CA2037123A1 - Substituted ethylamines, their process of preparation, their use as medication and their synthetic intermediates - Google Patents

Abstract

ABSTRACT

Substituted ethylamines, their process of preparation, their use a a medicament and their synthesis intermediates.
A compound which is a substituted ethylamine of general formula (I) in which :
Q represents an ethylene-1,2-diyl group or a cyclopropane-1,2-diyl group R1 is an aromatic heterocyclic ring or a phenyl radical optionnally mono-, di- or tri-substituted, R2 is lower alkyl, R3 and R4 are hydrogen or lower alkyl radicals without, however, being both hydrogen, and R5 is an aromatic heterocyclic ring or a phenyl radical which is optionally mono-, di- or trisubstituted, and their addition salts 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.

Description

~317~;~3 Substituted ethylamines their process of ~reparation their use as a medicament and their sYnthesis intermediates The present invention relates to novel substituted ethylamines, to a process ~or prsparing them, to pharmaceutical composition containing them and to their used in medecine, as well as to intermediates useful in their synthesis.
These ethylamines correspond to the general formula (I) :
Rl / H2 / R5 C Q
R2 N~ (I) in which :
Q represents an ethylene-1,2-diyl group (-CH=CH-) or 5 a cyclopropane-1,2-diyl group ~-C~-CH-), C~2 Rl is an aromatic heterocyclic ring of 5 to 7 members, in which the sole hetero-atom is nitrogen, oxygen or sulphur, or, with the proviso that Q represents a cyclopropane-1,2-diyl group or with the proviso that R5 represents an aromatic heterocyclic ring as defined below, Rl is a phenyl radical which is optionally monosubstituted, disubstituted or trisubstituted by identical or different radicals which are lower alkyl or lower alkoxy, R2 is lower alkyl, R3 and R4, which are identical or different, are hydrogen or lower alkyl radiaals without, however, both R3 and R4 representing hydrogen, and R5 is an aromatic heterocyclic ring of 5 to 7 members, in which the sole hetero-atom is nitrogen, oxygen or sulphur, or is a phenyl radical which is optionally monosubstituted, disubstituted or trisubstituted by identical or different radicals which are lower alkyl or lower alkoxy.
In the preceding definitions, the qualification "lower"
comprises the radicals having from 1 to 5 carbon atoms in a linear or branched chain.
It is preferred that :
Rl is an aromatic heterocyclic ring of 5 memb~rs, in . ', ' , 2 i~l37~3 which the sole hetero-atom is oxygen, as in a Z-furyl or 3-furyl radical, or is sulphur in a 2-thienyl or 3-thienyl radical or is nitrogen in a 2-pyridyl, 3-pyridyl or 4-pyridyl radical, or is a phenyl radical which can be monosubstituted, disubstituted or trisubstituted by lower alkoxy radicals such as methoxy, with the proviso that Q represents a cyclopropane-1,2-diyl group or with the proYiso that R5 represents an aromatic heterocyclic ring as de~ined above, lQ R3 and R4 are hydrogen or lower alkyl, such as methyl, without, however, both R3 and R4 representing hydrogen, and R5 is an aromatic heterocyclic ring of 5 members, in which the sole hetero-atom is oxygen, as in a 2-furyl or 3-furyl radical, or is sulphur in a 2-thienyl or 3-thienyl radical, or is phenyl which is optionally monosubstituted, disubstituted or trisubstituted by lower alkoxy radicals such as methoxy.
The invention also compri~es the addition salts of the ethylamines of the formula (I) as well as those of their optical or geometrical isomers which form an integral part of the present invention, with inorganic or organic acids. Among the~e salts, those obtained by reaction of the ethylamines with pharmaceutically acceptable acids are prPferred. For example, preferred salts are those prepared with acetic, benzenesulphonic, camphosulphonic, citricl ethanesulphonic, fumaric, hydrobromic, hydrochloric, lactic, maleic, malic, methanesulphonic, mucic, nitric, pamoic, phosphoric, salicylic, stearic, succinic, sulphuric or tartaric acid.
The ethylamines (I) of the invention have low toxicity in animals and e~hibit valuable psychotropic properties which are responsi~le for their usefulness in therapy in the form of medicaments.
For this application, the preferred compounds are those in which R1 i~ a furyl or thienyl radical, R5 is phenyl, furyl or thienyl, R2 is ethyl and R3 and R4 are identical and are methyl. More especially, these preferred compounds are the following ethylamines (I) :

3 ~37~23 - 4-N,N-Dimethylamino-l-phenyl-~-(3-thienyl)-hex-1-en and its salts, - trans 1-[2-N,N-Dimethylamino-2-(3-thienyl)-butyl]-2-phenyl-cyclopropane and its salts, - 4-N,N-Dimethylamino-4-(2-furyl)-1-phenyl-hex-1-en and its salts, - trans 1-[2-N,N-Dimethylamino~2-(2-furyl)-butyl]-2-phenyl-cyclopropane and its salts.
The invention al50 provides a process for the preparation of the ethylamines of the formula (I), characterised in that it essentially consists, as shown in Scheme 1 below, for obtaining an ethylamine of the formula (I) in which R3 is methyl and R4 is hydrogen, i) in reducing an isocyanate of the formula (II) or an isonitrile of the formula (II') Rl~ ~CH2\ R5 C\ Q (II) 20Rl fCH2 R5 /C\ Q (III) with a metal hydride or or~ano-metallic hydride (Hm) of the general formula Ml(t) M2 H(r) Rx(s) (Hm) in which :
Ml represents an alkali metal which is preferably lithium or sodium, and whose index (t) has a value of O or 1, M2 is a metal of group III of the periodic classification of the elements and 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 represents a carbonitrile group, or a lower alkyl or lower alkoxy group whose index (s) has values of 0, 1, 2 or 3, the indices (t), (r) and (s) defined above correspond to the relation (r) + (5~ - (t) = 3 and the hydrides (Hm.1) in which M2 is aluminium or is boron, . : .: . ~ .
. . . . . ~ ; : ,:: : .
':
. , - ~ .
, 4 ~3~3 when (r) = 3, (t) and (s) having a value of 0, are preferred for the reduction of the compounds (II) and (II'~
ii) or in hydrolysing an isocyanate of the formula (II) or an isonitrile of the formula (II') to give an amine (III) of the formula \ / \~
~C Q (III) which is acylated wi~h formic acid in the presence of N,N'-carbonyldiimidazole to give an int~rmediate N-formyl compound:

Rl CH2 R5 ~C\ Q

which is reduced with a hydride (~m.2) of formula (Hm) in which M2 is aluminium or, if M2 represents boron, (r) has a value of 3 and (t) has a value of 0, and, to obtain an ethylamine of ~ormula (I) in which R3 is lower alkyl other than methyl and R4 is hydrogen, i) in alkylating an amine (III) with a halide ZlR3 in which R3 has the meanings stated above and Z1 is chlorine, bromine or iodine, or ii) in acylatiny an amine (III~ with a reagent (R6-CO)n Z2 in which R6 is the carbon homologue immediately lower than R3 (R3 = -CH2-R6) and n has a value of 1 if Z2 is a halogen, such as chlorine or bromine, or if ~2 is a hydroxyl radical, and n has a value of 2 if Z2 repres~nts an oxygen atom, to give an intermediate carboxamide (IV) o~ the ~ormula C Q (IV) which is then reduced with a hydride (Hm.2) defined above, ..

: .
~
,~, , Z~37~2~

S CHEME

Rl&H2 ~ 5 Rl CH2 ~R5 R2NC (II ~ ) R2 NCO (II~

Rl CH2 R5 R2 NX (R3=CH3 ) CO
~ R6 ~

Rl CH2 ~R5 Rl ~ H2~R5 2 0 C Q ~ ~ C
R2 NH2 (III) R2 NH (I~

(R3=R4=CH3) RI C~2 R5 Rl ~CH2 ~R5 Rl ~CH2~R5 R2 N~ (VI) R2 N ~ ( ~) R2 N ~

~,,~" . ;. i.~.~

6 ~(~3~3 to obtain an ethylamine of formula (I), in which R3 and R4 are identical and are methyl, in dimethylating an amine (III3 by reacting it with formaldehyde and with either formic acid or a reducing metal hydride or reducing organo-metallic hydride (Hm.3) of formula ~Hm), in which M2 is boron,and among which the preferred compounds are those where Rx represents a carbonitrile group, to obtain an ethylamine (I~ in which R3 and R4 are lower alkyl and are different, i) in acylating an ethylamine (I), in which R3 is lower alkyl and R4 is hydrogen, with an agent R7 COZ5, in which R7 is the homologue immediately below ~4 (R4 = -CH2-R7) and Z5 represents bromine or chlorine, to give the carboxamide (V) Rl C~2 R5 \/C \Q (V) R2 N\

which is then reduced with a hydride (Hm.2) defined above, ii) or in reacting an organo-magnesium reagent R2MgZ3, in which R2 is lower alkyl and Z3 is a chlorine, bromine or iodine atom, with an amino nitrile (VI) Rl CH2 R5 C Q (VI) NC N~

in which R3 and R4 wich are identical or different and are lower alkyl, and to obtain an ethylamine (I) in which R3 is lower alkyl and R4 is methyl, in N-methylating an ethylamine (I), in which R3 is lower alkyl and R4 is hydrogen, with formaldehyde and a reducing agent such as a metal hydride or organo-metallic hydride (Hm.3) de~ined above.

