IE44705B1 - Imino compounds and processes for their production - Google Patents

Description

The present invention relates to imino compounds and to their acid addition salts, to processes for their production, as well as to pharmaceutical compositions which contain these new substances.

The imino compounds according to the invention correspond to the general formula X wherein represents an aliphatic or cycloaliphatic hydrocarbon radical, an optionally substituted phenyl, or an optionally ring-substituted mono- or diphenyl-lower-alkyl, R2 represents ,optionally substituted phenyl, optionally substituted monocyclic heteroaryl or lower alkyl, or o-phenylene linked with a carbonyl group R^, R^ represents hydrogen, lower alkyl, a carbonyl group linked with an o-phenylene radical R2 to form an o-phenylene radical, or the group Rg-CO wherein Rg represents lower alkyl or optionally substituted phenyl, R^ . represents,' if present, hydrogen or lower alkyl, or together with R, a saturated bivalent aliphatic or 4 7 0 5 cycloaliphatic radical having a minimum of 4 and a maximum cf 5 carbon atoms- between the two linkage points and 51 total of 4 to 12 carbon atoms, a N-lower alkyl-ethyieneimino-ethylene-or the ethyleneoxyethylene radical.

Rg represents, if-present, hydrogen or lower alkyl, A represents an optionally branched-chain lower alkylene having 2 to (5-η,-η. ) chain members, between the two linkage mints -L Z Z represents epoxy, epithio, imino or lower alkylimino, and 2nd m2 represent 0 or 1 and together always represent 1, n^ represents 1 or, if Z represents imino or lower alkylimino and n2 represents 1, ean also represent 0, iu represents 0 or 1, and wherein two additional bonds, either corresponding to the dashed lines or corresponding to the dotted lines, are present, with representing 0 in the former case and m^ representing 0 in the latter case.

By lower radicals are meant, in the foregoing and in the following, radicals having a maximum of 7 carbon atoms and preferably a maximum of 4.

The subject matter of the invention embraces also the acid addition salts, particularly the pharmaceutically acceptable acid addition salts, of the compounds of the general formula I, as well as the production of these acid addition salts. - 3 In the compounds of the general formula I, R^ as aliphatic or cycloaliphatic hydrocarbon radical preferably contains a maximum of 12 carbon atoms and preferably no more than one multiple bond, with this preferably not emanating from the carbon atom linked with the nitrogen atom.

