CA2037114C - N-cycloalkylalkylamines, their process of preparation, their use as medication and their synthetic intermediates - Google Patents

Abstract

A compound which is a N-cycloalkylalkylamine of general formula (I):

(see Formula I) in which:
R1 is a furyl radical or a thienyl radical, or, with the proviso that Q represents a cyclopropane-1,2-diyl group (see Formula II) R1 is a phenyl radical, R2 is lower alkyl, R3 is hydrogen or lower alkyl, m has a value of 1 or 2, R4 is cycloalkyl -CH(CH2)n, in which n has values from 2 to 5, R5 is phenyl which can be monosubstituted, disubstituted or trisubstituted by halogens or by identical or different lower alkyl or alkoxy radicals, and R5 is thienyl, Q represents an ethylene-1,2-diyl group (-CH=CH-) or a cyclopropane-1,2-diyl group (see Formula III), and their salts additions with pharmaceutically acceptable acids.

A pharmaceutical composition comprising a compound of general formula (I) with the above definitions for the treatment of disturbances of a neurological type and/or psychic type, the dysfunctions of the gastro-intestinal tract, and/or gastric-duodenal ulcerations.

Description

N-Cycloalkylalkylamines, their process of preparation, their use as a medicament and their synthesis intermediates.
The present invention relates to novel N-cyclo-alkylalkylamines, their process of preparation and their usefulness in the form of medicaments, as well as their synthesis intermediates.
The amines correspond to the general formula (I):

~C\

R3/ ( CH2 ) m in which:
R1 is a furyl radical or a thienyl radical, or, with the proviso that Q represents an cyclopropane-1,2-diyl group (-CH CH-), R1 is a phenyl radical, R2 is lower alkyl, R3 is hydrogen or lower alkyl, m has a value of 1 or 2, R4 is cycloalkyl -CH(CH2)n, in which n has values from 2 to 5, R5 is phenyl which can be mono, di or trisub-stituted by halogens or by identical or different lower alkyl or alkoxy radicals, or R5 is thienyl, Q represents an ethylene-1,2-diyl group (-CH=GH-) or a cyclopropane-1,2-diyl group (-CH-CH-).

In the present description:
a lower alkyl radical means linear or branched radicals comprising from 1 to 5 carbon atoms, halogen means bromine, fluorine and preferably chlorine, and lower alkoxy means radicals comprising up to 3 carbon atoms which are linear or branched and optionally substituted by halogen atoms such as fluorine, but with methoxy radicals being preferred.

p Furthermore, the optical and/or geometrical isomers resulting from the dissymmetry centres of the cycloalkylalkyl amines (I) form an integral part of the invention. The addition salts of the amines (I) with inorganic or organic pharmaceutically acceptable acids, as well as their possible solvates, also form an integral part of the invention.
By way of acids which are frequently used for the preparation of the addition salts there may be mentioned, without implying any limitation, acetic, benzenesulphonic, camphosulphonic, citric, ethanesulphonic, fumaric, hydrobromic, hydrochloric, lactic, malefic, malfic, methanesulphonic, music, nitric, pamoic, n-phosphoric, salicylic, stearic,.succinic, sulphurfic and tartarfic acfids.
When studied in animals, the cyaloalkylalkylamines (I) of the invention and their salts prove to be weakly toxic and exhibit, at the same times a psychotropic activity shown by their ability to inhibit convulsive attacks brought about by picrotoxin, and an inhfibiting actfivity in respect of the ulcerogenic effect of cysteamfine in the gastro-duodenal area, which property is attributed to the particular affinity of the compounds for the sigma receptors present in these organs.
Accordingly, the compounds of the inventfion in the form of medicaments are of undeniable usefulness and in these indications it is preferred that at least one of the following conditions shall be met:
R1 is a thienyl radical, R2 is lower alkyl comprising from 1 to 3 carbon atoms, and is especially ethyl, R3 is methyl, m has a value of 1, R4 is cycloalkyl CH(CH2)n, fin which n has a value of 2, R5 is phenyl, and Q is the ethylene-1,2-diyl group (-CH=CH-) or the cyclopropane-1,2-diyl group (--C~-CH-).

The invention also proposes a process for the preparation of the amines (I) which COTIS7.stS, as is shown in scheme 1:
for preparing of a compound (II) of the general formula I, in which R3 is hydrogen and R1, R2, m, R4, R5 and Q have the meanings stated above, i) in acylating an amine (V) of the formula:

in which R1, R2, R5 and Q are as defined above, with a reagent (VI) (R4-[CH2)m-1J-CO)pZ1 VI
in which:
R4 and m have the meanings defined earlier, p has a value of 1 or 2 , and Z1 is hydroxyl (-°OH) or halogen, such as chlorine or bromine, if p = 1, and is an oxygen atom if p=2, to give an intermediate carboxamide (IV) R1'C/CH2\Q R5 2 5 R2~ ~NH
CO IV
t (CH2)m-1 I

which is reduced with a metal hydride (Hm) of the formula M1(t) M2 H(r) Rx(s) (Hm) in which M1 represents'an alkali metal atom such as lithium or sodium in which the index (t) has values of 0 or 1, M2 is an element of group ITI of the pexiodic classification of the elements and is preferably boron or aluminium, (r) is the index representing the number of hydrogen atoms of the hydride and has values of 1, 2, 3 or 4, Rx is a carbonitrile group or a lower alkyl or alkoxy radical in which the index (s) has values of 0, 1, 2 or 3, in which the indices presented above correspond, for these hydrides, to the relation: (r) + (s) - (t) = 3 and in which it is preferred to reduce the compounds (IV) with the hydrides (Hm.2) in which M2 is aluminium or is boron if (r) has a value of 3 and (s) and (t) have a value of ~. 0 0 , to give a cycloalkylalkylamine (II) of the general formula (I) in which R3 is hydrogen R1~ ~CH2e PR5 ~ C~ Q
R2 IdH II

(CH2)m ~4 ii) in alkylating an amine (V) with an alkyl halide R4-(CH2)m-Z2 in which R4 and m have the meanings already mentioned and Z2 is a halogen such. as chlorine, bromine or iodine, and, for preparing a cycloalkylalkylamine (TII) of the general formula (I) in which R3 is lower alkyl and R1., R2, m, R4, R5 and Q have the meanings already specified, it consists i) in carrying out a reductive alkylation of a compound (II) of the invention, which consists in reacting the compound with an aldehyde R6-CHO, in which R5 is the carbon homologue immediately lower than the radical R3 which is to be introduced (R3 = CH2-R6), and with a reducing agent such as a metal hydride or organo-metallic hydride (Hm.3) of the formula (Hm) already defined, and in which, more particularly, ~I2 is boron and, preferably, Rx is a carbonitrile group, ,'-~ ~~5 r,~
ii) or in acylating an amine (VTI) R ~C~H2\Q/R5 VII

in which R1, R2, R3, R5 and Q have the meanings specified for (I), with an acyl halide of the formula R4-((CH2)m-1]COZ4, in which R4 and m have the meanings already defined and Z~ is a halogen and more particularly chlorine or bromine, to give the intermediate N-carboxamide (VIII) / ' Q

I
( ~H2)m-1 which is reduced with a metal hydride (Hm.2) defined above, to give a cycloalkylalkylamine (III) of the invention, iii) or in reacting an aminonitrile intermediate (IX) R \ 'CH a / 5 C Q
NC/ ~N IX
R3/ ( H2 ) m I

in which R1, R3, m, R4, R5 and Q are as defined for (I) with an organo-magnesium reagent R2MgZ3, in which R2 is lower alkyl and Z3 is halogen such as chlorine, bromine or iodine, to give a cycloalkylalkylamine (III), iiii) or in alkylating an amine (VII) defined above, with an alkyl halide R4-(CH2)m-Z2 in which R4 and m have ttie meanings defined far (I) and Z2 is a halogen such as chlorine, bromine or iodine.

u.
~- L.t ~ C~ ~' ~ V \C! \ Q/ V I I
/ \ !