7 ~ 3 The invention also provides the intermediates (XX) of the general formula / ~ Q~ (XX) in which :
Q' represent~ an ethylene-1,2-diyl group (-CH=CH-~ or a 0 cyclopropane-1,2-diyl group (-CH-C~-), R11 is an aromatic heterocyclic ring of 5 to 7 members, in which the sole hetero-atom is nitrogen, oxygen or sulphur, or, if Q' represents a cyclopropane 1,2-diyl group or if R15 represents an aromatic heterocyclic ring as de~ined below, Rll is a phenyl radical which i~ optionally monosubstituted, disubstituted or tri~ubstituted by identical or dif~erent radicals which are lower alkyl or lower alkoxy, R12 is lower alkyl or a carbonitrile radical -CN, R15 is an aromatic heterocyclic ring of 5 to 7 members in which the sole hetero-atom is nitrogen, oxygen or sulphur, or is a .phenyl radical which is optionally monosubstituted, disubstituted or trisubstituted by identical or different radicals which are lower alkyl or lower alkoxy, and R16 represents an isoGyanate radical -NC0 or an isonitrile radical -NC, or a radical -N(R13)R14 in which R13 and R14 are hydrogen, lower alkyl or radicals R~-CO- or R7-CO-, in which R6 and R7 ar~ hydrogen or alkyl which is the carbon homologue below R13 or R14 (R13 = -CH2-R6; R14 = -CH2-R7).

.
~: , . . .
'.' .:', : , ' , . . .

8 ;~3~23 Rl W

Rl Rl Rl 1 0 CH r ~ (~H CHO
R2 CN R2 COOH ~VII ) Rl CH2 lR5 Rl CH2 R5 Rl ~C~ Q ~ C Q C~I
R2 CN R2 COOH ~I~) NC ~N (XI) Rl~ CH2~ ~R5 Rl CH2~ ~5 Rl CH2 R5 lR2 NC ~II ' ) R2 NCO (II) NC N (VI) 1' Rl~ Rl Rl~
CH ~ ~CH ~ C=O

: . ~
. . ~
: . , , : . :
:, , , :

,, :. -` ::
: . . : ,,.. .~ , , . . ~ ' ~ ', ........... .: ' .
::

9 2~37~23 The process of preparation of the intermediate compounds (XX), of formulae (II), (II'), (III), (IV), (V) and (VI) consists, as shown in Schemes 1 and 2 :
to prepare the isocyanate compounds (II), in alkylating a compound Rl-CH2~W, in which W is a carbonitrile radical ( CN) or carboxyl radical (-COOH), with an alkyl halide of formula R2Z6, Z6 being a halogen, to give, if W = -COOH, an acid of formula (VII) Rl(R2~-CH-COOH, and, if W = -CN, a nitrile of ~ormula Rl(R2)-CH-CN, which 0 is hydrolysed to the acid (VXI), and thereafter alkylating ~he acid (VII) with a reagent ~VIII) of formula Z7-C~2-Q-R5, Z7 being a halogen or an alkylsulphonyloxy radical, to give an acid (IX) Rl(R2)C~COOH)CH2-Q-R5, and therea~ter preparing the 5 isocyanates (II) by the Curtius reaction, and to prepare the isonitrile compounds (II'), in utilizing a suitable process, for example that described in European Patent Application No. 0,298,703, and which consists in reacting a ketone Rl-CO-R2 with formamide and formic acid to 0 give the N-substituted formamide o~ formula Rl(R2)C~~NH-CHO, which is dehydrated with phosphorus oxychloride to convert it to the corresponding isonitrile Rl(R2) CH-NC, which, when alkylated with the reagent (VIII) already described, gives the isonitrile (II'), and to prepare an amine (III), in hydrolysing either an isocyanate (II) or an isonitrile (II') and to prepare an intermediate carboxamide (IV), in acylating an amine (III) with a reagent (R6-CO)nZ2 already defined, and to prepare an intermediate carboxamide (V), in acylating 0 an ethylamine (I) /C Q

with a hali~e of ~ormula ~7-COZ5, in which R7 is lower alkyl and Z5 is bromine or chlorine and ~, ~ 7~ 23 to prepare an aminonitrile (VI), in reacting an aldehyde ~l-CHO with an amine of ~ormula R3-NH-R4 and an alkali metal cyanide to give the intermediate aminonitrile (XI) Rl(CN)CH-N(R3)R4, in which R3 and R4 are both lower alkyl, and then alkylating it with a reagent (VIII~ already described.
The compounds (I) of kh~ invention differ from the nearest known compounds in respect of their chemical structure and also their application.
Thus, European Patent Application No. 0,29,703 describes thiophene derivatives of the formula :
Rt ~(CH2)p-Rph R~ N

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 a value of 1, 2 or 3, and in which, for the pre~erred compounds, 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 a value 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 of slowed activity and conversely by an inhibiting e~ect on a hyperactive tract.
The compounds of the European Application are different from the ethylamines (I) of the invention in re~pect of their chemical structure, especially the nature of the carbon chain linking the two aromatic sites, and also in respect of their properties.
Essentially, a psychotropic-type activity has not been 11 ~C337~23 reported for the compounds of EP Application No. 0,298,703, and it is such an activity which makes it possible to envisage the usefulness o~ the ethylamines (I) in the treatment of neuro-psychic disturbances.
Among the processes for the preparation of the compounds (I) which have been described above and presented in Scheme 1, it is preferred, if R3 and R4 are lower alkyl, to use the method which consists in reacting an aminonitrile intermediate (VI) with an organo- magnesium derivative R2MgZ3.
Explici~ly, this process consists :
i) in reacting an aldehyde of formula R1-CHO with a secondary amine R3~ R~, ~o obtain the aminonitril~ (XI) of the formula NC(Rl)-CH-N(R33(R4).
This reaction is frequ~ntly used for the preparation of amino acids according to the Strecker method. It is applied to the synthesis of compounds (XI) and consists in reacting 1 mole of aldehyde with 0.8 to 3.0 mole of sodium cyanide or potassium cyanide and with 0.8 to 3.0 mole o~ a salt of a secondary amine of formula R3-NH-R4 in an alcoholic or aqueous-alcoholic medium, at a temperature of between 5C and the reflux temperature of the mixture, for from 1 to 24 hours.
The secondary amine salts used preferably are water-soluble, as in the case of, inter alia, the hydro-chloride, hydrobromide and sulphate.
The reaction solvent comprises a low molecular weight alcohol which is miscible in all proportions with water, such as methanol or ethanol. In the case of aqueous-alcoholic media, the respective proportions are between 95 and 10 % of alcohol, and water to make up to 100 %, this ratio making it possible to obtain a homogeneous reaction medium in a favourable manner.
In a usual procedure, loO mole of aldehyde dissolved in 75 to 200 ml of methanol is added to a solution of 1.1 to 1.3 mole of sodium cyanide and of 1.1 to 1.3 mole of secondary amine hydrochloxide dissolved in lS0 to 400 ml of water. The mixture is stirred for 3 to 5 hours at a temperature of between 15 and 30C and is then treated to isolate the aminonitrile (XI), which, if necessary, i8 purified by distillation.

, , .~ , .

12 ;~:~3~2~3 ii) and thereafter in alkylating this compound with ~
reagent (VIII) to obtain the intermediate (VI) of the invention.
The reaction consists, in a first stage, in preparing the anion of the aminonitrile by treatment with a strong base. For this purpose, lithium N,N-diisopropylamide (L~A) is preferred;
it is prepared l'in situ" from equimolecular amounts of diisopropylamine and butyl- lithium. Per mole of LDA thus prepared, there is then added, in THF, from 1.0 to 0.6 mole of intermediate (XI), so as to obtain the anion thereof. The reagent (VIII) is then introduced at a temperature between -10 and 50C, after which the mixture is left to react for 2 to 48 hours, depending on the reactivity of the compounds.
Thus, preferentially there is added to 1 mole of diisopropylamine in 500 ml of TH~, at about -20C, from 0.95 to 1 mole of butyl-lithium followed by from 0.8 to 1.0 mole of intermediate (XI) dissolved in about 500 ml of THF. After reacting for 1 to 2 hours at between 20 and 100C to form the anion, the mixture is cooled to about 0C and 0.8 to 1.0 mole of the reagent (VIII) is added thereto.
The reaction proceeds for 1 to 2 hours at ambient temperature and the mixture is then treated to isolate and purify the intermediate aminonitrile (VI) obtained, iii) and thereafter in reacting the intermediate (VI) with an organometallic reagent such as a Grignard organo-magnesium derivative of the formula R2MgZ3, in which Z3 is a halogen and more especially bromine or chlorine, in accordance with a reaction described, for example, by N.J. Léonard et al.l J. Am. Chem. Soc., 1956, 78, p. 1986 and 1957, 79, p. 5279.
This replacement of the nitrile radical of the compound (VI) by the alkyl radical R2 of the organo-magnesium derivative i5 carried out in ethers such as diethyl ether, methyl t-butyl ether, diisopropyl ether or dibutyl ether or in tetrahydrofuran, which is the preferred solvent, and consists in reacting l mole of compound (VI) with 1. 5 tG 6 mole of organo-magnesium derivatiYe at a temperature of between 5 and 50C for 30 minutes to 12 houxs.
The preferred method consists in adding 1 mole of .
,..
.
-, 13 ~37~

compound (VI), optionally dissolved in THF, at a temperature ofbetween 10 and 20C, to 4-5 mole of the organomagnesium compound, also dissolved in THF. The reaction is continued for 2 to 5 hours at th~ same temperature and the complex obtained is then decomposed by adding an aqueous ammonium chloride solution. After treatments, the ethylamine (I) is isolated and purified.
The working methods which ~ollow illustrate, without howevPr implying any limitation, the preparation of the essential intermediate d~rivatives and the preparation of the ethylamines ~I) o~ the invention.
Depending on the reactions carried out, the products are obtained directly in a satisfactory state of purity or are purified by appropriate techniques indicated in the examples, thPse techniques generally being crystallisation, vacuum distillation or column chromatography. In the latter case, it is advantageous to use the so-called "chromatoflash" technique on a silica carrier (trademark "Merck", product Kieselgel 60, particle size 230 to 400 mesh).
Furthermore, the purity, identity and physicochemical characteristics of the products prepared are reported and are determined by :
their boiling point under the degree of vacuum prevailing during their distillation (in Pascal), their meltiny point, determined by the capillary tube method, the value indicated being uncorrected, and the thin layer chromatography (TLC) on silica (ready-to-use plates : a "Merck" product ref. 60 F 254), in accordance with a technique which will be briefly recorded : the products to be studied are deposited on the plate in an amount of about lO0 mcg and then subjected to ascending elution with the solvents or their mixtures enumerated below, their respective proportions being given in volume/volume in the list which follows :