Suitable aliphatic hydrocarbon radicals R^ are, for example, alkyl, alkenyl and alkynyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, j pentyl, isopentyl, 1-methylbutyl, 1-ethylpropyl, neopentyl, tert.-pentyl, hexyl, Isohexyl, heptyl, isoheptyl, 1-methylhexyl, octyl, 1-methylheptyl, nonyl, decyl, undecyl, dodecyl, allyl, 2-butenyl, 2-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 2hexenyl, lsl-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 2-heptenyl, l-methyl-3-hexenyl, 2-octenyl, 7-octenyl, 1-methyl15 3-heptenyl, l,5-dimethyl-2-hexenyl, 2-nonenyl, 8-nonenyl, 2-decenyl, 9-decenyl, 10-undecenyl, 11-dodecenyl, 2-propynyl, l-mefchyl-2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 5hexynyl, l,l-dimethyl-2-butynyl or 6-heptynyl. Aliphatic hydrocarbon radicals preferably contain up to 8 carbon atoms. 2o By cycloaliphatic hydrocarbon radicals are meant in general radicals in which all or a part of the carbon atoms belong to one or more cycloaliphatic rings, and which contain no aromatic rings. In bi- and polycyclic radicals, adjacent cycloaliphatic rings can contain no common carbon atoms or they can contain one, two or more common carbon atoms, i.e. these - 4 4 47 θ » radicals can be derived from compounds having two or more independent cycloalkyl rings bound directly or by way of alkylene radicals, or they can be radicals af cycloaliphatic spiro compounds, of cycloaliphatic fused (condensed) compounds or of cycloaliphatic bridge compounds, or they can contain such compounds, and in polycyclic radicals there can.also be different types of ring linkages. Cycloaliphatic hydrocarbon radicals are, for example, optionally lower-alkyl-substituted cycloalkyl, cycloalkylalkyl, bicyelo10 alkyl-lower-alkyl, cycloalkylcycioalkyl, spirocycloalkyl, bicycloalkyl and bicycloalkyl-lower-alkyi radicals, as well as polycycloalkyl radicals and corresponding singly unsaturated radicals, such as cyclopropyl, cyclobutyl, cyclopropyImethyl, cycloheptyl, 1- methylcyclcpropyl, cyclopentyl, cyclohexyl,/ cyclohexylmethyl, 1-methyl-, 2-methyl-,3-methyl-or 4-methylcyclohexyl, 2,5dimethylcyclopentyl, cyclooctyl, 2,4-dimethyl-, 2,6-dimethyl-, 3,5-dimethyl- or 4,4-dimethylcyclohexyl, 4-ethylcyclohexyl, 4-isopropylcyclohexyl, 4-tert.-butylcyclohexyl, cis- and trans2- cyclohexylcyclopentyl, cis- and trans-2-eycl.ohexylcyclohexyl, spiroi4.4]non-l-yl, spiro[4.5]dec-l-yl, spirot4.53dec-6-yl and spiro[4.5Jdec-8-yI, spiro[5.5jundec-l-yl and spiro[5.5jundec-3-yl, hexahydroindan-l-yl and hexahydroindan-2-yl, dec2hydronaphthalen-l-yl, 1-norbornanyl, 2-norbornanyl, bicycloj2,2,2]oct-2-yl, 2-norbornanyImethyl, 2-bornanyl, I-adamantyl, cyclododecyl, - 5 - 2-cyclohexenyl, 3-cyclohexenyl, 3-cycloheptyl, l-methyl-2cyclohexenyl, 2-methyl-2-cyc'lohexenyl, 2-norbornen-l-yl, 2-norbomen-7-yl and 5-norbornen-2-ylmethyl. Cycloaliphatic - ' ; hydrocarbon radicals R^ contain preferably up to 12 carbon atoms A phenyl radical can be substituted, for example, by halogen up to atomic number 35, particularly by chlorine, by optionally:halogenated lower alkyl such as ethyl, propyl, isopropyl, butyl, tert.-butyl and especially methyl or tri10 fluoromethyl, or by lower alkoxy or lower alkylthio such as ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, ethylthio, propylthio, isopropylthio, butylthio and, in particular, methoxy or methylthio, whereby several, preferably however a maximum of three, substituents, identical or differing from each other, can be present. There can also he present as substituent, e.g., a nitro group, a di-lower-alkylamino group such as the dimethylamino group, or a lower alkanamido group such as the formamido, propionamido, hutyramido and, in < particular, the acetamido group. As mono- or diphenyl-lower20 alkyl, R^ is; for example, bensyl, phenethyl, a-methylbenzyl, ; a-methylphenethyl, α-ethylbenzyl, 3-phenylpropyl, 4-phenylbutyl, s diphenylmethyl or α-benzylbenzyl, the phenyl radicals of which j can be substituted, for example, by the radicals mentioned ί above as substituents of phenyl radicals R^. 1 25 A phenyl radical R^ can carry the substituents mentioned above for R^. As a monocyclic hetero aryl radical, R2 is, for - 6 4 4 7 0» example, a five- to six-membered heteroaryl radical, bound by way of one of its ring carbon atoms, with an oxygen, sulphur or nitrogen atom, and optionally an additional nitrogen atom, as ring members, such as furyl, imidazolyl, oxszolyl, thiazolyl, pyridyl, pyrimidinyl or pyrazinyl and particularly tbiaayl. These radicals can be substituted t· one nr r.ore of the radicals mentioned above as substituents of phenyl radicals Rp especially by one or more of the aforementioned lower alkyl, lower alkoxy and lower alkylthio radicals, also by fluorine or chlorine. R^ as lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert.-butyl.

If Rg represents a group R^-CO-, βθ as lower alkyl therein is, e.g., ethyl, propyl, isopropyl, butyl or tert.-butyl, and particularly methyl. A phenyl radical R, can carry for example the substituents given for phenyl radicals R,. is, for example, one of the lower alkyl radicals given under R^. R-, and R^ together with the inclusion of the adjacent nitrogen atom, form, for example a polymethyleneimino radical such as the 1-pyrrolidinyl, piperidino or hexahydro-lHazepin-l-yl radical. - 7 the 3-azabicyclo[3.2.2]non-3-yl, 3-asabicyclo]3.3.l]non-3-yl or l,8,8-trimethyl-3-azabicyclo[3.2.ljoct-3-yl radical, or the 4-methyl-1-piperazinyl or morpholino radical.

A lower alkylene A is, for example, propylene, 1,25 dimethylethylene, 2-methyltrimathylene, 1,1-dimethyltrijnethylene, 2,2-dimethyltrimetb.ylene, especially hovzever tetramethylene or trimethylene and particularly ethylene.