R \ /CH2\ !R5 R1\ ~CH2e /R5 C Q C Q
R2/ eNH IV R2/ ~N~ VIII

(CH2)m-1 (CH2)m°

R \ /CH2\ /R5 R1\ lCH2\ 'R5 C Q ---~~. Ce Q
R2/ \NH II R2/ ~N~ III
(1:H2)m R3 (CH2)m R4 R~

\ C/ ~Q
/e NC N IX
R3 e( CH2 ) m European Patent Application EP 0 298 703 dated January 11, 1989 describes thiophene derivatives of the formula:
Rte /(CH2)p-Rph /C~

in which, in the broadest sense, Rt is a thienyl radical, R1, R2 and R3 represent lower alkyl radicals, Rph is an optionally substituted phenyl radical, and p has values of 1, 2 or 3 and in which, for the preferred campounds, R1 is an ethyl radical, R2 and R3 are methyl radicals, Rph is a phenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or 4-chlorophenyl radical, and p has values of 1 or 3.
These compounds are presented as having low toxicity and having a regulating effect on the motility of the gastro-intestinal tract, characterised by a stimulant effect on a tract exhibiting slowed activity and, conversely, characterised by an inhibiting effect on a hyperactive tract.
Being different in respect of their chemical structure, especially in respect of the nature of the carbon chain linking the two aromatic sites which are referred to as Rt and Rph in the preceding formula, and in respect of the nature of the substituents of the amine group, the compounds of the European Application differ fram the cycloalkylalkylamines (I) of the invention in respect of their properties. Essentially, no psychotropic-type activity has been reported for the compounds of Application No. 0 298 703, such activity making it possible to envisage, inter alia, that the amines (I) are useful in the treatment of neuropsychic disturbances. Equally, no mention is to be found that the compounds of this previous art are active in respect '~~ ~~~~~

of acting on ulcerous lesions of the gastro°ihtestinal tract.
As has been explained above, the intermediate compounds which permit the preparation of the products (I) of the invention are essentially the derivatives of structure (V), (VII) and (TX).
The process for the preparation of the compounds (V) consists in alkylating a compound R1°CH2°W, in which R~. is as defined for (I) and W is a carbonitrile radical (°CN) or a carboxyl radical (-COON) by means of an alkyl halide of formula R2Z6, R2 being defined for (I) and Z6 being a halogen, to give, far W = -COOH, an acid of formula (XV) R1(R2)-CH°COOH, and, for W = -CN, a nitrile of formula (XVI) R1(R2)-CH-CN, which is hydrolysed to the acid (XV), and in alkylating the acid (XV) by means of a reagent (XIII) of formula Z5-CH2-Q-R5, Z5 being a halogen or an alkylsulphonyloxy radical and R5 and Q being as defined for (I), to give the acids (XIV) R1(R2)C(COOH)CH2-Q°R5, and in thereafter preparing, as shown in scheme 2, the isocyanates (X) by a Curtius reaction, from these acids R1\ /CH2~ ~R5 / C'.. Q X

in which isocyanates R1, R2, R5 and Q have the meanings stated for (I), and finally in hydrolysing their isocyanate group under conditions identical with those stated later for the compounds (X') to give the primary amine (V).
It is also possible, in order to obtain the latter compounds, to use a process adapted from that described in European Patent Application No. 0 298 703, already mentioned, and which consists, as shown in scheme 2, in reacting a ketone R1-CO-R2 with formamide and formic acid to prepare the N-substituted formamide of the formula R1(R2)CH°NH°CHO, which is dehydrated with phosphorus oxychloride to give a corresponding isonitrile of formula R7.(R2)CH-NC which, when alkylated with a reagent (XIII), gives the isonitrile ~~~~~~~c intermediate (X') of the formula Rl\C CH2e~ R5 X' R2 \NC
which is hydrolysed with a strong inorganic acid such as hydrochloric acid, the latter being preferred, in an ac~teous solvent containing a ketone of low molecular weight such as acetone in sufficient amount to give a homogeneous reaction medium, so as to yield a primary amine (V).
For preparing the intermediates of formula (VII), if R3 is methyl, the preferred process consists in reducing the isocyanate group of an intermediate (X) or the isonitrile group of an intermediate (X') with a metal hydride or organo-metallic hydride (Hm.l) of formula (Hm) already defined, in which M2 is preferably aluminium, and, if R3 is lower alkyl, either reacting a compound (V), already described, with an alkyl halide Z5R3, in which Z5 is chlorine, bromine or iodine, or acylating an intermediate (V) with an acyl halide R6COZ6, in which R6 is the homologue lower by one carbon atom than R3 (R3 = CH2-R6), to give an intermediate of the formula \~/

CO
!

followed by reducing this with a metal hydride (Hm.2) as described above.
The process of preparation of the aminonitriles (IX) consists in preparing an aminonitrile (XI3) Rl(NC)CH-N(R3) (CH2)m- R4 from an aldehyde Rl-CHO, from a secondary amine HN(R3)-(CH2)m-R4 and from an alkali metal cyanide in accordance with the Strecker reaction and using a technigue n ~J ~ B
described by S.F. Dyke et al., Tetrahedron 1975, 31, p. 1219, and then alkylating the derivative (XII) with a reagent Z5-CH2-Q-R5 (XIII) in which R5 has the values defined for (I) and Z5 is chlorine, bromine or iodine or an alkylsulphonyloxy 5 radical.
This alkylation is carried out by first preparing the anion of aminonitrile (XII) by the action of an appropriate strong organo-metallic base in an inert solvent such as THF.
Lithium N,N-diisopropylamide (LDA) is preferred. It is 10 prepared "in situ" from equimolecular amounts of N,N-diisopropylamine and butyl-lithium.
After reaction of the compound (XII), which takes 1 to 2 hours at between 20 and 100°C, the reactant (XIII) is added to the anion and the reaction is allowed to proceed for 1 to 2 hours at ambient temperature close to 20°C to give the intermediate (IX), which is purified.

f, , 6~ Y A .9 ;3 4rn u~ e;7 v ~ .'~. '.'se;

/C=O

~ H /CH / H
R2 NH R2 COON (XV) NC ~T~ (XII) CHO R3 (CH2)m a R \ R1\ CH2\ j 5 NCH /C\ Q
R2 NC R2 COOH (XIV) R \C CH2~~SR5 R1\C/CH2Q, R5 R1' % H\ /R5 C Q
R2/ NC (X') R2~ \NCO (X) NC/ ~ \ (IX) R3 (CH2)m The preparation of compounds of the invention, (II) and (III), of the general formula (I) is presented explicitly in the text which follows:
a) if the process consists in acylating a compound (V) with a reagent (VI) [R4-[(CH2)m-1]-CO]p21 to give a N-carboxamide intermediate (IV), which is subsequently reduced.

If the reagent (VI) is an acid halide (p = 1, Z1 = halogen), the preferred reaction is carried out in a single-phase medium, in toluene or more advantageously in methylene chloride, and consists in adding, to a solution containing one mole of derivative to be acylated, from 1.0 to 1.5 mole of an amine, which is generally triethylamine, and then adding the reagent (VI) in an amount equimplecular to the triethylamine. The solution is thereafter kept for 3 to 48 hours at a temperature of between 15 and 30°C so as to achieve as complete a reaction as possible.
Further, if the acylating reagent (VI) is an acid anhydride (p = 2: Z1 = oxygen), the reaction may, if the boiling point of the anhydride is below 140°C, be carried out without solvent, by reacting the compound (V) in a large excess and at the reflux temperature of the reagent (VI). The preferred method consists however in carrying out the reaction by using pyridine as the solvent and reacting from 1 to 5 mole of anhydride per mole of compound to be acylated.
Generally, the use of 1.2 to 1.8 mole of anhydride at the reflux temperature of pyridine, for from 1 to 3 hours, gives suitable results.
The preferred method of acylation of (V), if the reagent (VI) is a carboxylic acid (p = 1t m = 1 or 2; Z1 =
OH) consists in preparing, in_situ, an anhydride which can be a mixed anhydride, from this carboxylic acid, and then acylating the intermediate (V) with this anhydride.
Advantageously, the reaction is carried out in anhydrous non-polar solvents of the ether category. Tetrahydrofuran is preferred and the mixed anhydride is first formed at a temperature of between -40 and 0°C by adding, per mole of acid (VI), from l.O~to 1.5 mole of 'tertiary amine such as N-methylmorpholine followed by from 0.~ to 1.2 mole of isobutyl chloroformate.
Thereafter, one mole of the intermediate (V) to be acylated is added and the reaction is allowed to proceed for from 1 to 48 hours at a temperature of between 0 and 6o°C.
Usually, the outcome of the reaction is satisfactory at a temperature of between 10 and 25°C after a duration of 10 to 20 hours.
Alternative methods can employ other dehydrating agents, enumerated, for example, in "Advanced Organic Chemistry°', J. March, Ed. Wiley 1985, p. 349. Thus, the reaction has been carried out using dicyclohexyl-carbodiimide as the dehydrating agent in an anhydrous medium, and, more particularly, with formic said, using N-N'-carbonyldiimidazole.
The reduction of the N-carboxamide intermediates is carried out with metal hydrides or organo-metallic hydrides (Hm.2), defined above, in a manner appropriate to the specific reduction of the carboxamide group.
For this purpose, it is advantageous to use lithium aluminium hydride or aluminium hydride, the latter being preferred. The reactions are carried out in solvents which are inert to the reagents used, such as in ethers as, for example, diethyl ether, 1,2-dimethoxyethane or tetrahydrofuran (THF), the latter being preferred.
Again preferably; the reducing agent used, aluminium hydride, can be prepared °'~.n situ" from aluminium halides and metal hydrides as described, for example, in "Reduction with complex metal hydrides" - N.G. Gaylord, 1956, Ed.
Interscience - p.6 to 8 and 51 to 53.
Advantageously, the reduction reaction in THF of one mole of intermediate (IV) or (VIII) consists, in a first stage, in preparing aluminium hydride (in situ) by reaction of 0.75 to 2 mole of aluminium chloride with 2.25 to 6 mole of lithium aluminium hydride, these reactants being used in a molecular ratio close to 1:3, followed by introducing the N-carboxamide intermediate at a temperature of between -10 and +30°C, leaving the reduction reaction to praceed for 1 to 24 hours at the same temperature and then decomposing the reduced complex obtained and isolating the compounds of the invention (II) or (III) by appropriate methods.
Most commonly, tha reductions are carried out at a temperature of between 10 and 20°C for 2 to 6 hours.