14 ~37~3 Ref. S.A - hexanes 100 / ethyl acetate 10 S.B - " 60 / " 10 S.C - ll 40 / ll 10 S.D - " 20 / 1- 10 S~E - " 10 / " 10 S.F methylene chloride 20 / hexanes 80 S.G - methylene chloride S.H - 7l 90 / acetone 10 S.I - " 85 / " 15 S.~ _ l 80 / " 20 S.K - l 98 / methanol 2 S.L - " 95 / " 5 S.M - " 90 / '~ 10 S.N - " 85 / " 15 After development, the chromatograms are observed under ultraviolet light of wavelength 254 nm and/or after colour development by spraying with Dragendorff reagent or tolidine reagent. The ~f value~ observed as well as the references of the elution solvents used are indicated in the examples.
elementary percentage analysis, o~ which the results, in accordance with accepted standards, are not reported numerically but are indicated as having been carried out by mentioning the element detexmined, infrared spectrography of the compounds in pellets in KBr or in the form of films between two NaCl windows or in suspension in Nujol (R) or in solution in CC14; the most intense absorptions are reported in terms of the value of their wavelength in cm~1 proton nuclear magnetic resonance (MMR) i5 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.

..
: --, . ,.. -: ... . ...
. ~
;. :, : ': . .:
:~ , , . ~, . .
- , . ..

- , Z~3'7~3 PREPARATION OF THE INTER~EDIATES
Com~ounds of formula (XI~) XI.l. ~-Dimethyla~ino-phenylacetonitrile (Rl = C6H5; R3 = R4 = CH3~
In a reactor, a solution of benzaldehyde (0.200 mole) in 20 ml of methanol is added in the course of one hour, at a temperature o~ between 30 and 40C, to a solution of 11.82 g (0.~41 mole) of sodium cyanide and of 19.61 g t0.240 mole) of dimethylamine hydrochloride in 40 ml of water. The mixture is stirred ~or 4 hours at ambien~ temperature and is then precipitated in 150 ml of iced water and extracted with ether.
The ether phases are washed successively with water, with a 25 % sodium bisulphite solution and again with water. ~fter evaporation of the ether, the residue is purified by distillation. B.p/93 Pa = 74~79C.
Weight = 30.4 g Yield = 95 %
The intermediate ~-amino-acetonitriles XI.2 to XI.6 were prepared in accordance with this method of working, starting from the appropriate aldehydes and secondary amine salts.
XI.2. a-Dimethylamino-~-~3 ~.5-trimethoxyPhenvl~acetonitrile (Rl = 3,4,5(CH30)3-C6H2; R3 = R4 = CH3) yield = 54 % M.p = 77C (petroleum ether) XI.3. ~-Dimethylamino-~-(2~pyridyl)-acetonitrile (R1 = 2-pyridyl; R3 = R4 = CH3) yield = 67 % B.p/66 Pa = 98-110C
XI.4. ~-Dimeth~lamino-~-(2-furyl)-acetonitrile L
~Rl = 2-furyl; R3 = R4 = CH3) yield = 58 % B.p/13 Pa = 55-75C
XI.5. ~-Dimethylamino-~-(2-thienyl)-acetonitrile (Rl = 2-thienyl; R3 = R4 = CH3) yield = 84 ~ B.p/7 Pa = 75D-85C
XI.6. ~-Dimethylamino-~-(3-thienvl~cetonitrile (R1 = 3-thienyl; R3 = R4 = CH3) yield = 72 % B.p/200 Pa = 86C

~6 ~3~ 3 Compounds of formula (VIII) VIII.l. 1-(2-Thienyl) 3-chloro-~roP-l~ene (R5 = 2-thienyl; Q = -CH=CH-; Z7 = Cl) First stage 104.06 g of malonic acid (1.0 mole), 56.07 g (0.50 mole) of ~-thiophene-carboxaldehyde, 250 ml of pyridine and 5 ml of piperidine are ~eated on a water bath for 2 hours and then to ~he reflux temperature for 5 minutes. After cooling, the solution is precipitated in water and treated with an excess of hydrochloric acid (250 ml of 37 % concentrated solution) to preci~itate the product, which i5 thereafter filtered off and then recrystallised from an ethanol-water mixture to give the purified 2-thienylacrylic acid.
Weight = 42.38 g yield = 58 % M.p = 143-144C
Second stage : 37.34 g (0.24 mole) of the preceding acid and 30 ml (0.24 mole) of BF3-ether complex in 310 ml of methanol are heated to the reflux temperature for 6 hours. The cooled solution is precipitated in water and then 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 which is obtained after removal of the solvents by distillation is recrystallised from hexane to give the purified methyl 2 thienylacrylate.
Weight = 32.65 g yield = 81 % M.p = 46-47 a C
Third stage : A suspension of 4.51 g (118.9 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 10C, under a nitrogen atmosphere.
A solution of 10.0 g (59.45 mmol) of the preceding methyl ester in 50 ml of THF is added slowly at -10C and the solution is then stirred at the same temperature for one and a half hours. The complexes of the solution are decomposed by adding a 3M sulphuric 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 ov~r MgS04. ~vaporation of the ether in vacuo gives 7.83 g (94 %) of residual product in the form of a brown oil. The ;:

17 2~3~23 crude 1-(2-thienyl)-prop-1-en-3-ol, which is unstable at ambient temperature, is kept at a temperature below 0C.
Fourth stage : 21.74 ml (296 mmol~ of dimethyl sulphide are added slowly, at a te~perature of 0C, to a mixture of 39.53 g (296 mmol) of N-chlorosuccinimide in 180 ml of anhydrous methylene chloride. The mixture is cooled to -10C
and a solution of 11.86 g (84.6 mmol) of the preceding alcohol in 50 ml of methylene chloride is added.
The temperature of the solution is brought back to 0C
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 i~ reextracted with ethex. The combined ether phases are washed and then drie~. The ether is removed by vacuum distillation and crude 1-(2-thienyl)-3-chloro-prop-1-ene is obtained in the form of an unstable reddish brown oil which is used as it is.
Weight = 12.06 g yield = 94 %
VIII.2. 1-~3-Thienvl)-~-chl ro-prop-l-ene (R5 = 3-thienyl; Q = -CH=CH-; Z7 - Cl) The intermediate is obtained from 3-thiophenecar-boxaldehyde in accordance with the process described in the preceding example.
First stage : 3-thienylacrylic acid M.p = 46~C (ethanol/water) Second stage methyl 3-thienylacrylate M.p = 49C (hexanes) Third stage : 1-(3-thienyl)-prop-1-en-3-ol unpurified oil Fourth stage : 1-(3-thienyl)-3-chloro-prop-1-ene unpurified amorphous white solid.
VIII.3. 1-(2-Furyl)-3-chloro-Pro~1-ene (R5 = 2-furyl; Q = -CH=CH-; Z7 = Cl) The intermediate is obtained from 2~furylcarboxaldehyde in four stages, in accordance with the process described for the preparation o~ the intermediate VIII.1.
VIII.4. trans-1-M sYloxvmeth~l-2-~henvl-cvclopro~ane (R5 = C6H5; Z7 = ~H3-SO3; Q = cyclopropane-1,2-diyl) " :.
.
- , ' ' .
, ~ , ~7~2~

First stage o A solution of 25.0 g (154 mmol) o~ trans-2-phenyl-cyclopropanecarboxylic acid in 100 ml of THF is added dropwise, under a nitrogen atmosphere, to a solution o~
borane-THF complex. The solution is heated to the reflux temperature for 3 hours, after which 130 ml of 2N NaOH solution are added slowly, and the mixture is stirred for 30 minutes.
The ether extracts are concentrated in vacuo to give 20.78 g o~
crude trans-1-hydroxymethyl-~-phenyl-cyclopropane which is purified by distill~tion~
Weight Y ~8.19 g yield = 80 % ~.p/33 Pa = 90-97DC
Second stage : 9.18 g (66.2 mmol) of the alcohol obtained above and 13.83 ml (99.25 mmol) of triethylamine are added to 100 ml of methylene chloride. 5.63 ml ~72.8 mmol) of methanesulphonyl chloride are added dropwise under a nitrogen atmosphere, at 1o1C. The mixture is stirred for 15 minutes at -10C and then washed successively with iced water, with a 10 % strength HCl solution, with a saturated NaHC03 solution and then with a saturated NaCl solution. After having been dried over MgS04 at 0C, the solution is concentrated in vacuo to give a yellow oil. The intermediate thus obtained is dissolved in anhydrous THF and used as it is.
VIII.5. trans-1-Bromomethyl-2~phe~ yclopropane (R5 = C6H5; Z7 = Br; Q = cyclopropane-1,2 diyl) 61.0 g (0.34 mol) o~ N-bromosuccinimide are added to 300 ml of methylene chloride and the mixture is cooled to 0C
under a nitrogen atmosphere, after which 23.4 ml (0.41 mol) of dimethyl sulphide are added dropwise. The mixture is stirred at 0C for 30 minutes and then cooled to -5C; a solution of 33.6 g (0.23 mol) of trans-1-hydroxymethyl-2-phenyl-cyclopropane obtained in preparation VIII.4, in 100 ml ofmethylene chloride, is then introduced dropwise. The mixture is stirred for ~ hours at 0C and then for 16 hours at 25C;
thereafter it is diluted by addition o~ 250 ml of hexanes and the mixture is pr~-cipitated in 250 ml of iced water. The organic phase is washed with a saturated NaC1 solution and then dried over MgS04. The solvents are removed by concentration in vacuo and the residue is purified by distillation Weight = 40.81 g yield = 85 % B.p/27 Pa = 72C