As lower alkylitnino, 2 is for example ethylimino, propylimino, isopropylimino, butylimino, isobutylimino and especially methylimino.

The imino compounds of the general formula ΐ and their addition salts with inorganic and organic acids possess valuable pharmacological properties, particularly hypoglycaemic activity, as can ba demonstrated on rats with normal metabolism, after oral administration of doses from 10 mg/kg, as well as on rats that 'have been put into a diabetes-like metabolic condition by injection of streptozotocin [see A. Junod et al., Proc.

Soc.Exp.Biol.Med. 126, 201-205 (1967)]. The lowering of the blood-sugar level is not accompanied by a hyperlactacidaemia.

The pharmacological findings characterise the iminocompounds of the general formula I and their pharmaceutically acceptable - 3 acid addition salts as antidiabecics which can be used for the oral treatment ef hypergiycaemia in maamjals, particularly for the oral treatment of Diabetes mallitus.

The invention relates in particular to compounds of tha general formula I wherein R, represents an aliphatic or cycloaliphatic hydrocarbon radical having a maximum of 12 carbon atoms, R-2 represents a phenyl or thienyl radical optionally substituted by lower alkyl, lower alkoxy, halogen up to atomic number 35 and/or trifluoromethyl, Rj represents hydrogen or lower alkyl, R^, if present, represents lower alkyl, or together with R^ a saturated bivalent aliphatic or cycloaliphacic hydrocarbon radical having a minimum of 4 and a maximum of 6 carbon atoms between the two linkage points and a total of 4 to 12 carbon atoms, ar ths ethyleneoxyethylene radical, R^, if present, represents hydrogen or lower alkyl, and A, Z, rr^, ir and have the meanings given under the formula I, and to their pharmaceutically acceptable acid addition salts. Of special importance are compounds of the general formula I wherein Rp R£, Rj, R4 and R^ Lave the meanings just defined and and m2 have the meanings given under the formula I, n^ represents 1 and represents 0 and simultaneously A represents ethylene, trimethylene or tetramethylene, or represents 0, rig represents 1, Z represents imino or lower alkylimiao and simultaneously A represents ethylene, and their pharmaceutically acceptable acid addition salts. The invention relates above all to compounds of the general formula ϊ wherein R represents an aliphatic - 9 hydrocarbon having a maximum of 8 carbon atoms, or a cycloaliphatic hydrocarbon radical having a maximum of 12 carbon atoms / i<2 represents a phenyl radical optionally substituted as defined in the foregoing, or a thienyl radical optionally substituted by lower alkyl and or by halogen up to atomic number 35, and Rg represents hydrogen, R^ and R^, if present, have the aforesaid meanings, and and m2 have the meanings given under the formula I, n^ represents 1, A represents ethylene, trimethylene or tetramethylene, and η,. represents 0 and hence Z is omitted, and to their pharmaceutically acceptable acid addition salts. The invention primarily relates to compounds of the general formula I wherein R^ represents a preferably saturated aliphatic hydrocarbon radical which has a maximum of 8 carbon atoms and which is preferably bound by way of a secondary or tertiary carbon atom, or a preferably saturated cycloaliphatic hydrocarbon radical which has a maximum of 12 carbon atoms and which preferably contains a maximum of two rings, particularly a saturated cycloaliphatic hydrocarbon radical having 5 to 12 carbon atoms, represents a phenyl radical optionally substituted by methyl, methoxy or halogen up to atomic number 35, or a thienyl radical, Rg represents hydrogen, R^, if present, preferably represents lower alkyl, or, together with R^ represents tetra-.to hexamethylene, Rg, if present, represents hydrogen or lower alkyl and A represents trimethylane, tetramethylene and especially ethylene, and m2 have tha meanings - 10 4 4 7 0 5 given under formula I, n^ represents 1 and rig represents 0 and hence Z is omitted, such as 2-i2-(cyclohexyl-imino)-2phenyl-ethylidena]-pyrrolidine and 2-[2-(cis-2-cyclohexylcyc?.opentylimino)-2-phenyl-ethylidene]-pyrrolidine, and to the pharmaceutically acceptable acid addition, salts of these compounds .