~~, 9. , , 14 ~ 69 e~ ~~ ~. ~ ';t As has been described earlier for the use of the reactant (VI) if the latter is an acid halide, the reaction is equally applicable to the acylation of the intermediates (VII) by the reactants R4-[(CH2)m-1]-CO-Z4, in which Z4 is chlorine or bromine, so as to prepare the intermediate carboxamides (VIII) which, when reduced as indicated, make it possible to obtain the cycloalkylalkylamines (III) of the invention.
b) If the process consists in N-alkylating an intermediate (V) or.(VII) with an alkyl halide R4-(CH2)m-Z2, already described, in which Z2 is chlorine, bromine or iodine, the reaction is carried out in solvents which are inert to the reactants, such as, for example toluene and acetonitrile, one mole of intermediate (V) or (VII) being reacted with from 0.5 to 1.5 mole of halide.
Preferably, from 0.80 to 1.20 mole of derivative in which the halogen is bromine or iodine are used and optionally an organic or inorganic base is added to assist the reaction, which consists in heating the reaction mixture to a temperature of between 20 and 110°C for 2 to 5 hours, the products thereafter being isolated and purified by the usual methods, especially by chromatographic methods.
c) If the process consists in carrying out a reductive N-alkylation to obtain a compound of the invention (III) from a compound (IL) and~an aldehyde R6-CHO, various techniques can be employed, of which the essential aspects axe presented in "Advanced Organic Chemistry", J. March - 3rd edition -Wiley 1985 - p. 798-800.
Advantageously, for the various carbonylated reactants employed, except formaldehyde, the reaction can be carried out in an anhydrous protic solvent such as a lower alcohol, for example methanol or ethanol, one mole of compound (II) being reacted with 1.5 to 10 mole of carbonylated compound in the presence of an anhydrous acid catalyst such as acetic acid or p-toluenesulphonic acid.
The reaction is thus carried out for between 30 minutes and 8 hours at a temperature between 20°C and the reflux temperature of the solvent. Thereafter, at a temperature aloes to 20°C, a reducing hydride of formula (Hm.3), defined above, among which sodium borohydride or sodium cyanobarohydride are preferred, is added in an amount of 0.5 to 2.5 mole per mole of compound (II) employed.
In particular, if the process consists in the alkylation of a compound (II) with formaldehyde to give a product of the invention (III) in which R3 is methyl, the method described in J. Med. Chem. 1982, 25, 4, p. 446-51 is advantageously carried out, this method consisting in reacting, in acetonitriie, the aqueous formaldehyde solution in the presence of sodium cyanoborohydride.
d) If the process for preparing a compound of the invention (III) consists in reacting an aminonitrile (TX) with an organo-magnesium reagent R2Mg~3, the replacement of the carbonitrile group by the radical R2 is carried out in accordance with a method based on that described by N.J.
Leonard et al., J. Am. Chem. Soc., 1956, 78, p. 1985 and 1957, 79, p. 5279. It is parried out in ethers such as diethyl ether, methyl t-butyl ether, diisopropyl ether or dibutyl ether or tetrahydrofuran, the latter being preferred, and consists in reacting one mole of compound (IX) with 1.5 to 6 mole of organo-magnesium derivative at a temperature of between 5 and 50°C for between 30 minutes and 12 hours.
Advantageously, the method consists in adding 1 mole of compound (IX), generally in solution in THF, to 4 to 5 mole of the organo-magnesium compound, also in solution in THF, at a temperature of between 10 and 20°C. The reaction is continued for 2 to 5 hours at the same temperature and the complex obtained is~then decomposed by adding an aqueous ammonium chloride solution. After treatments, the compound of the invention (III) is isolated and purified.
The working methods which follow illustrate the preparation of intermediate derivatives and of the compounds (I) of the invention, without implying any limitation.
Depending on the reactions carried out, the compounds are either obtained as such, in a satisfactorily pure state, ~. 6 or are purified by appropriate techniques indicated in the examples, such as crystallisation, vacuum distillation or column chromatography. In the latter case, it is advantageous to use the so-called "chromato-flash" technique on a silica carrier (trademark '°Merck", Kieselgel 60 product, particle size 230 to 400 mesh).
Further, the purity, identity and physicochemical characteristics of the products prepared are reported and determined in terms of:
their boiling point under the degree of vacuum (in Pascal) prevailing during their distillation, their melting point, determined by the capillary tube method, the stated value being uncorrected, and thin layer chromatography (TLC) on silica (ready-to-use plates, "Merck" ref. 60 F 254), the technique thereof being briefly stated below:
the products to be studied are deposited on the plate in an amount of about 100 mcg and are then subjected to ascending elution with the solvents or mixtures enumerated below, the respective proportions being stated in volume/volume:
ref. S.A. - 100 hexane/10 ethyl acetate S.B. - 40 hexane/10 ethyl acetate S.C. - 20 hexane/10 ethyl acetate S.D. - 99 methylene chloride/1 triethylamine After development, the chromatograms axe observed under ultraviolet light of wavelength 254 nm and/or after being revealed in colour by spraying with Dragendorff reagent or tolidine reagent. The Rf values observed as well as the references of the elution solvents used are given in the examples.
Elementary percentage analysis, the results of which, in accordance with accepted standards, are not reported, but are indicated to have been carried out by mentioning the element determined, infrared spectrography of the compounds in pellets in KBr or in the form of films between two NaCl windows or in ~~~I~~~''i suspension in Nujol (R) or in solution in CC14: the most intense absorptions are reported by stating their wavelength in c~ri 1, and the proton nuclear magnetic resonance (NMR) is studied at 60 or 90 MHz, the products being solubilised in deuterochloroform. The appearance of the signals and their chemical shift expressed in ppm relative to the tetramethylsilane used as the internal reference are indicated. The so-called °'exchangeable'° protons after addition of deuterium oxide are also indicated.
Finally, various reagents or solvents may be indicated in their common abbreviated form, one example being THF for tetrahydrofuran.
EXPERTMENTAL PART-PREPARATIONS
A intermediate reacents of the formula (XIII) Z5-CH2-O-R5 A-~ trans-1-Mes~laxvmethyl-2-phenyl-cvclot~ropane (R5 = C6H5: Z5 = CH3-S02-O; Q = cyclopropane-1,2-diyl) A solution of 25.0 g of trans-2-phenyl-1-cyclo propanecarboxylic acid (154 mmol) in 100 ml of THF is added dropwise under a nitrogen atmosphere to 230 ml (230 mmol) of a solution of borane in THF. The solution is heated to the reflux temperature for 3 hours and 7130 ml of 2 N NaOH
solution are then added slowly. The mixture is stirred for minutes and is then extracted with ether; the ether phases 25 are dried over MgS04 and then concentrated in vacuo to give the crude residual product: 20.8 g.
The trans-1-Hydroxymethyl-2-phenyl-cyclopropane intermediate is purified by vacuum distillation.
Weight = 18.2 g, yield = 80%, by 90-97°C/35Pa.
30 9.2 g (66 mmol) of the product obtained above and 13.8 ml (99 mmol) of triethylamine are dissolved in 100 ml of methylene chloride. 5.6 ml (73 mmol) of methanesulphonyl chloride are added dropwise at -10°C, under a nitrogen atmosphere. The mixture is stirred for 15 minutes at -10°C
and then washed by extraction with water, with cold dilute hydrochloric acid and then with a saturated NaHC03 solution and a saturated NaCl solution, and is thereafter dried over MgS04 at 0°C.
The solvent is removed by vacuum distillation at a temperature below 10°C and the unstable product is dissolved in anhydrous THF and employed as such in the subsequent preparations.
A-2J traps-1-Bromomethyl-2-phengl-~C ~olopronane.
(R5 = C6H5; 25 = Br; Q = cyclapropane-1,2-diyl) 61.0 g (0.34 mol) of N-bromosuccinimide are added to 300 ml of methylene chloride. The suspension is cooled to 0°C
and 29.4 ml (0.41 mol) of dimethyl sulphide are added under a nitrogen atmosphere; the mixture is then stirred for 30 minutes and thereafter cooled to -25°C, after which a solution of 33.6 g (0.23 mol) of traps-1-Hydroxymethyl-2-phenyl-cyclopropane.is added dropwise.
The mixture is stirred for 6 hours at 0°C and then for 16 hours at 25°C; after dilution with 250 ml of hexanes, the mixture is precipitated in 250 ml of iced water. The organic phase is washed with a saturated sodium chloride solution and then dried over MgS04. The solvents are removed by vacuum distillation and the residue is purified by distillation.
Weight = 40.8 g, yield = 85%, by 72°C/25Pa A-3/~1-f2-Thienyl)-3-ohloronro~-1-ene.
(R5 = 2-thienyl; Z5 = C1; Q = -CH=CH-) First stage: 104,06 g of malonic acid (1.0 mol), 56,07 g (0,50 mol) of 2-Thiophene-carboxaldehyde, 250 ml of pyridine and 5m1 of piperidine are heated on a water bath for 2 hours and then to the reflux temperature for 5 minutes.
After cooling, the solution is precipitate in water and treated with an excess of hydrochloric acid (250 ml of 37%
concentrated solution) to precipitate the product, wich is thereafter filtered off and then recrystallised from an ethanol-water mixture to give the purified 2-Thienylacryli.c acid.
Second stage: 37.34 g (0.24 mol) of the preceding acid and 30 ml (0.24 mol) of BF3-ether complex in 310 ml of methanol axe heated to the reflux temperature for 6 hours.
The cooled solution is precipitated in water and then S