19 ~3~23 VIII.5. tran~-1 Mesyloxymethyl-2-~3,4 s-trimethoxyphenYl~-cyclopropane (R5 = 3,4,5(CH30)3-C6H2; Z7 = CH3-S03; Q = cyclopropane-1,2-diyl).
First stage : 55.0 g (0.~3 mol) of 3,4,5-tri-methoxycinnamic acid and 28.39 ml (0.23 mol) ~f BF3- ~ther complex are added to 400 ml o~ methanol and the olution is haated for 6 hours to the reflux temperature. The mixture is cooled, then precipitated in water, and extracted with methylene chloride. The combined organic phases are washed by extraction with water and dried, and the solvent is then removed by distillation in vacuo. The methyl 3,4,5-trimethoxycinnamate is purified by recrystallisation from methanol.
Weight = 46.17 g yield = 80 % M.p c 96-98C
Second stage : 106.83 ml (213.7 mmol) of n-butyl-lithium, as a 2M solution in hexane, are added slowly, under a nitrogen atmosphere, to a solution of 20.15 ml (21~ mmol) of 2-methyl-~-propanol in 125 ml of anhydrous THF~ After 30 minutes, the solution is treated by dropwise addition of a solution of 17.97 g (71.22 mmol) of the preceding methyl ester in 100 ml of THF. The reaction mixture is heated to the reflux temperature for 2 hours and a half and is then cooled by means of an ice bath and hydrolysed by addition of 200 ml of water. The aqueous phase is extracted with ethyl acetate and the organic fractions are dried over MgS04. The ~olvents are evaporated in vacuo to give a residue of t~rt-butyl 3,4,5-trimethoxycinnamate which is purified by recrystallisation from hex~ne.
Weight = 16.27 g yield = 78 % M.p = 83-85C
Third stage : 3.0 g of sodium hydride as a 60 % strength oily disper~ion (75 mmol) are added, under nitrogen, to a stirred suspension of 15.47 g (70.3 mmol) of trimethylsulphonium iodide in 150 ml of DMS0, which is kept at 25-30~C.
After the evolution of hydrogen as ceased (about 30 minutes), a solution of 15.9 g (54 mmol) of the preceding tert-butyl ester in 100 ml of DMS0 is added, without exceeding 35C.

, ~ :
. .

~37~L23 The mixture is stirred for 30 minutes at 25-30C and then for one and a half hours at 55-60C. It is thereafter precipitated in 3~0 ml of water and extracted with ethyl acetate. The combined extracts are dried and concentrated in vacuo to give a residue of tertrbutyl trans-2-(3,4,5-trimathoxy-phenyl)cyclopropanecarboxylate in the form of a yellow oil which solidifies. The product is purified by recrystallisation from hexane.
Weight = 9.69 g yield = 58 % ~.p = 68-70C
Fourth stage : 3.66 g (~6.5 mmol~ of lithium aluminium hydride are dispersed in 150 ml of T~F under a nitrogen atmosphere. 9.92 g (32.2 ~mol3 of the preceding tert-butyl ester dissolved in 100 ml of THF are added slowly. The mixture is heated to the reflux temperature for one hour and a half and 5.58 ml of 10 % strength NaOH solution ar~ added cautiously, followed by 7.32 ml of water. The suspension obtained is stirred overnight; the insoluble matter is ~iltered off and the filtrate is concPntrated in vacuo to give crude trans-l-hydroxymethyl-2-(3,4,5-trimethoxyphenyl~-cyclopropane, which is purified by distillation in vacuo.
Weight = 6.65 g yield 87 ~ B.p/3 Pa = 145-165C
Fifth stage : Following the procedure described for Stage 2 of the preceding intermediate VIII.4, but using the derivative obtained above, trans-l-mesyloxymethyl-2-(3,4,5-trimethoxyphenyl)-cyclopropane i5 obtained in the form of a white solid which is used without further purification.
VIII.7. trans-1-Chloromethyl-2-(2-thienyl~-cyclopropane (R5 = 2-thienyl; Z7 = Cl: Q = cyclopropane-1,2-diyl) In accordance with the process described in the preceding example (stages 2, 3 and 4) the trans-l-hydroxymethyl-2-~2-thienyl~-cyclopropane is obtained from the methyl 3-(2-thienyl)-propenoate. 15,50g (100 mmol) of the prec~ding alcohol and 40,0g of dichlorotriphenylphos-phorane (85% - 102 mmol) are added in 75,0 ml of anhydrous triethylamineO The mixture is stirred at 25C during 24 hours then precipitated in 500 ml of water. After adding 100 ml of hexanes the mixture is filtred then the aqueous layer is extracted twice with 100 ml of hexanes. The. organic phases are .

.
.

21 ~37~3 combined and therea~ter dried over Na2S04.
After removal of the solvant by vacuum distillation the crude product is puri~ied by distillation.
Weight = 9,7 g yield 56% ~.p/40 Pa = 65-70C
VIII.8. trans-1-Chloromethy~ L3-thienYl~-cYclopropane (R5 = ~-thienyl; Z7 = Cl; ~ = cyclopropane 1,2 diyl) With the same process described in the preceding example, the product is obtenaid from the methyl 3-(3-thienyl)-propenoate.
the crude product is puri~ied by vacuum distillation in the ~orm of yellowish oil B.p/400 Pa = 60 - 7~C
VIII.g. trans-l-Chloromethyl-2-(2~furYl)-cyclopro~ane (R5 = 2~furyl; Z7 = Cl; Q = cyclopropane 1,2 diyl) The compound is obtenaid from the methyl 3-(2-furyl)-propenoate with the same process des cribed in the precedingexample. It is purified by vacuum distillation. B.p/1,3 Pa =

~-Amino-acetonitriles of ~ormula ~VI) The compounds are prepared by alkylation of the acetonitriles (XI) with the reagents (VIII) described above.
After reaction, the compounds obtained, which are often unstable, axe either purified by crystallisation or employed as they are in the subsequent reactions.
The purity and identity of the products is confirmed by thin layer chromatography and by NMR.
General workinq method In a reactor protected from moisture and under a nitrogen atmosphere, 1.025 moles of n-butyl-lithium (as a lOM solution in hexanes) are added dropwise at -20C to a solution of 1.025 moles of diisopropylamine in 1 litre of anhydrous tetrahydrofuran.
The mixture i kept at -20C for 15 minutes. At -72C, 1.0 mole of nitrile (XI) dissolved in 200 ml of THF is introduced, stirring is continued for 1 hour 30 minutes at khis temperature and 1.025 moles of reagent (VIII) dissolved in 500 ml of THF are then added. After 20 minutes at 72C, the mixture is stirred ~or 1 hour at ambient temperature.
Thereafter, 1.5 1 o~ 10 % (weight/volume) NH4Cl solution .

: .
, ~2 ~ 3 and 750 ml of a 1 :1 (volume/volume) mixture of hexanes and ethyl acetate are added.
The organic phase is separated off and the aqueous phase is reextracted with the same mixture of solvent~. The combined organic phases are washed by extraction with a saturated sodium chloride solution and then dried over MgS04. The solvents are removed by distillation in vacuo and on a water bath. ~he oily residue is, depending on circumstances, cry~tallized by addition of hexanes or used as it is ~or the next stage.
The intermediates VI.l to VI.22 are prepared in accordance with this method of working.
VI.l. trans~ 2-Cyano-2-phenyl-N.N-dimethylaminoethyl)-2-phenvl-cyclo~ropane.
(Rl = R5 = C6H5; R3 = R4 = CH3; Q = cyclopropane-1,2-diyl) From XI.l and VIII.4 Yield = 57 % (crude) TLC : 0.65-0.70; S.C.
NMR 0~60-Oo~O (m,3H); 1.28 (m, lH); 2.15 (m, 2H); 2030 (d~
6H); 6.78-7.78 (m, lOH).
VI.2. _ trans~ Cyano 2- ~3,~5-trimethoxYphenyl)-N,N-dimethYlaminoethyll-2-~henyl-cYcloPro~ane.
(Rl = 3,4,5(CH30)-C6H2, R3 = R4 = CH3; R5 = C6H5; Q =
cyclopropane-1,2-diyl) Fxom XI.2 and VIIIo5 Yield = 87 % (crude) TLC : 0050-0.55; S.D.
25 NMR : 0.60-0~80 (m, 2H); 1.10-1.30 (m, lH); 1.60-1.90 (m, lH);
2.28 (d, 8H); 3.86 (m, ~H); 6.78 (d, 2H); 6.89-7.39 (m, 5H) VI.3. 1-Cy~ano-1-N N dimethylamino-l-phenyl-4-(2-thienyl~-but-3-ene.
(R1 = C6H5; R3 = R4 = CH3; R5 = 2-thienyl; Q = -CH=CH-) From XI.1 and VIII.l Yield = 80 % (crude) TLC : 0.70; S.D.
NMR : 2.23 (s, 6H); 2.80 (d, 2H); 5.88-6.19 (dt, lH); 6.60 td, lH); 6.87-7.38 (m, 8H) VI.4._1-Cyano-1-N.N-dimethylamino-1-phenyl-4-(3-thienYl)-but-3-ene.
(R1 = C6H5; R3 = R4 - CH3; R5 = 3-thi~nyl; Q = -CH=CH-) From XI.l and VIII.2 Yield = 75 % (crude) TLC : 0.60; S.A.

