamines showed significantly increased locomotion compared to the control animals especially during the last phase of the observation period (Fig. 1). The tertiary amine (N,N-dimethyl-3,3-diphenylcyclobutylamine) was the most potent and its effect on movement was therefore further studied.

Pretreatment with the NA receptor blocker phenoxybenzamine (Fig..2) did not counteract the hyperactivity caused by the tertiary amine nor that caused by amphetamine. The 5-HT receptor blocker metergoline did not prevent the hyperactivity caused by the tertiary amine. These results with phenoxybenzamine and metergoline 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 the amphetamine-induced hyperactivity (Fig. 3). After treatment with the tyrosine hydroxylase inhibitor, α-methyltyrosine, which reduces 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 and 5-HT levels in the brain by weakening the granule binding of monoamines, greatly reduced the activity of the tertiary amine (Fig. 2), but did not reduce the amphetamine-induced hyperactivity.

The result that the hyperactivity induced by the compounds of formula I is not blocked by the tyrosine hydroxylase inhibitor α-methyltyrosine, in contrast to the hyperactivity induced by D-amphetamine, suggests that the increase in activity of the compounds of formula I is resistant to catecholamine synthesis inhibition . This shows that the compounds can have particular value in the treatment of diseases characterized by reduced catecholamine synthesis in the brain, such as depression and Parkinson's disease.

Claims (2)

1. Analogous method for the preparation of therapeutically effective cycloalkylamines with the general formula: where R and R', which may be the same or different, are each a hydrogen atom or a methyl group, as well as therapeutically acceptable acid addition salts thereof, characterized in that a) a compound with the formula: where E is ^rC=NOR", 7~C=N0C0R", 7^C=NOS02R" , ^=C=NR, ^CHNRCOR", "^CHNRCOOR" , ~TrCHN3, ^rCHN02 or ;^C=NNHR" , where R has the above meaning and R" is a hydrogen atom, an alkyl group or an aryl group, is reduced to form a compound of formula I, or b) a compound of the formula: where D is ^C=0 or !^CHM and where M is a reactive ester group, is reacted with a compound of the formula: where R and R' have the meaning given above, and R'" is a hydrogen atom, an acyl or a sulfonyl group, the reaction being carried out in the presence of a reducing agent when D is ^C=0, and, if desired, preparation from a primary/secondary amine prepared according to any of the above-mentioned methods, from the secondary/tertiary amine by methylation in a manner known per se. 2. Analogous method according to claim 1, characterized in that N,N-dimethyl-3,3-diphenylcyclobutylamine is produced.