extracted with methylene chloride. The organic extraction phases are combined, washed with a saturated NaHC03 solution and then with a saturated NaCl solution, and thereafter dried over MgS04. The solid brown-coloured residue wick is obtenaid after removal of the solvents by distillation is recristallised from hexane to give the purified Methyl 2-thienylacrylate.
Weight = 32.65 g yield = 81 % mp 46°47°C
Third stage: A suspension of 4.51 g (11.8.9 mmol) of Lithium aluminium hydride in 150 ml of THF is added slowly, with stirring, to a mixture of 5.28 g (39.6 mmol) of aluminium chloride and 40 ml of diethyl ether cooled to -10°C, under a nitrogen atmosphere.
~1 solution of 10.0 g (59.45 mmol) of the preceding methyl ester in 50 ml of THF is added slowly at -10°C and the solution is then stirred at the same temperature for one and half hours. The complexes of the solution are decomposed by adding a 3M sulfuric acid solution and the mixture is extracted with ether. The combined ether phases are washed with a saturated NaHC03 solution and then with a saturated NaCl solution, and dried over MgS04. Evaporation of the ether in vacuo gives 7.83 g (94~) of residual product in the form of a brown oil. The crude 1-(2-Thienyl)-prop-1-en-3-ol, which is unstable at ambient temperature, is kept at a temperature below 0°C.
Fourth stage: 21.74 ml (296 mmol) of Dimethyl sulphide are added slowly, at a temperature of 0°C, 'to a miacture of 39.53 g (296 mmol) of N-Chlorosuccinimide in 3.80 ml of anhydrous methylene chloride. The mixture is cooled to -10°C and a solution of 1.1.86 g (84.6 mmol) of the preceding alcohol in 50 m1 of methylene chlaride is added.
The temperature of the solution is brought back to 0°C and kept thereat for 2 hours. The mixture is diluted with 100 ml of hexanes and then precipitated in 200 ml of iced water. The organic phase is separated off and the aqueous phase is reextracted with ether. The combined ether phases are washed and then dried. The ether is removed by vacuum distillation and crude 1-(2-Thienyl)-3-chloro-prop-1-ene is obtenaid in the form of an unstable reddish browm oil which is used as it is.
Weight = 12.06 g yield = 940 A-~ -1- ~3-Thienvl)-3-chloropron-1-ene.
(R5 = 3-thienyl; Z5 = C1; Q = -CH=CH-) The intermediate is obtenaid from 3-Thiophenecarboxaldehyde in accordance with the process described in the preceding example.
First stage: 3-Thienylacrylic acid mp 146°C (ethanol/water) Second stage: Methyl 3-thienylacrylate mp 49°C (hexanes) Third stage: 1-(3-Thienyl)-prop-1-ene-3-of unpurified oil Fourth stage: 1-(3-Thienyl)-3-chloro-prop-1-ene unpurified amorphous white solid.
A-5~ trans-1-Chloromethyl-2-(2-thienyl)-cvclopropane.
(R5 = 2-thienyl; Z5 = Cl; Q = cyclopropane-1,2-diyl) First stage: 33,9 mi of dry t-butanol and 25 ml of THF
are introduced in a dry apparatus under a nitrogen atmosphere. 144 ml of a 2,5 M butyl lithium solution is added at 0°C under stirring.
After return to the ambient temperature, the mixture is kept under stirring 30 minutes.
Then a solution of 20,0 g of purified methyl 2-thienylacrylate (prepared as indicated in stages 1 and 2 for compound A.3) in 125 ml of THF is added.
The mixture is stirred 3 hours then is poured in 600 ml of ice water, then extracted three times with 10o ml of ethyl acetate. The collected organic phases are dried over MgSO4, then ethylacetate is removed by vacuum distillation.
The reddish brown residue weights 26,0 g.
The t-butyl 2-thienylacrylate is purified by vacuum distillation.
Weight= 21,3 g, yield= 85 ~, bp= 82-90°C/4 Pa.
Second stage: A dispersion of 11,1 g of 80 % sodium ~> ~~ r.J ~~ ~ ~. ~~

hydride in a mineral oil is added to a stirred suspension of 74,8 g trimethylsulfoxonium iodide in 150 m1 of anhydrous DMSO.
After the end of hydrogen emission (about 30 minutes), a solution of 54,6 g of the above prepared t-butyl ester in 60 ml of DMSO is added, keeping the temperature below 35°G.
The mixture is stirred for 30 minutes at the ambiemt temperature, then at 55°-60°G for one and a half hours.
The solution is cooled to 25°G then poured into 1000 ml of water. The mixture is extracted 4 times with 100 ml of ether, the collected ether phases are washed with a saturated sodium chloride solution and then dried over Mgs04. The solvents are removed by vacuum distillation and 47,7 g of trans 2-(2-thienyl)-1-cyclopropane t-butyl carboxylate is obtained as a yellow oil residue which is used as it is in the following stage.
Third stage: A solution of 20,4 g of this above t-butyl ester in 75 ml of THF is added dropwise keeping the temperature below 5°C to a suspension of 6,~ g of lithium aluminium hydride in 75 ml of anhydrous THF in an anhydrous reactor.
After return to the ambient temperature, the mixture is stirred for 2 hours, then 16 ml of water are cautiously added dropwise followed by the dropwise addition of a 10 sodium hydroxide solution in water. After a further addition of 48 ml of water, the obtained suspension is filtered, the precipitate is washed with ethyl acetate, then the collected organic phases are dried over sodium sulfate.
The solvents are removed by vacuum distillation. The residue is chromatographied on a silica column to give purified trans 1-hydroxymethyl-2-(2-thienyl)-cyclopropane.
Weight = 16,4 g, yield = 76 ~.
Fourth stage: A solution of 15,5 g of the above obtained alcohol in 75 ml of anhydrous triethylamine is added to 40,0 g of dichlorotriphenylphosphorane in an anhydrous reactor under a nitrogen atmosphere.
The suspension is kept at 25°G under stirring for 24 ~~e~ ~~~.~'a hours. The mixture is poured into 500 ml of water and 100 ml of hexane are added. The mixture is filtered, the organic phase is separated off and the aqueous phase is reextracted with 100 ml of hexane. The collected organic phases are dried over MgS04, then the solvents are removed by vacuum distillation. The residue is distillated under vacuum to give purified traps 1-chloromethyl-2-(2-thienyl) cyclopropane as a colourless oil.
Weight = 9,7 g, yield = 56 0, by = 65-70°C/40 Pa.
A-6,L traps-1-Chloromethgl-2-(3-thienyl~j-cyclopropane.
(R5 = 3-thienyl; 25 = C1: Q = cyclopropane-1,2-diyl) The product is obtained from methyl-3-thienylacrylate (A.4 - second stage) according to a process similar to the one described above for the preparation of the compound A.5.
First stage: t-butyl 3-thienylacrylate, by = 95-110°C/13 Pa.
Second stage: traps 2-(3-thienyl)-1-cyclopropane t-butyl carboxylate, unpurified oil.
Third stage: traps 1-hydroxymethyl-2-(3-thienyl)-cyclopropane, by = 88-120°C/20 Pa.
Fourth stage: traps 1-chloromethyl-2-(3-thienyl)-cyclopropane, by = 60-78°C/400 Pa.
B - intermediate reacxents of formula (Ix) General procedure:
Stage 1: preparation of the aminonitriles (XII) 5.90 g (0.12 mol) of sodium cyanide and 0.12 mole of a water-soluble salt of an amine R3-NH-(CH2)m-R4 are dissolved in 20 ml of water in a reactor.
Into this solution there is introduced, in the course of one hour at a temperature of between 30 and ~0°C, a solution of 0.10 mol of aldehyde R1-CHO in 10 ml of methanol.
The mixture is stirred for 4 hours at ambient temperature and then precipitated in 75 ml of iced water, after which it is extracted with ether.
The combined ether phases are washed successively with water, with a 25~ strength sodium bisulphite solution and then again with water.