.

23 2~3~23 NMR : 2.30 (~, 6H); 2.85 (m, 2H); 5.40 (m, lH); 6.30 ~d, lH~;

6.90-7.80 (m, 8H~
VI.5. trans-1-f2-Cyano-2-~he~l-N,N-dimethylaminoethYl]-2-(3,4,5-trimethoxyphenylL~cyclopropane.
(Rl = C6H5 ; R3 = R4 = CH3; R5 = 3,4,5(CH30)-C6H2; Q =
cyclopropane-1,2-diyl) From XI.1 and VIII.6 Yield = 78 % (crude) TLC : 0.35-0.40; S.D~
NMR : 0.55-1.45 (m, 4H~; 2.20 (d, 2H); 2.35 ~s, 6H) 3.85 (s, 9H); 6.28 (~, 2H); 7.50 (m, 5H) VI.6. trans-1-r2- ~ano-2-~2-p~ridyl)-N,N-dimethYlaminoethyl]-2-phenvl-cyclopropane.
(Rl = 2-pyridyl; R3 = R4 = CH3; R5 = C6H5; Q = cyclo- propane-1,2-diyl) From XI.3 and VIII.5 Yield = 79 % (crude) TLC : 0.25; S~Eo NMR : 0.62-1.65 ~m, 4H); ~.35 (s, 6H~; 2.40 (d, 2H); 7.16 (m, 6H); 7.65 (m, 1~); 7.75 (m, lH); 8.78 (m, lH) VI.7. l-Cyano-l-N,N-dimethYlamino-l-~ 2-fur~1)-4-phenyl-but-3-ene.
(Rl = 2-furyl; R3 = R4 = CH3; R5 = phenyl; Q = -CH=CH-) From XI.4 and cinnamyle chloride Yield = 98 % (crude) TLC : 0.50; S.C.
NMR : 0.20-0.85 (m, 5H): 2.31 (m, 2H); 2.45 (s, 3H): 3.00 (d, 2H); 5.81 (dt, lH); 6.35-6.51 (m, 3H); 7.28 (s, 5H); 7.48 (m, lH) VI.8. trans-l- r 2-Cyano-2-(2-furYl~-N~N-dimethylaminoethyll-2 phenvl-cyclop~epaneO
(Rl = 2-furyl; R3 = R4 = CH3; R5 = C6H5: Q = cyclo- propane-1,2-diyl) Fro~ XI.4 and VIII.5 Yield = 91 ~ (crude) TLC : 0.25-0.30, S.C.
NMR : 0.46-1.43 (m, 4H); 2.17~2.30 (m, 8H); 6.35 (m, lH); 6.62 (m, lH); 7.20 (m, 5H); 7.45 (m, lH) VI.9. 1-Cy_no-l-N,N-dim~thylamino-1-(2 furyl)-4-~2-thieny~)-but-3-ene~.
(Rl = 2-furyl, R3 = R4 - CH3; R5 = 2-thienyl; Q =-CH=CH-) From XI.4 and VIII.1 , 24 ;~-3'73L23 Yield a 96 % (crude) TLC : 0.40~0.45; S.C.
NMR : 2.31 (s, 6H); 2.98 (d, 2H~; 5.68 (dt, lH); 6.31-6~61 (m, 3H); 6.90-7.18 (m, 3H); 7.49 (m, lH) VI.10. 1-Cx~o-1-N,N-d _ethYlamino-4-pheny~ (2-thienyl) -but-3-ene.
(R1 = 2-thienyl; R3 = R4 = CH3; Rs = phenyl; Q = -CH=CH-) From XI.5 and 3-phenyl-1 chloropropene Yield - 91 % (crude) ~LC : 0.45-0.50; S.C.
NMR : 2.45 (s, 6H~; 2~88 (d, 2H); 5.82 (dt, lH); 6.43 (d, lH);
6.88-7.01 (m, lH); 7.28 (m, 7H) VI.ll. trans-l- r 2-Cyano-2-(2-thienyl)-N~N-dimethylamino ethyll-2-phenyl-cyclo~ropane.
(Rl = 2-thienyl; R3 - R4 = CH3; R5 = C6H5; Q = cyclo- propane-1,2-diyl) From XI.5 and VIII.5 Yield = 79 % (crude) TLC : 0.80-0.85; S.D.
NMR : 0.65 -1.40 (m, 4H); 2.10 - 2.25 (m, 2H); 2.37 (s, 6H);
6.73 -7~32 (m, 8H) VI.12. 1-Cyano-l-N,N-dimethylamino-4-(2-furyl)-l-(2-thienvl~-but-3-ene.
(Rl = 2-thienyl; R3 = R4 = CH3; R5 = 2-furyl; Q = CH=CH-) From XI.5 and VIII.3 Yield = 79 % (crude) TLC : 0.50; S.CO
NMR : 2.38 (g, 6H); 2.90 (d, 2~); 5.78 (dt, lH); ~.15-6.33 (m, 3H); 6.89-7.05 (m, lH); 7.20-7.30 (m, 3H) VI.13. l-CYano-l-N~N-dimethy~amino-l 4-di(2-thienylL-but-3-ene.
(Rl = R5 = 2-thienyl; R3 = R4 = CH3; Q = -CH=CH-) From XI.5 and VIII.3 Yield = 84 % (crude) TLC : 0.50; S.C.
NMR : 2.38 (s, 6H); 2.80 (d~ 2H); 5.67 (dt, lH); 6.51 (d, lH~;
6.88-7.38 (m, 6H) VI.14. 1-Cyano-l~N~N-dimeth~lamino-1-[2-thienY1)-4-(3-thienyl)-but-3-ene.
(Rl = 2-thienyl; R3 - R4 = CH3; R5 = 3-thienyl; Q =
-CH=CH ) Fr~m XI.5 and VIII.2 Yield = 87 % (crude) TLC : 0.50; S.C.
NMR : 2.35 ~s, 6H); 2.9-3.2 (m, 2H); 5.7 ~dt, lH); 6.4.~ (d, .

.
, ;

25 ~3~23 lH); 6.85-7.50 (m, 6H) VI.15. 1-Cyano-l-N,N-dimethylamino-4-pheny~-1-(3-thien~l) -but-3-ene.
(R1 = 3-thienyl; ~3 = R4 c CH3: R5 = phenyl; Q - -CH=CH-) From XI.6 and 3-phenyl-1-chloropropene Yield = 87 % ~crude) TLC : 0.40-0.45; S.C.
NMR : 2.35 (s, 6H); 2.5-3.2 (m, 2H); 5.5-6.0 (dt, lH~; 6.3 (d, lH); 7.3 (~, 5H); 7.0-7.6 (m, 3H) VI.16. trans~ 2-Cyano-2-(3-thienyl)~N,N-dimethylamino sthyl~ r 2-phenyl-cyclopro~ane.
(Rl = 3-thienyl; R3 = R4 = CH3; R5 = C6H5; Q = cyclo- propane-1,2-diyl) From XI.6 and VIII.4 Yield = 83 % (crude) TLC : 0.45-0.50; S.B.
15 NMR : 0.50-2.30 ~m, 6H); 2.27 (s, 6H); 6.7-7.5 (m, 8H) VI.17. l-Cyano-l-N,N dimethylamino-1-(3-thienyl)-4-f2-thienyl) but-3-ene.
(Rl = 3-thienyl; R3 = R4 = C~3; R5 = 2-thienyl; Q =
-CH=CH-) From XI.6 and VIII.l Yield = 85 % (crude) TLC : 0.50; S.C.
NMR : 2.35 (s, 6H); 2.9-3.2 (m, 2H); 5.7 (dt, lH); 6.45 (d, lH); 6.85-7.50 (m, 6H) VI.18. 1-Cyano-l N,N-dimethylamino-1.4-di(3-thienyl)-but-3-ene.
25 (Rl = R5 = 3-thienyl; R3 = R4 = CH3; ~ = -CH=CH-) From XI.6 and VIII.2 Yield = 75 % (crude) T~C : 0.75; SOC.
NMR : 2.30 (s, 6H); 2.9 (m, 2H); 5.6 (dt, lH); 6.40 (d, lH);