The compounds of the general formula I and taeir acid addition salts are produced according to the invention by a process in which a) a compound of the general formula 11 wherein represents lower alkoxy or together with Y^ the oxo radical, Y^ represents lower alkoxy, together with Yg an additional bond, or together with X, the oxo radical, and Yg represents hydrogen, or together with Y^ or Y„ an additional bond, Y3 . represents together with Y7 or Y4 an additional bond, and Y^ represents hydrogen, lower alkyl, or together with Y3 an additional bond, and R2, Rj, A, Z, and n2 have the meanings given under formula I, 5 is reacted with a compound of the general formula III (III) wherein Rda has the meaning given for Rd under the formula X, but always represents hydrogen in the case where Yz. represents lower alkyl in the compound of the general formula II, and R^ has the meanings given under the formula I; or b) for the production of compounds of the general formula I wherein R^ is hydrogen, m is 0 and m2 is I and therefore R^ is absent, and R^, R2, R3, A, Ζ, n and have the meanings given under Formula I, a compound of the general formula IV (Z)n.

(CiH2)nl (IV) X2 wherein X2 represents lower alkoxy, lower alkylthio or halogen, and A, Z, n^ and n2 have the meanings given under the formula I, or an acid addition salt thereof, is reacted with a compound of the general formula V CH„ wherein R., R? and have tha meanings given under the .Lorr.-il:. z, cr wren uh :ci: acumen ra..t mercor; mc/or c) in a resulting compound of the general formula 1, in which 5 a hydrogen atom is present as R, cr cr in a compound *+ J corresponding thereto, which contains a hydrogen atom instead of the radical Rp the hydrogen atom, or the two said hydrogen atoms, is, or are, replaced by lower alkyl; and, optionally, a resulting compound of the general formula I is converted ΪΟ into an acid addition salt, or the compound of the general formula I is liberated from an acid addition salt obtained.

In accordance with the definition for Yg in the starting materials of the general formula II, there is always at least one double bond present, either in acyclic or in cyclic position. In the latter case, Y. and Y^ can together represent an additional bond. Starting materials of the general formula II which contain only one single double bond and no lower alkyl group as Y^ need not be homogeneous with regard to tha position of the double bond; on the contrary, an additional bond of γ can be formed both with Yn and with Y, . The reaction of 3 2 4 compounds of the general formula II with compounds of the 1 *“* j, ,3 * general formula III is preferably performed in the presence of a condensation agent. Suitable condensation agents for the reaction according to a) are, in particular, strong acids, especially mineral acids or organic sulphonic acids, as well as Lewis -acids. There may be mentioned as examples of mineral acids: tetrafluoroboron hydride, hydrochloric acid and perchloric acid; as examples of organic sulphonic acids: methanesulphonic acid and p-toluenesulphonic acid; and as examples of Lewis acids: sine chloride, boron trifluoride, particularly as etherate, and phosphorus oxychloride. The mineral acids and organic sulphonic acids are introduced into the reaction optionally in the form of corresponding addition salts of one of the two starting materials; for example, the salts of tetrafluoroboron hydride obtained in a process subsequently described for producing compounds of the general formula II having lower alkoxy, especially ethoxy, as are Used for the reaction; or the starting materials of the general formula III are used in the form of their hydrochlorides or,‘optionally, in the form of their perchlorates. As the reaction medium, it is possible to use for example an excess of the compound of the general formula III to be reacted, or an inert organic solvent, particularly a liquid aromatic hydrocarbon, such as benzene, toluene or xylene, or a mixture of xylenes. With the use of such hydrocarbons, the formed water or the liberated alcohol can, if required, be azeotropically - 14 4 4 7 0 5 distilled off, so that employment of a condensation agent becomes unnecessary or the amount thereof can be reduced.

The reaction temperature is for example between 50 and 16O°C, preferably between 60 and 120°C, and within this range the reaction is performed, in particular, at the boiling temperature of the reaction mixture. The reacticr. with low-boiling starting materials can be performed if necessary in. a closed vessel.

In the starting materials of the general formula IV for the process b), ^s, in particular, lov?er alkoxy, e.g. methoxy, butoxy and especially ethoxy. X? as lower alkylthio is in particular ethylthio and especially methylthio; and as halogen it is, e.g., bromine and particularly chlorine.

The reactions according to b) arc performed essentially under the same reaction conditions as for a) and likewise preferably in the presence of the condensation agents mentioned under a), particularly methanesulphonic acid, provided that one of the two starting materials is not used in the form of an addition salt with a strong acid, especially a mineral acid or an organic sulphonic acid. The reaction temperature is preferably between and 150°C; it is particularly about 100°C. A solvent, or diluent is not absolutely necessary; in some cases it is of advantage not to use one. It is possible to use if desired, instead cf the aforementioned solvents, polar solvents, such as dimethylformamida, dimethylsulphoxide or Ν,Ν,Ν',N* ,N‘',K- 15 £470 5 hexamethylphosphoric acid triamide.