:a1 The ether is then evaporated and the crude residual product is optionally purified, for example by distillation.
Stage 2: preparation of the intermediate (IX) 1.025 mole of n-butyl-lithium (a 7L0 M solution in hexanes) is added dropwise, at 20°C, to a solution of 1.025 mole of diisopropylamine in 1 litre of anhydrous tetrahydro-furan in a reactor protected from moisture, and under a nitrogen atmosphere.
The mixture is kept at 20°C for 15 minutes. At -72°C, 1.0 mole of aminonitrile (XII) dissolved in 200 ml of THF is introduced, stirring is continued far 1 hour 30 minutes at this temperature and 1.025 mole of the alkylation reagent (XIII) dissolved in 500 ml of THE' are then added. After 20 minutes at -72°C, the mixture is stirred for 1 hour at ambient temperature.
Thereafter 1.5 1 of 10~ (weight/volume) NH4C1 solution and 750 ml of a 1:1 (volume/volume) mixture of hexanes/ethyl acetate are added.
The organic phase is separated off and the aqueous phase is re-extracted with the mixture of solvents. The combined organic phases are washed by extraction with a saturated sodium chloride solution and then dried over MgSO4.
The solvents are removed by distillation in vacuo on a water bath. The crude oily product is generally in a satisfactory state of purity for being used as such in the sequence of preparations of the compounds of the invention.
B-1/ 1-Cyano-1-~N°ovclopropylmethyl°N-methvl)amino-1-(2-furyl~-4-phenyl-but-3-ene (formula IX; R7. = 2-furyl; R3 = CH3; m = 1; R4 = (CH2)2CH; R5 - C6H5; Q = -CH=GH-) The intermediate (XII) 1-(N-Cyclopropylmethyl-N-methyl)amino-(2-furyl)acetonitrile is prepared from 2-furaldehyde, N-Methyl-N-cyclopropylmethylamine and sodium cyanide. The oily product obtained is purified by vacuum distillation. by 82-92°C/lSPa.
Using the general procedure described earlier, the product is alkylated with cinnamyl bromide. The crude oily r Gp ~ ~ ~ .~ ~. E~:
product obtained (yield = 1000 is employed as such in the reaction with the organo-magnesium derivative.
NMR: 0.10-0.15 (m, 5H); 2.10°2.45 (m, 2H); 2.55 (s, 3H); 2.90 (d, 2H); 5.70 (t, 1H); 6.35 (d, 1H); 6.85-6.95 (m, 1H); 7.10 7.45 (m, 7H) B-2/ 1-Cyano-1-~~N-cYcloprop_ylmethyl-N-methyl)amino-4_-_ phenvl-1-~2-thienvl)-but-3-ene (formula IX; R1 = 2-thienyl; R3 = CH3; m = 1; R4 = (CH2)2CH;
R5 = C6H5; Q = °CH=CH-) The intermediate (XII) is prepared from 2-thio-phenecarboxaldehyde, N-methyl-N-cyclopropylmethylamine and sodium cyanide. The ~-Amino-N-cyclopropylmethyl-N-methyl-(2-thienyl)acetonitrile derivative obtained is used without purification.
25 Following the general procedure, the compound is alkylated with cinnamyl bromide. The reddish-brown oily product obtained (yield = 1000 is employed as such in the reaction with the organo-magnesium derivative.
NMR: 0.10-0.15 (m, 5H); 2.20-2.45 (m, 2H); 2.55 (s, 3H); 2.90 (d, 2H); 5.80 (t, 1H); 6.35 (d, 1H); 6.85-6.95 (m, 1H); 7.10 7.40 (m, 7H) B-3/ 1-Cyano-1-(N-cyclourobylmethyl-N-methyl)amino-4-phenyl-1-~~3-thienyl Z but-3-ene (formula IX; R1 = 3-thienyl; R3 = CH3; m = 1; R4 = (CH2)2CH;
R5 = C6H5; Q = -CH=CH-) The compound is prepared in a manner identical to the preceding product B-2, starting from 3-thiophene-carboxaldehyde.
NMR: 0.0-1.10 (m, 5H); 2.30 (m, 2H); 2.50 (s, 3H); 3.95 (q, 2H); 5.80 (m, 1H); 6.50 (d, 1H); 7.00-7.50 (m, 8H) B-4/ trans 1 f2 Cyano-2-~2°furg~-N-ycyclo~ropylmethvl-N-methyl)aminoethyll-2-phenyl-cyclomropane (formula IX; R1 = 2-furyl; R3 = CH3; m = l; R4 = (CH2)2CH; R5 - C6H5; Q = cyclopropane-1,2-diyl) The preliminary preparation of the intermediate (XII), 1-(N-cyclopropylmethyl-N-methyl)amino-(2-furyl)acetonitrile, is carried out starting from 2-furaldehyde and N-methyl-N-cyclopropylmethylamine as described for the general procedure. The general procedure also applies to the al3cylation with traps-1-bromomethyl-2-phenylcyclopropane, of which the preparation is described in B-2. The reddish-brown oil obtained is used without purification in the subsequent reaction with the organo-magnesium derivative.
NMR: 0.10-0.90 (m, 8H); 1.30-1.80 (m, 1H); 2.20-2.30 (m, 4H);
2.40 (s, 3H); 6.30 (m, 1H); 6.50 (t, 1H); 7.10 (m, 5H) 7.40 (m, 1H) B-5/ traps 1- [2-Cyano-2-~2-thienvl ) -N- (cyclopropylme~thvl-N-methyl aminoethyl]-2-phen)~l-cyclopro~ane (formula IX; R1 - 2-thienyl; R3 = CH3; m = 1; R4 = (CH2)2CH;
R5 = C6H5; Q = cyclopropane-1,2-diyl) The oily reddish-brown product, prepared from the intermediate described in B-2 and the bromine derivative A-2, is used in the unpurified form.
NMR: 0.10-1.10 (m, 10H); 2.10-2.40 (m, 3H); 2.60 (s, 3FI);
6.75-6.90 (m, 1H); 7.05-7.40 (m, 7H) B-6/ traps 1-f2-Cyano-2-_~,3-thienvl,~-N-fcyclopropylmethyl-N-meth~rl)aminoethyl'~°2°phenyl-cyclopropane (formula IX; R1 = 3-thienyl; R3 = CH3; m = 1; R4 = (CH2)2CH;
R5 = C6H5; Q = cyclopropane-1,2-diyl) The oily product, prepared from the intermediate (XII) described in B-3 and the bromine derivative A-2, is used in the unpurified form.
NMR: 0.30-1.90 (m, 9H); 2.20 (m, 4H); 2.45 (s, 3H); 6.80-7.50 (m, 8H) B-7 1-Cyano-1-I~N-cYalopropylmethyl-N-methyl)amino-1-l2-thienyl)°4-(3-thienYl~-but-3-ene (formula IX; R1 = 2~thianyl; R3 = CH3; m = 1; R4 = (CH2)2CH;
R5 = 3-thienyl; Q = °CH=CH-) The amino-nitrite (XII) is prepared from 2-thio-phenecarboxaldehyde, as described in example B.2 then condensed with the intermediary (XIII) following the general procedure. The crude product obtained (yield = 1000 is used without purification in the reaction with the organo-magnesium derivative.