7.0~7.45 ~m, 6~) 30 VI.l9. trans-1-(2-Cvano 2- ~enYl-N,N-dimethylaminoethyl~ -2-(2-thienvl)-cYclopro~ane., (R1 = C6H5; R3 - R4 = CH3; R5 c 2-thienyl; Q = cyclo- propane-1,2-diyl) From XI.l and VIII.7 35 Yield = 64 % (crude) ~LC : 0.70; S.D.
NMR : 0.50-2.80 (m, 6H); 2.27 (s, 6H); 6.49-7.10 (m, 3H); 7.35 (m, 3H); 7.60 (m, 6H) 26 ~Gi37~23 VI.20. trans-l ~2-CYano=2-(2-thienyl-y~ N-dimethyl amino ethvl ~ -2-(2-thienyl)-cyclo~ropane.
(Rl - R5 = 2-thienyi ; R3 - R4 = CH3 ; Q = cyclo- propane-1,2-diyl) From XI.5 and VIII.7 Yield - 58 % (crude) TLC : 0.50-0.55 ; S.C.
NMR : 0.60-2060 (m, 6H~; ~.35 (s~ 6~); 7.00 (m, 4H); 7.40 (m, 2H) VI.21. trans-l- r 2-Cyano-2-~3-thienyl~-NI~-dimethYlamino ethyl~-2-(2-furYl) cycloPro~ane.
(Rl = 3-thienyl ; R3 = R4 = CH3 ; R5 = 2-furyl ; Q =
cyclopropane-1,2-diyl) From XI.6 and VIII.9 Yield = 98 ~ (crude) TLC : 0.60 ; S.C.
VI.22. trans-l- r 2-Cyano-2-(2-furyl)-N,N dimethylamino eth~l]-2-(3-thienylL~cyclopro~ane.
(Rl = 2-furyl ; R3 = R4 = CH3 ; R5 = 3-thienyl ; Q =
cyclopropane-1,2-diyl) From XI.4 and VIII~8 Yield = 95 % (crude) TLC : 0.45 ; S.c.
NMR : 0.40-2.40 (m, 6H); 2.25 (s, 6H); 6.20-6.60 (m, 6H) ETHY~AMINES OF T~E INVENTION - ~XAMPLE5 General workina method :
2.26 l of a 2.0 M solution of ethyl-magnesium bromide (4.52 mol) in THF are introduced into a reactor protected from moisture, under a nitrogen atmosphere.
275.0 g (1.0 mol) of a-amino-acetonitrile (VI) dissolved in 1.6 l of THF are introduced over 15 minutes, with stirring and at ambient temperature.
The mixture is stirred at laboratory temperature for 3 hours and 4.5 l of an aqueous saturated ammonium chloride solution are then added cautiously, without exceeding 20C.
The aqueous phase is decanted and extracted with twice 650 ml o~ a 1 :3 (volume/volume) mixture of hexanes and ethyl acetate.
The combined organic pha~es are extracted with twice 600 ml of N HCl solution. The combined acid aqueous phases are rendered alkaline with a concentrated sodium hydroxide solution ., 27 ~37~3 and the mixture is then extracted with 3 times ~50 ml of hexanes/ethyl acetate mixture.
The combined organic phases are washed with water, dried over MgSO4 and then evapora~ed in vacuo. The residual product is purified by crystallisation or by preparing and then purifying one o~ its additio~ salts which most commonly is the hydrochloride.
This experimental method is applied to the intermediates VI.1 to VI.22, using ethyl-magnesium bromide, to obtain the compounds of the invention (I)) of Examples 1 to 22.
Example 1 : trans 1-~2-N~N-Dimethylamino-2-phenvl-butyl)-2-phenyl-cvclopropane.
(Rl - R5 = C6H5; R2 = C2H5; R3 = R4 = CH3; Q = cyclopropane 1,2 diyl) Starting material : the intermediate compound VI.1 Yield = 47 % boiling point/13 Pa = 14~-152C TLC : 0.60; S.C
IR (film) : 3080, 3060, 3020, 2980, 2960, 2875, 2820, 2780, 1579, 1490, 1452, ~44~, 1352, 1220, 1180, 1085, 1025, ~9~, 750, 690 cm~l NMR : 0.65-2.15 (m, llH); 2.26 (d, 6H); 6.87-7.50 (m, lOH) Analysis (C21H27N) C, H, N
ExamPle 2 : trans 1~I2-N ! N-Dimethylamino-2-(3.4.5-trimethoxyphenvl)-butyl~-2-phenyl cyclo~ropane.
(Rl = 3,4,5~CH30)3-C6H2; R2 = C2H5: R3 = R4 = CH3; R5 = C6H5;
Q = cyclopropane-1,2-diyl) Starting material : the intermediate compound VIo2 Yield = 38 ~ TLC : 0.35; S.C
IR (film) : 3036, 2940, 2860, 2780, 1600, 1585, 1500, 1460, 1400, 1320, 1240, 1185, 1160, 1140, 1020, 750, 700 cm~1 NMR : 0.62-0.95 (m, 6H); 1.41-1061 (m, lH); 1.87-2.02 (m, 4H);
2.31 (d, 6H); 3.70-3.88 (t, 9H): 6.66 (s,2H); 6.90-7.22 (m, 5H) Analysis (C24H33N03) C, H, N, O
Example 3 : 4-N N-Dimethylamino-4-phenyl-1-(2-thienyl~-hex-1_ ene.
(Rl = C6H5; R2 = C2H5; R3 - R4 = CH3; RS = 2-thienyl;
Q = -CH=CH-) Starting material : the intermediate compound VI.3 Yield = 62 % melting point 77-78C l'LC : 0.60-0.65; S.C

28 ~al3~23 IR (~ilm~ : 3220, 2960-2880, 1465, 1380, 950, 760, 730, 700 cm~l NMR : 0-72 (t, 3H); 1.90 (q, 2H); 2.25 (s, 6H); 2.80 (d, 2H);
5.90-6.22 (dt, lH); 6.58 (d, lH); 6.89-7.41 (m, 8H) Analysis (C18H23NS) C, H, N, S
Exam~le 4 : 4-N.N-Dimethvlamino-4-phenYl-1-(3-thienYl)-hex-1-ene.
(Rl = C6H5); R2 = C2H5; R3 = R4 = CH3; R5 = 3-thienyl;
Q = -CH=CH-) Starting matexial . the intermediate compound VI.4 Yield = 58 % melting point = 95-96C TLC : 0.50 IR (sol. CC14) : 3080, 3040, 2980, 2930, 2850, 2820, 2775, 1500, 1470, 1460, 1450, 1250, 1190, 1140, llOOr 1040, 1020, 980 cm~l NMR : 0.78 (t, 3H)f 1.95 (q~ 2H~; 2.26 (s, 6H); 2.87 (d~ 2H);
5.90-6.26 (dt, lH); 6.55 (d, lH~; 7.05-7.50 (m, 8H) Analysis (C18H23NS) C, H, N, S
Example 5 : trans ~-(2-N N-Dimethylamino-2-phenYl-butYl)-2-(3 4,5-trimethoxvphenyl)-cYclopropane.
(Rl = C6H5; R2 = C2H5; R3 = R4 - CH3; R5 = 3,4,5(CH30)3-C6H2;
Q = cyclopropane-1,2-diyl) Starting material : the intermediate compound VI.5 Yield = 37 % TLC : 0.45; S~M
IR (KBr) : 3060, 2980, 2930, 2780, 2740, 2400, 1585, 1515, 1470, 142~, 1320, 1255, 1235, 1150, 1130, 1010, 910, 850, 810, 760, 705 cm~l NMR : 0.95-1.15 (m, 6H); 1.88 (m,2H); 2.48 (m, lH); 2.71 ~s, 6H); 3.30 (m, 2H); 3.77 (d, 9H): 6.33 (s, 2H); 7.50-7.82 (m, 5H) - Hydrochloride : melting point = 205-208C
Analysis (C24lH33N03.HCl) C, H, N, 0, Cl Exame~Le 6 : trans 1- r 2-N.NIDimethy~ no-2-(2-pyridYl2 butYl1-2-~henyl-cyclopro~ane.
(Rl = 2-pyridyl; R2 = C2H5; R3 - R4 - CH3; R5 = C6H5;
Q = cyclopropane 1,2 diyl) Starting material : the intermediate compound VI.6 Yield = 52 % boiling point/13 Pa = 130C TLC : 0.30; S.E
IR (film) : 3060, 3020, 2970, 2940, 2875, 2820, 1610, 1590, ~, ~ ,. , -,;
.

29 ~37~l23 1570, 1500, 1465, 1430/ 1150, 1100, 1050, 1000, 915, 785, 740, 700 cm~l NMR : 0.66-0.91 (m, ~) 1.44-1.63 (m,2H); 1.80-2.24 (m, 4H);
2.30 (s, 6H~, 6.89-7.35 (m, 6H); 7.52-7.69 (m, 2H); 8.62 (d, lH) Analysis (C2OH26N2) C, H, N
ExamPle7:4-N N-Dimethylamino-4-(2-~uryl~-1 phenyl-hex-l-ene.
(R1 = 2-furyl; R2 = C2~5; R3 ~ R~ - CH3; R5 = C6H5;
Q = -CH=CH-) Starting material : the interm~diate compound VI.7 Yield = 37 % TLC : 0.35; S.C
IR (film) : 3020, 2980, 2940, 2880, 2820, 2780, 1600, 1575, 1495, 1470, 1450, 1160, 1040, 968, 800, 735, 690 cm~1 NMR : 1.81 (t, 3H); 1.86 (q,2H); 2.20 (5, 6H); 2.62-2.85 (m, 2H~; 5.98-6.58 (m, 4H~; 7.21-7.38 (m, 6H) Analysis (C18H23NO) C, H, N, O
Exam~le 8 : trans 1-r2-N N-Dimethylamino-2-(2-furyl)-butyll~2-~henyl-cyclgpropane.
(R1 = 2-furyl; R2 = C2H5; R3 = R4 = CH3; R5 = C6H5;
Q = cyclopropane~1,2-diyl) Starting material : the intermediate compound VI.8 Yield = 65 % TLC : 0.40; S~A
IR (film) : 306Q, 3020, 2980, 2960, 2870, 2820, 2780, 1610, 1500, 1465, 1380, 1160, 1020, 940, 887, 805, 740, 700 cm~1 NMR : 0.80-0.97 (m, 6H); 1.23-1.70 (m, lH); 1.91-2003 (m, 4H);
2.16 ~8, 6H); 6.06 (d, lH); 6.26 (dd, lH); 6.80-7.20 (m, 5H);
7.32 (d, lH) Analysis (C19H26NO) C, H, N, O
Example 9 : 4-N N-Dimethvlamino-4-(2-furvl)-1-(2-thienvl)-hex-1-ene.
(R1 = 2-furyl; R2 = C2H5; R3 = R4 = CH3; R5 = 2-thienyl;
Q = -CH=CH-) Starting material : the int~rmediate compound VI.9 Yield = 56 % melting point = 68-69C TLC : 0.50-0.55; S~C
IR (Nujol) : 2880-2940, 2840, 1460l 1370, 1150, 1040, 1020, 1000, 955, 850, 800, 740, 700, 695 cm~1 NMR : 0.85 (t, 3H~; 1.90 (q, 2H); 2.25 (s, 6H); 2.80 (m, 2H);
5.80-6.12 (dt, lH); 6.18 (m, lH); 6.34 (m, lH); 6.60 (d, lH);