B-8 1-C~ano-1-_fN~",cvclobronylmethyl-N-methvl)amino-1-(2-furyl~-4- ~2-thienyl)--but-3-ene (formula IX; R1 = 2-furyl; R3 = CH3: m = 1; R4 = (CH2)2CH; R5 - 2-thienyl; Q = -CH=CH-) The compound is prepared in a manner identical to the preceding product, starting from 2-furaldehyde and the intermediate (XIII) described in A.3. The crude product obtained (yield = 100%) is used without purification in the reaction with the organo-magnesium derivative.
B-9/ trans 1-'[_22-Cyano-2°ph2nvl,~N-cyclopropylmethyl-N-methyllaminoethvll-2-(2-thienyl)-cvclopropane (formula IX; R1 = C6H5; R3 = CH3; m = 1; R4 _ (CH2)2CH; R5 =
2-thienyl; Q = cyclopropane-1,2-diyl) The compound is prepared in a manner identical to the preceding product, starting from benzaldehyde and the intermediate (XIII).described in A.S. The crude product obtained (yield = 100%) is used without purification in the reaction with the organo-magnesium derivative.
NMR: 0.30-2.60 (m, 6H); 2.25 (t, 2H); 2.50 (s, 3H); 6.90 (m, 3H); 7.37 (m, 3H); 7.60 (m, 2H) B-10/trans 1 f2 Cvano 2 (3 thienvl~N-cyclox~robylm~thyl-N-methyl L) aminoeth~ll °2- ~(~3-thienyl ~-cyclot~rot~ane (formula IX; R1 = R5 = 3-thienyl; R3 = CH3; m = 1; R4 =
(CH2)2CH; Q = cyclopropane-1,2-diyl) The compound is prepared in a manner identical to the preceding product, starting from thiaphenecarboxaldehyde and tyke intermediate (XIII) described in A.6. The crude product obtained (yield = 100%) is used without purification.
N-CYCLOALKYLALKYLAMINES: EXAP~IPLES
General procedure:
76.0 ml of a 3 M solution of ethyl--magnesium bromide (227 mmol) in ether are introduced into a reactor protected from moisture, under a nitrogen atmosphere.
Thereafter, 50.4 mmol of an aminonitrile (IX), dissolved in 65 ml of THF which has bean dried over a molecular sieve, are added at a temperature of between 20 and 30°C.

,. :. r-. c i~
'3( 2 7 Sn t,~ r~
The mixture is stirred for 3 hours at ambient temperature of about 20°C and is then introduced, without exceeding 10°C, into 260 ml of a saturated aqueous ammonium chloride solution.
The aqueous phase is removed and the organic phase is extracted 3 times with a 2 N hydrochloric acid solution.
The combined hydrochloric acid phases are rendered alkaline with a concentrated sodium hydroxide solution and are then extracted with ether. The ether phases are combined, washed with water and then dried over Na2S04. After removing the ether by distillation, the product is purified by the appropriate techniques.
This procedure is applied to the intermediates (IX) B-1 to B-10, using ethyl-magnesium bromide, to obtain the compounds of the invention of formula (I), of Examples 1 to 10.
Example 1 4-fN-Cycloprgpylmethyl-N-methyl)amino-4-l2-furyl)-1-phenyl-hex-1-ene (R1 = 2-furyl; R2 = C2H5; R3 = CH3; m = 1; R4 = CH(CH2)2: R5 - C6H5; Q = -CH=CH-) From the aminonitrile B-1.
Yellow oil TLC = 0.55; S.B
IR: 3080, 3030, 2980, 2880, 2800, 1600, 1560, 1500, 1465, 1380, 1230, 1160, 1020, 980, 810, 740, 695 Cm'~1 NMR: 0.10-0.60 (m, 5H)s' 0.90 (t, 3H); 1.90 (q, 2H); 2.30 (d, 2H); 2.40 (s, 3H); 2.80-2.90 (m, 2H); 6.20-6.60 (m, 4H);
7.30-7.40 (m, 6H) Analysis (C21H27N0) C, H, N, O.
Example 2 4-fN-Cycloprop~tlmethyl-N-methvl)amino-1-phenyl-4-~2-thienyl)-hex-1-ene (R1 = 2-thienyl; R2 = C2H5; R3 = CH3; m = 1; R4 = CH(CH2)2;
R5 = C6H5; Q = -CH=CH-) From the aminonitrile B-2.
Yellow oil - by 160°C/35Pa. - TLC = 0.25; S.D
IR: 3070, 3020, 2960, 2930, 2895, 1665, 1640, 1595, 1570, 1490, 1450, 1230, 1030, 970, 825, 745, 690 cm~1 NMR: 0.05-0.55 (m, 5H); 1.90 (m, 5H); 2.30 (d, 2H): 2.50 (s, J '~' 3H); 2.90 (d, 2H); 6.10-6.60 (m, 2H); 7.00-7.10 (m, 2H);
7.20-7.30 (m, 6H) Analysis (C21H27NS) C, H, N, S.
Example 3 4-(N-Cyclopropylmethyl-N°methylJ~amino-1-phenyl-4-(3-thienYl,~i-hex-1-ene (R1 = 3-thienyl; R2 = C2H5; R3 = CH3; m = 1; R4 = CH(CH2)2;
R5 = C6H5; Q = -CH=CH°) From the aminonitrile B-3.
Yellow oil - by 140°C/3.5Pa. - TLC = 0.45; S.A
IR: 3075, 3055, 3020, 2990, 2965, 2930, 2875, 2840, 2790, 1595, 1495, 1460, 1015, 980, 965, 845, 775, 740, 690, 665 cm 1 NI~IR: 0.10°0.55 (m, 4H); 0.70 (s, 1H): 0.75 (t, 3H); 1.85 (q, 2H); 2.25 (d, 2H); 2.40 (s, 3H); 6.00-6.50 (m, 2H); 7.00-7.40 (m, 8H) Analysis (C21H27NS) C, H, N, S.
Example 4. traps 1-,L2-i(N-Cyclopry~,ylmethyl-N-methyl)amino-2-j2-furyl)-butyl -2-phenyl-cyclo~ropane (R1 = 2-furyl; R2 =~C2H5; R3 = CH3; m = 1; R4 = CH(CH2)2; R5 - C6H5; Q = cyclopropane-1,2-diyl) From the aminonitrile B-4.
Reddish-brown oil. TLC = 0.45; S.B
IR: 3060, 2990, 2970, 2930, 2790, 1605, 1499, 1460, 1220, 1158, 1015, 940, 885, 830, 800, 730, 700 cm 1 NMR: 0.40-0.95 (m, 11H); 1.20-1.70 (m, 2H); 1.95 (m, 3H);
2.15 (m, 2H); 2.35 (s, 3H): 6.05 (m, 1H); 6.35 (m, 1H); 6.85-7.35 (m, 6H) Analysis (C22H29N0) C, H, N, O.
Example 5 traps 1-(~wN-Cyclonropylmethyl-N-methyl)amino-2-j2-thienyl)-butvl~-2-phenyl-cvclopropane.
(R1 = 2-thienyl; R2 = C2H5; R3 = CH3; m = 1; R4 = CH(CH2)2;
R5 = C6H5; Q = cyclopropane-1,2-diyl) From the aminonitrile B-5.
Reddish-brown oil. TLC = 0.45;S.A
IR: 3060, 2980, 2960, 2940, 2860, 2790, 1610, 1500, 1465, 1240, 1020, 830, 750, 700 om~'1 NMR: 0.10 (m, 2H); 0.40-0.50 (m, 2H); 0.80-0.95 (m, 5H); 1.30 ,,-, r, s~ r~ r.~ .~ j 29 yn'e.3 s .1~.'='-(s, 1H); 1.50-1.90 (m, 2H); 2.00-2.10 (m, 4H); 2.30 (d, 2H);
2.45 (s, 3H); 6.80-7.25 (m, 8H) Analysis (C22H29NS) C, H, N, S.
Example 6 trans 1-f2-(,N-C~rclopropylmeth~l-N-methvl)amino-2-j3-thienyl)-but_yll-2-phenyl-cyclopropane (R1 = 3-thienyl; R2 = C2H5; R3 = CH3; m --- 1; R4 = CH(CH2)2;
R5 = C6H5; Q = cyclopropane-1,2-diyl) From the aminonitrile B-6.
Reddish-brown oil. TLC = 0.75; S.C
IR: 3070, 2990, 2965, 2930, 2875, 2840, 2785, 1604, 1497, 1460, 1015, 777, 750, 693 cm ~
NMR: 0.05-0.15 (m, 1H): 0.25-0.55 (m, 2H), 0.60-1.10 (m, 7H);
1.30-1.75 (m, 2H); 1.75-2.10 (m, 4H); 2.15-2.35 (m, 2H); 2.40 (s, 3H); 6.85-7.40 (m, 8H) Analysis (C22H29NS) C, H, N, S.
Example 7 4-(N- ~clobropvlmethyl-N-methyl)amino-4-(2-thienv ~ -1-,~3-thienvl~-hex-1-ene (R1 = 2-thienyl; R2 = C2H5; R3 = CH3; m = 1; R4 = CH(CH2)2;
R5 = 3-thienyl; Q = -CH=CH-) From the aminonitrile B-7.
Yellow Oil - by 143-151°C/SPa. - TLC = 0.505 S.A
IR (film): 3076, 3050, 2968, 2942, 2908, 2848, 2820, 2768, 1448, 1237, 1222, 1074, 1008, 957, 852, 832, 793, 757, 687 cm-1 NMR: 0.10-0.20 (m, 2H); 0.30-0.70 (m, 2H); 0.70-1.10 (m, 1H);
0.85 (t, 3H); 1.90 (q, 2H); 2.30 (d, 2H); 2.45 (s, 3I-I); 2.80 (d, 2H); 6.10 (m, 1H); 6.52 (d, 1H); 6.80-7.50 (m, 6I-I) Analysis (C19H25NS2) C, H, N, S.
Example 8 4-~(N-C_yclo~rop~lmethyl-N-methyl)amino-4-(2-furyl)-1-I'2-thienyl~-hex-1-ene (R1 = 2-furyi; R2 = C2H5; R3 = CH3; m = 1; R4 = CH(CH2)2; R5 - 2-thienyl; Q = -CH=CH-) From the aminonitrile B-8.
Yellow oil - by 125-145°C/lOPa. - TLC = 0.40; S.A
IR (film): 3070, 2965, 2870, 2820, 2795, 1500, 1465, 1225, 1210, 1160, 1125, 1080, 1045, 1020, 990, 960, 860, 830, 805, 737, 695 cm-1 C"~ P~ ~ j~ 1 .c. l i.
NMR: 0.10-0.20 (m, 2H); 0.20-0.60 (m, 2H); 0.60-1.10 (m, 4H);
1.88 (q, 2H); 2.26 (d, 2H); 2.3? (s, 3H); Z 2.50-3.20 (m, 2H); 5.80-6.20 (m, 2H) ; 6.20-6.40 (m, 1H); 6.60 (d, 1H);
6.80-7.20 (m, 3H); 7.42 (s, 1H) 5 Analysis (C19H25NOS) C, H, N, O, S.
Example 9 traps 1-f2-lN-Cyclopropylmethyl-N-methyl)amino-2-phe~l-butyll°2 =(2-thienyl)-cyclopropane (R1 = C6H5; R2 = C2H5; R3 = CH3; m = 1; R4 = CH(CH2)2; R5 =
2-thienyl; Q = cyclopropane-1,2-diyl) 10 From the aminonitrile B-9.
Yellow oil - by 135-145°C/l3Pa - TLC = 0.50;S.B
TR: 3062, 2962, 2786, 1596, 1490, 1442, 1018, 759, 697 c1ri 1 NMR: 0.30-0.60 (m, 2H); 0.60-1.20 (m, 8H); 1.60-2.20 (m, 6H);
2.35 (d, 2H); 2,45 (s, 3H); 6.50-6.70 (m, 1H);
15 6.80-6.90 (m, 1H); 6.90-7.10(m, 1H); 7.19-7.60 (m, 5H) Analysis (C22H29NS) C, H, N, S.
Example 10 traps 1-__[2-~~N-Cyclourop~lmethyl-N-methyl)amino-2-(,3-thienyll-butyll-2- 3-thienyl), -cyclox~ropane (R1 = R5 = 3-thienyl; R2 = C2H5; R3 = CH3; m = 1; R4 =
20 CH(CH2)2; Q = cyclopropane-1,2-diyl) From the aminonitrile B-10.
Yellow oil ° by 163°166°C/1Pa - TLC = 0.25; S.A
IR: 3060, 2960, 2780, 1680, 1460, 1020, 850, 780 cm 1 NMR: 0.30-0.60 (m, 2H); 0.60-1.10 (m, 7H); 1.50-2.40 (m, 9H);
25 2.37 (s, 3H); 6.70-6.90 (m, 2H); 7.00-7.40 (m, 4Hj Analysis (C20H27NS) C, H, N, S
The toxicological and pharmacological tests carried out with the compounds of the above Examples 1 to 1o show their low toxicity and also, in the mouse, the ability to 30 inhibit convulsions induced by picrotoxin.
This property makes it possible to envisage usefulness of the products of the invention as psychotropic agents in the treatment of neuropsychic disturbances.
Furthermore, the affinities for binding °'in vitro" to the mu, delta and ~Cappa opioid receptors were studied, as were those for binding to the sigma receptors.
The results of the studies carried out show that the compounds of the invention have a particular binding affinity for the sigma receptors, which is linked to their anti-psychotic activity and is more manifest if, in the compounds, R1 is a 2-thienyl radical and R5 is a phenyl radical.
Equally, "in vivo°' in the rat, the cycloalkyl-alkylamines (I) inhibit, in the gastro-duodenal area, ulcers brought about by administration of cysteamine. This activity is also attributed to the particular affinity of the compounds for local sigma receptors.
All of these properties together, demonstrated by the studies carried out and their results, set out in the present note, make the compounds according to the invention useful in the prevention and treatment of asthenias and of neurological and/or psychic disorders, as well as the treatment of various dysfunctions of the gastro-intestinal tract.
The studies which demonstrate the properties of the products of the invention and the results obtained are reported below:
a) the toxicity of the products of the invention is investigated in the mouse by approximate determination of their LD 50, which is the lethal dose causing 50% of deaths in the animals under the conditions of the experiment. The study is carried out on batches of four male °'Swiss" mice weighing about 20 g and kept without food on the day before the study.
Each determination is carried out with four doses respectively corresponding to an oral administration of 100, 300, 600 and 1,000 mg of product, expressed in the form of the base, per kg of animal.
It is found in this study that the products of the invention have an acute toxicity corresponding to an LD 50 greater than or equal to 1,000 mg/kg. Exceptionally, this toxicity can be about X00 mg/kg.
b) The psychotropic properties of the compounds were determined by examining the protection against convulsions induced by picrotoxin in the mouse, the study being carried out in accordance with a method based on that of Krall et ~~ ~i al., °'Epilepsia", 1978, 19, p. 409-428.
The administration of picrotoxin produces a convulsive attack in the animal, characterised by a myoclonic extension syndrome followed by extension of the limbs, leading to 'the death of the animal. Certain substances, especially those which act on the GABA/benzodiazepines/C1-ionophorP complex make it possible to protect the animals against this convulsive attack.
In practice, the study is carried out on batches of 10 ZO male "Swiss°' mice, weighing about 20 g, to which the product to be studied is administered in aqueous solution, either intraperitoneally (i.p.) or orally (p.o.).
Thereafter, a picrotoxin solution is injected intraperitoneally in an amount of 24 mg/kg, using a volume of 0.2 ml per animal, either 30 minutes after the intraperitoneal administration of the product or 60 minutes after the oral administration of the product, the dose of product thus injected bringing about a clonic attack which leads to the death of the untreated animals. Under the test conditions, it is found that the tonic extension phase is suppressed in the treated animals.
The results are expressed either as a percentage of the animals protected against this phase tinder the action of 50 mg/kg of the compound being studied, administered i.p. or under the action of 100 mg/kg administered p.o., or as the ED 50 for each of these methods of administration, the ED 50 being the effective dase of the compound being tested, expressed in mg/kg, which protects 50%
of the animals against this extension phase, the significance of the results generally being indicated as followse * Results significant to p. < 0.05 ** Results significant to p. < 0.01 The results of the study are reported far the products of the invention in Table 1 below, and show the protective activity of the studied compounds of the invention for the two methods of administration.

3 3 ~ ~~ ~ t,~ ~y ~
cn ~~
Table 1: Inhibition of the convulsions induced by picrotoxin Example i.p. . % protected p.o. . % protected or ED 50 or ED 50 1 N.T. 60% **
2 50% * N.T.

4 50% * N.T.