, :

21~37~Z3 6.90-7.12 (m, 3H); 7.40 (d, lH) Analysis (C16H21NOS~ C, H, N, O, S
ExamPle 10 : 4-N,N-Dimethylamino-l-phenvl-4-(2-thienyl)-hex-1-ene.
(R1 = 2 thienyl; R2 = C2H5; R3 = R4 = CH3; R5 = C6H5;
Q = -CH=CH-) Starting material : the intermediate compound VI.10 Yield = 32 % TLC : 0.45-0.50; S.C
IR (film) : 3070, 3050, 3010, 2960, 2930, 2~60, 2810, 2770, 1590, 1580, 1490, 1440, 1240, 960, 820, 735, 685 cm~l NMR : 1.87 (t, 3H); 1.94 (q,2H~; 2.24 (s, 6H); 2.86 (d, 2H);
6.05-6.63 (ddt, 2H); 6.87-7.07 (m, 2H); 7.17-7.37 (m, 6H) Analysis (C18H23NS) C, H, N, S
Exam~le 11 :trans l- r 2-N N-Dimeth~ylamino-2-(2-thienyl)-butYl]-2-phenYl-cycloPropane.
(R1 = 2-thienyl; R2 = C2~5; R3 = R4 = CH3; R5 = C6H5;
Q = cyclopropane-1,2-diyl) Starting material : the intermediate compound VI.11 Yield = 58 % boiling point/0.1 = 155-~67~C TLC : 0.60, S.C
IR (film) : 3060, 3020, 2970, 2930, 2870, 2820, 2780, 1610, 1500, 1460, 1375, 1250, 1240, 1225, 1090, 1040, 1030, 850, 830, 750, 700 cm~1 NMR : 0.75-0.98 (m, 6H); 1.55-1.77 (m, lH); 2.00-2.10 (m, 4H);
2.23 (s, 6H); 6.83-7.26 (m, 8H) Analysis (C19H26NS) C, H, N, S
Examplel2:4-N,N-Dimethylamino-1-(2-furyl~-4-(2-thien~l)-hex-l-ene.
(Rl = 2-thienyl; R2 = C2H5; R3 = R4 =CH3; R5 = 2-furyl;
Q = -CH=CH~) Starting material : the intermediate compound VI.12 Yield = 51 % melting point = 59-60C TLC : 0.50-0.55; S.C
IR (Nujol) : 2940-2900, 2840, 1470, 1450, 1380, 1150, 1110, 1060, 740, 730, 700 cm~1 NMR : 0.85 (t, 3H); 1.95 (q, 2H); 2.25 (s, 6H): 2.85 (m, 2H);
35 6.10-6.35 (m, 4H); 6.85-7.06 (m~ 2H); 7.23-7.32 (m, 2H) Analysis (C16H2lNOS) C, H, N, O, S
Example 13 4-N.N-Dimeth~lamino-1 4-di(2-thienyl)-hex-1-ene.
(R1 = 2-thienyl ; R2 = C2H5 ; R3 = R4 = CH3 ; R5 = 2-thienyl ;

31 ~37~23 Q = -CH=CH-) Starting matarial ~ the intermediate compound VI.13 Yield = 65 % melting point = 69-71C TLC : 0.60; 5.C
IR (Nujol) : 2820-2980, 1455, 1375, 1040, 995, 960, 850, 820, 720, 690 cm~l NMR : 0.72 (t, 3H); 1~90 (q, 2H); 2.25 (s, 6H~ 2.80 (d, 2H);
6.08 (dt, lH); 6.60 (d, lH); 6.82-7.25 (m, 6H) Analysis (C16H2lNS2) C, H, N, S
Example 14 : 4-N.N-Dimethylamino-4-f2-thienyl)-1-(3-thienvl)~
hex-l-ene.
(R1 = 2-thienyl; R2 - C2H5; R3 = R4 = CH3; R5 - 3-thienyl;
Q = -CH=CH-) Starting material : the intermediate compound VI.14 Yield = 61 % melting point = 85.5-86C TLC : 0.40; S.M
IR (CC14) : 2970, 2930, 2860, 2820, 2780, 1550, 1250, 1225, 1010, 960 cm-~
NMR : 0.90 (t, 3H); 1.95 (q, 2H); 2.25 (s, 6H); 2.85 (d, 2H);
5.90-6.25 (m, lH); 6.60 (d, lH); 6.90-7~35 (m, 6H) Analysis (C16H2lNS2) C, H, N, S
Example 15 : 4-N.N-Dimethylamino-1-phenyl-4-(3-thienyl)-hex-1-ene.
(Rl - 3-thienyl; R2 = C2H5; R3 = R4 = CH3; R5 = C6H5;
Q = -CH=CH-) Starting material : the intermediate compound VI.15 Yield ~ 45 ~ melting point = 91C TLC ~ 0.60-0.65; S.E
IR (KBr) : 3100, 3020, 2950, 2930, 2850, 2810, 2770, 1590, 1490, 1470, 1450, 1290, 1245, 1000, 962, 843, 780, 690, 665 cm l NMR : 0.83 ~t, 3H); 1.92 (q,2H~; 2.20 (s, 6H); 2.75-3.00 (d, 2H); 6.00-6.65 (m, 2H); 6.90-7.45 (m, 8H) Analysis (C18H23NS) C, H, N, S
Example 16: trans 1-L2-N.N-DimethYlamino-2-(3-thienyl)-butyll-2-phenyl-cyalopropane.
(Rl = 3-thienyl; R2 = C2H5; R3 = R4 = CH3; R5 = C6H5;
Q = cyclopropane-1,2-diyl) Starting mat~rial : the intermediate compound VI.16 Yield = 47 ~ boiling point/6,6 Pa = 140C TLC 0.30; S.B
IR (film) : 3050, 3010, 2960, 2930, 2860, 2810, 2770, 1600, ,, . .. . , : ~ : :

.
, 32 ~37~3 1492, 1455, 1087, ~028, 856, 838, 772, 7~5, 691, 668 cm~1 NMR : 0.~5-1.05 (m, 6H); 1.55 2.10 (m, sH); 2.2s (s, 6H); 6.90-7.50 (m, 8~) Analysis ~C19H26NS) C, H, N, S
Example 17 : 4-N N-Dimethylamino-l-L2-thienYl)-4-(3-thienyl)-hex-l-ene.
(Rl = 3-thienyl; R2 = C2H5; R3 - R4 = CH3; R5 = ~-thienyl; Q =
-CH=CH-) Starting material : the intermediate compound VI.17 Yield = 64 % melting point = 91-92C TLC : 0.50; S.E
IR (CC14) : 2960, 2920, 2810, 2775, 1545, 1245, 1000, 950 cm~
NMR : 0.85 (t, 3H); 1.95 (q, 2H) 2.2 (5, 6H); 2.8 (d, 2H):
5.9-6.25 (m, lH); 6.65 (d, lH); 6.9-7.35 (m, 6H) Analysis (C16H21NS2) C, H, N, S
Example_18 : 4-N,N-Dimethylamino-1 4-di(3-thienylL-hex-l-ene.
(Rl = 3-thienyl; R2 = C2H5; R3 ~ R4 = CH3; R5 = 3-thienyl; Q =
-CH=CH-) Starting material : the intermediate compound VI.18 Yield = 59 % melting point = 104-105C TLC : O.~o; S.E
IR (CC14) : 2970, 2930, 2870, 2820, 2780, 1550, 1255, 1225, 1020, 9~0, 775 cm~1 NMR : 0.85 (t, 3H); 1.95 (q, 2H); 2.2 (5, 6H); 2.85 (d, 2H);
5.9-6.6 (m, 2H); 7.05-7.40 (m, 6H) Analysis (C16H21NS2 ? C, H, N, S
Exam~lel9:trans-1-(2-N N-pimethylamino-2-phenyl~butyl)-2~2 thienyl~-cyclopropane.
(Rl = C6H5; R2 = C2H5; R3 = R4 = CH3; R5 = 2-thienyl; Q =
cyclopropane-1,2-diyl) Starting material : the intermediate compound VI.l9 Yield = 66 % TLC : 0.25; S.D.
IR (film) ~ 3060, 2980, 2960, 2820, 2780, 1450, 850, 760, 700 cm-l NMR : 0.70-0.90 (m, 6H); 1.62-1.85 (m, lH); 1.91-2.0~ (m, 4H);
2.21 (s, 6H); 6.61 (t, lH); 6.81 (m, lH): 6.98 (d, lH); 7.21-7.40 (m, 5H) Analysis (C19H25NS) C, H, N, S
Example20 trans-1 r 2-N,N-Dimethvlamino-2-t2-thienYl)-butyll-2-(2-thienyl)-cyclopro~ane.

.. . . .