5 50% * 50 %
& 50% * 50% *
9 N.T ED 50 = 90 mg 10 50% ED 50 = 74 mg N.T. = Not tested c) the "in vitr~" study of the affinity of the compounds for sigma receptors is carried out in accordance with the technique described by B.L. Largent et al. in J.
Pharmacol. Exp. Ther. 238, 1986, p. 739°748, the principle of which is to bring into competition the respective affinities of the product to be studied and of (+) [3H] SKF 10,047, which is the characteristic radioactive ligand of the sigma receptors of the guinea pig brain membranes which are used in this study.
The test is carried out by incubating solutions, of appropriate concentrations, of the products with standard samples of membranes and then, after filtration, determining the residual radioactivity of the solution.
The results are processed so as to calculate the IC 50 of the product being studied which, in this case, is the nanomolar concentration of solution capable of inhibiting 50%

~~, a.J ~ ~ .~.

of the bonds of the radioactive ligand to the sigma receptors of the membranes used.
The results are presented in Table 2 below and, by way of reference, the table also shows the result obtained with ditolylguanidine (DTG) which is a pharma calogical tool considered to be a selective ligand having a high affinity for the sigma receptors (Btephen G. Holtzman, J. Pharm. Exp.
Ther. Vol. 248, No. 3, 1989, p. 1054-1062).
Table 2: Bindinct affinity of the compounds of the invention to sigma receptors Compounds tested IC 50 (nmol) Example These results show that the products according to the invention have an affinity for sigma receptors which is from the same order of magnitude to 3 times as great as that of DTG.
These affinities, coupled with the low toxicities of the cycloalkylalkylamines (Z), demonstrate their value.
The specificity of the affinity of the compounds for the sigma receptors is shown by a study which compares the affinity of the products for mu, delta and kappa opioid receptors, as well as for phencyclidine (PCP) receptors, which are receptors recognised as being involved as mediators in the effect of psychomimetic drugs (Eric J. Bimon -"Opiates receptor binding in Drug Research" p. 183°199 in "Receptor Binding in Drug Research" ° Ed. Robert A. O'Brien°
Marcel Dekker ° 1986 and also Brian ~. bargent et al., in .~) iS% c.J .:.'3 r:.4 a l.;.eh:
Eur. J. of Pharmacol. 155 (1988) p. 345-347).
The "in vitro" study of the affinity of the campounds, namely of the products of Examples 2 and 5 of the invention, for three ppioid receptors is carried out in accordance with 5 the technique described by F. Roman et al. in J. Pharm.
Pharmacol. 198?, 39, p. 404°407 and the study of the affinity of PCP for the receptors is carried out in accordance with the technique described by J. Vignon et al. in "Brain Res."
1983, 280, p. 194-7 and 1986, 378, p. 133-41.
10 The results shown in Table 3 are, for each receptor studied, expressed in TC 50, which are the nanomolar concentrations of the products in solutions capable of inhibiting 50~ of the bonds of the specific radioactive ligand bonded to the receptor in question.
15 Table 3 : Affinity of the products of the invention for sigma receptors, compared with their affinities for mu, delta and kappa receptors, and PCP receptors 20 Compounds Mu Delta Kappa Sigma PCP
tested receptor receptor receptor receptor receptor Example The specificity of sigma affinity is clearly shown for the preferred compounds of the invention.
Taking a arbitrarly value of 1 for the IC 50 of sigma affinity, the IC 50 values for mu, delta and kappa receptors are calculated for the compound of Example 5, whose sigma affinity is the most intense. These values are compared with those obtained with DTG, shown as a reference compound.

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compounds Mu Delta Kappa Sigma PcP
tested receptor receptor receptor receptor receptor Example This method of presentation shows that under the working conditions described, one of the preferred compounds of the invention shows an affinity for the sigma receptors which is at least 100 times as great as that found for the mu and kappa receptors, and about 2000 times as great as that of the delta receptor.
Compared with the indices calculated for DTG, the compound of the invention, prepared in Example 5, proves to be at least two times more selective in respect of its affinity for sigma receptors than the said reference compound.
d) The activity of the compounds of the invention on the gastro-intestinal tract was shown in the rat in terms of their ability to inhibit the gastro-duodenal ulcers caused by administration of cysteamine.
This property was demonstrated in the rat in accordance with a technique described by Robert et al., in "Digestion", 1974, 11, p. 199-211.
rn the tests, batches of 6 female Wistar rats of average weight 200 g were given a subcutaneous infection of cysteamine hydrochloride in an amount of 400 mg/kg. The products to be tested axe tested orally or subcutaneously, respectively 1 hour or 30 minutes before the ulcerogenic agent.
Eighteen hours afterwards, the rats are sacrificed by cervical dislocation, arid their stomach and duodenum are removed, rinsed with physiological solution and pinned onto a ra 3~
piece of cardboard.,The presence of ulcers of the antro--pylor-duodenal zone is looked for and their surface area, expressed in mm2, is evaluated by multiplying the two principal perpendicular axes of the lesion. The statistical analysis of the results is carried out by means of the Student test for the ulcerated surface areas, in comparison with a control group which are only given the excipient.
The results shown in Table 4 are expressed in El~ 50 of ulceration scores which are the effective doses, expressed in mg/kg of product, which result in the inhibition of 50% of the ulcerations caused by cysteamine.
Table 4: Inhibiting activity on gastro-duodenal ulcers caused by cys°teamine Product tested ED 50 - scores of Example . ulcerations, mg/kg 2 48.2 5 45.7 These pharmacological properties, coupled with the low toxicity of the compounds of the invention, make it possible to envisage their usefulness, in the form of medicaments, far preventive and curative treatments of disturbances of a neurological type and/or psychic type in general, such as, fox example, depressive states, disturbances of memory and/or behaviour, schizophrenia, Alzheimer's disease, Parkinson's disease and senile dementia.
Also, the cycloalkylalkylamines (I) of the invention are suitable for the treatment of dysfunctions c~f the gastro-intestinal tract in general, such as, for example, disturbances of peristalsis and of motivi~ty, gastro-oesophagial and gastro-duodenal reflux phenomena as well as gastric and/or gastric-duodenal ulcerations.
Usually, the unit doses employed are between 1 and 500 mg and more especially between 5 and 200 mg of product, depending on the nature and gravity of the condition to be treated. The daily therapeutic doses can be divided between several administrations and are generally between 0.5 and 1,500 mg of product per day. In general, a daily posology of 5 to 500 mg of product per day, divided between two to four administrations, is~satisfactory.
The administration of the products of the invention to the patients to be treated is carried out in the form of medicaments of a type suitable for the condition to be treated. Depending on the circumstances, the medicinal preparations will be, for example (but without implying a limitation), tablets, pills, capsules, powders, solutions, suspensions, jellies or suppositories. These pharmaceutical forms are prepared from the products in the form of a base or in the form of their salts, and in accordance with methods usually employed in this industry.
In general, in the medicinal forms of a solid nature, the active principle represents from 5 to 90% by weight of the total of the final form, while the pharmaceutically suitable excipients represent from 95 to 10%. For liquid forms, or for forms'which may be considered as liquid, the amount of active principle is between 0.1 and 10% by weight of the final form, while the pharmaceutically suitable excipients can represent from 99.9 to 90% by weight of this form.
By way of illustration, the formulation and preparation of tablets, using the compound of Example 5, is described.
Formulation Active principle (compound of Example 5) 10.0 to 50.0 mg Polyvinylpyrrolidane 20.0 mg Carboxymethyl starch 8.0 mg Magnesium stearate 2.0 mg Colloidal silica 0.4 mg Lactose sufficient to maDce 200.0 mg 39 ~,~i~~~~.~L~
- Preparation The active principle, in aqueous-alcoholic solution, is mixed with the lactose and then granulated with the polyvinylpyrrolidone, which is also in solution. The particles are dried and sieved on a grid of 1 mm mesh size.
The carboxymethyl starch is mixed with the colloidal silica and added to the granules. Thereafter the magnesium stearate is thoroughly mixed in and the composition is tableted, using 200 mg per tablet.

Claims (9)

1. A compound which is a N-cycloalkylalkylamine of general formula (I):

in which:
R1 is a furyl radical or a thienyl radical, or, with the proviso that Q represents a cyclopropane-1,2-diyl group R1 is a phenyl radical, R2 is lower alkyl, R3 is hydrogen or lower alkyl, m has a value of 1 or 2, R4 is cycloalkyl -CH(CH2)n, in which n has values from 2 to 5, R5 is phenyl which can be monosubstituted, disubstituted or trisubstituted by halogens or by identical or different lower alkyl or alkoxy radicals, or R5 is thienyl, Q represents an ethylene-1,2-diyl group (-CH=CH-) or a cyclopropane-1,2-diyl group , and their additions salts with pharmaceutically acceptable acids.

2. A compound according to claim 1, wherein R1 is a thienyl radical.

3. A compound according to claim 1, wherein R5 is a phenyl radical.

4. A compound according to claim 1, wherein R2 is ethyl.

5. A compound according to claim 1, wherein R3 is methyl.

6. A compound according to claim 1, wherein m is equal to 1 and R4 is cyclopropyl.

7. A compound according to claim 1, which consists of trans 1-[2-(N-Cyclopropylmethyl-N-methyl)amino-2-(2-thienyl) butyl]-2-phenyl-cyclopropane and its salts.

8. A compound according to claim 1, which consists of 4-(N-Cyclopropylmethyl-N-methyl)amino-1-phenyl-4-(2-thienyl)-hex-1-ene, and its salts.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically suitable excipient.