.:
' ' ` `

33 ~37~Z3 (Rl = R5 = 2-thienyl; R~ = C2H5; R3 = R4 = CH3; Q =
cyclopropane-1,2 diyl) Starting material : the intermediate compound VI.20 Yield = 45 % TLC : 0.30; S.D.
IR (film) : 3060, 2960, 2920, 2870, 2~60, 2810, 1660, 1530, 1450, 1235, 1040, 845, 820, 690 cm-1 NMR : 0.85-1.00 ~m, 6H); 1.71-2.10 (m, sH); 2.25 (s, 6H) 6.70-7.28 (m, 6H) Analysis (C17H23NS2) C, H, N, S
Example21:trans~ 2-N,N-Dimethylamino-2-(3-thienyl?-butY11-2-(2-furYl~-cyclopropane.
(Rl = 3-thienyl; R2 = C2H5; R3 = R4 = CH3; R5 = 2-furyl;
Q = cyclopropane-1,2-diyl) Starting material : the intermediate compound VI.21 Yield = 26 % ~LC : 0.20; S.D.
IR (film) : 3060, 2960, 2930, 2865, 2810, 2765, 1595, 1510, 1375, 1250, 1090 cm-l NMR : 0060-2.20 ~m, llH); 2.21 (s, 6H) ; 5.80-6.00 (m, lH);
6.20-6.40 (m, lH); 7.10-7.20 (m, 2H); 7.20-7.50 (m, 2H) Analysis (C17H23NOS) C, H, N, O, S
Example22:trans-1-[2-N~N-DimethYlamino-2-(2-~uryl)-but~ 2-(3-thienyl)-cyclop~r2Pane.
(Rl = 2-furyl; R2 = C2H5; R3 = R4 = CH3; R5 = 3-thienyl;
Q = cyclopropane-1,2-diyl) Starting material : the intermediate compound VI.22 Yield = 30 % TLC : 0.30; S.D.
IR (film) : 3110, 3070, 2940, 2870, 2820, 2780, 1470, 1460, 1160, 1020, 775, 740 cm-l NMR : 0.50-1.10 ~m, 6H); 1.30-2.10 (m, 5H); 2.20 (s, 6H) 6.10-6.20 (m, lH); 6.30-6.50 (m, lH); 6.60-6.80 (m, lH); 6.80-6.90 (m, lH); 7.10-7.30 (m, lH); 7.40-7.50 (m, lH) Analysis (C17H23NOS) C, H, N, O, S
The toxicological and pharmacological tests carried out with the ethylamines o~ the invention, o~ the ~ormula (I), described in Examples 1 to 22 above demonstrate their low toxicity as well as valuable psychotropic properties which make these compounds useful for the treatment of neuro-psychic disorders.

, ~337~23 The study o~ the toxicity of the products of the invention is carried out in the mouse by oral administration, by approximate determination of kheir LD 50, which is the lethal dose causing~ 50 % of deaths in the animals under the conditions of the experiment. It is carried out on batches of four male "Swiss" mice weighing about 20 g and made to fast on the day before th~ test.
Each determination is carried out with four doses of products corresponding respectively to an administration of 100, 300, 600 and 1000 mg of product, expressed in the foxm of the base, per kg of animalO
It is found in this way that the products of the invention in general have an acute toxicity of LD 50 greater than or equal to 1,000 mg/kg. Exceptionally, some compounds exhibit an LD 50 of about 600 mg/kg.
The psychotropic properties of the compounds were determined by protection against convulsions induced by picrotoxin in the mouse, the teæt being carried out in accordance with a method based on that of Krall et al., "Epilepsiat', 1978, 19, p. 409-428.
The administration of picrotoxin causes a convulsive crisis in the animal, characteri~ed by a myoclonic extension syndrome followed by extension of the limbs, leading to the death of the animal. Certain substance~, especially those which act on the GABA/benzodiazepines/Cl-ionophore complex make it possible to protect the animals against this convulsive crisis.
In practice, the study is carried out on batches of 10 male "Swiss" mice, weighing about 20 g, to which the product to be studied is administered in agueous solution, either intraperitoneally (i.p.) in a volume of 0.2 ml of solution per animal, or orally (p.o) in a volume of ~-.0 ml of solution per animal.
Thereafter, a picrotoxin solution is injected intraperitoneally in an amount of 24 mg/kg, in a volume of 0.2 ml per animal, either 30 minutes after intraperitoneal administration of the product or 60 minutes after oral administration of the product. The dose of product injected causes a clonic crisis which leads to the death of the ~03'71Z3 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 in percentagas of animals protected against this phase under the action of 50 mg/Xg of the compound studied, administered i~p., or 100 mg~kg administered p.o., or a~ the ED50 for each of these methods of administration, this being the effective dose of compound tested, expressed in m~/kg, which protects 50 % of the animals against this extension phase.
The significance of the results is generally indicated as follows :
* result significant to p. c 0.05 ** result significant to p. < o.o ~** result highly significant to p. < o.OOl.
The results of the study are reported in the table which follows :

': :

Table: Resul1:B - inhibition of convulsions .
Examplei.p. : % prot~ction p. o. : % protection or ED50 or ED50 5-- -- _ 70 % ** 90 % ***
2 70 % ** N.T.
10 3 70 % ** 70 % **

4 70 % ** 80 % **

6 70 ~ ** 80 % ***
7 90 % *** 100 % ***

8 80 96 *** 60 % *
20 9 50 % * NoT~

N.T. 80 % **

11 60 % * 50 % *
2 5 -- --- - _ . _ .
12 70 96 * 50 % *
. _ _ .
13 90 % *** 50 % *

3015 70 % * 100 % ***

16 100 % *** N . T .

17 90 % *** 80 % **

18 80 % *** 100 % ***

19 ED 50 = 42 ED 50 - 75 4022 ED 50 = 20 50 % *

N . T . = not tested : -.

~3~2~

These results show, for the studied products of theinventiorl and regardless of the administration route used, an activity in the test for protection against convulsions induced by picrotoxin in the mouse.
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, for preventive and curative treatments o~ dis~urbances of a neurological type and/or psychic type in general, such as, for example convulsions, depressive s~ates, anxiety and/or psychotic states.
When presented in pharmaceutical forms, the useful unit doses are usually between 1 and 500 mg and more particularly between 5 and 200 mg of product, depending on the nature and gravity of the condition to be treatedO The daily therapeutic doses can be divided into several administrations and are generally between 5 and 2000 mg o~ product per day. In general, a daily dosage of 5~ to 500 mg of product, divided into two to four administrations, is satisfactory.
The products o~ the invention are administered to the patients to be treated in the form of medicaments of appropriate nature for the condition to be remedied. Depending on circumstances, the medicinal preparations are, to quote examples without implying any limitation, tablets, pills, capsules, powders, solutions, suspensions, gels or suppositories. These pharmaceutical forms are prepared from the products in the form of the base or from their salts, and in accordance with the methods usually employed in this industry.
Generally, in the solid medicinal forms, 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 the liquid forms, or for forms which may be considered a liquid, the amount o~ active principle is between 0.1 and 10 % by weight of the final ~orm, while the pharmaceutically suitable excipients can represent from 99.9 to 90 % by weight of this form.
The ~ormulation and the preparation of tablets is shown by way of illustration.

' ' 38 ~37~:3 Formulation Compound of Example 10 lo.o to 50.0 mg Polyvinylpyrrolidone 20.0 mg Carboxymethyl-starch 8.0 mg 5 Magnesium stearate 2.0 mg Colloidal silica 0.4 mg Lactose sufficient to make up to 200.0 mg Preparation The active principle is mixed with the lactose and then granulated with the polyvinylpyrrolidone in solution. The particles are dried and sieved on a 1 mm mesh. The carboxymethyl-starch is mixed with the colloidal silica and then added to the granules. Thereafter the magnesium stearate is thoroughly mixed in, and the mixture is then oompressed in an amount of 200.0 mg per tablet.

' . ~ .

:

Claims (10)

1. A compound which is a substituted ethylamine of general formula (I) (I) in which :
Q represents an ethylene-1,2-diyl group (-CH=CH-) or a cyclopropane-1,2-diyl group , R1 is an aromatic heterocyclic ring of 5 to 7 members, in which the sole hetero-atom is nitrogen, oxygen or sulphur, or, with the proviso that Q represents a cyclo-propane-1,2-diyl group or with the proviso that R5 represents an aromatic heterocyclic ring as defined below, R1 is a phenyl radical which is optionally monosubstituted, disubstituted or trisubstituted by identical or different radicals which are lower alkyl or lower alkoxy, R2 is lower alkyl, R3 and R4, which are identical or different, are hydrogen or lower alkyl radicals without, however, both R3 and R4 representing hydrogen, and R5 is an aromatic heterocyclic ring of 5 to 7 members, in which the sole hetero-atom is nitrogen, oxygen or sulphur, or is a phenyl radical which is optionally monosubstituted, disubstituted or trisubstituted by identical or different radicals which are lower alkyl or lower alkoxy, and their addition 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 R1 is a furyl radical.

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

5. A compound according to claim 1, wherein R3 and R4 are methyl.

6. A compound according to claim 1, which consists of 4-N,N-Dimethylamino-l-phenyl-4-(3-thienyl)-hex-1-en and its salts.

7. A compound according to claim 1, which consists of trans 1-[2-N,N-Dimethylamino-2-(3-thienyl)butyl]-2-phenyl-cyclopropane and its salts.

8. A compound according to claim 1, which consists of 4-N,N-Dimethylamino-4-(2-furyl)-1-phenyl-hex-1-en and its salts.

9. A compound according to claim 1, which consists of trans 1-[2-N,N-Dimethylamino-2-(2-furyl)butyl]-2-phenyl-cyclopropane and its salts.

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