The introduction of one or two lower alkyl radicals instead of a hydrogen atom R^ or R., and optionally of a hydrogen atom present in place of R^ according to c), can be performed in a manner known per se, for example by reaction of a reaction product of process a) or b), already embraced by the general formula I, or of a corresponding compound containing a hydrogen atom instead of R^, with a reactive ester of a lower alkanol, particularly with a corresponding hydrohalic acid ester, lower alkanesulphonic acid ester or arenesulphonic acid ester, especially with a lower alkyl iodide or lower alkyl bromide, such as methyl iodide or ethyl iodide or propyl bromide or butyl bromide, in the presence or absence of an organic solvent, e.g. a lower alkanol such as methanol, ethanol or isopropanol, a lower alkanone such as acetone or 2-butanone, a lower alkanoic * \ acid ester or lower alkanoic acid amide, such as ethyl acetate or dimethylformamide, or a low-boiling hydrocarbon or polyhalogenated hydrocarbon such as benzene, toluene or methylene chloride; and optionally of an acid-binding agent, e.g. a tertiary organic base or a weak inorganic base, such as triethyl amine, ethyldiisopropylamine or potassium or sodium carbonate or potassium or sodium bicarbonate, preferably at temperatures between 0°C and 120°C, and if necessary in a closed vessel, particularly however at room temperature up to the boiling - 16 -3 4 7 0 5 temperature cf the reaction mixture.

A farther process known per se for the introduction of one or two lower alkyl radicals, especially methyl radicals, is the reaction of a compound of the general formula I, wherein R^ or Rg is a hydrogen atom, or of a corresponding compound having a hydrogen atom instead of R^, with a lower oxcalkana, particularly with formaldehyde, in a reducing .nadium, especia^l in formic acid, at moderately elevated temperatures, preferably at 80~100°C. io The starting materials of the general formula II wherein Xg together with represents the o?:j radical and Yg with ig or Yrepresents an additional bond, whilst the remaining symbols have the meanings given under the formula I or the formula II, are obtained for example by reaction of compounds I5 of the general formula VI II wherein A, Z, n^ and n2 have the meanings given under the formula I, with halogenated ketones of the general formula VII R Hal 'S, o' CH r: (VII) '2 - 17 wherein Hal represents a halogen atom, especially chlorine and in particular bromine, and Rg and Rg have the meanings given under the formula 1, to form compounds of the general formula VIII wherein Rg, Rg, A, Z, n^ and Hg have the meanings given under the formula I; followed by splitting-off of sulphur, for example by heating with triethylphosphite in the presence or absence of a diluting agent, such as toluene, to moderately elevated temperatures of, for example, 6O-9O°G; and optionally subsequent introduction of a lower alkyl radical Rg, e.g. by reaction with a reactive ester of a lower alkanol, especially with a lower alkyl halide.

By a further process are obtained compounds embraced by the general formula II wherein together with Y^ represents the oxo radical, Rg has the meaning given under the formula I with the exception of lower alkyl, and the remaining symbols have the 4 7 0 5 meanings given under the formula I or the fcrraula II, which process comprises condensing lactira ethers, embraced by the general formula IV, of the general formula IK wherein Ry represents lower alkyl, particularly methyl or ethyl, and A, Z, n^ and n,; have the meanings given under the formula I, with compounds of the general formula K wherein c.

(X) R. ‘3 represents a radical corresponding to the definition of Rg given under the formula I with exception of hydrogen and lower alkyl, and R2 has the meaning given under the formula I; and, optionally, splitting off a group R^-CO, present in the resulting compound embraced by the general formula II, by treatment with a sodium lower alkoxide, preferably in the corresponding lower alkanol, in benzene or toluene; and/or introducing a lower alkyl radical Rt·, as mentioned above.

Compounds of the general formula II wherein X| together with - 19 Y^ represents an additional bond, n1 represents 0, represents and Z represents imino or lower alkylimino, and R^i R3 and A have the meanings given under the formula I, can be obtained for example, also in a manner known per se, by reaction of imido ester hydrohalides of the general formula XI P-d NH (XI) wherein Rg represents lower alkyl, particularly methyl or ethyl, and “Hal” represents chlorine or bromine, and Rj and Rg have the meanings given under the formula I, with bifunctional compounds of the general formula XII HN (XII) Aa X wherein Aa represents an optionally branched-chain lower alkylene 15 having 2 to 4 chain members, and Rg represents hydrogen or lower alkyl, particularly with 1,2-ethanediamine [see in this respect, for example, J. Klosa, Arch. Pharm. 286, 397-401 (1953)].

The ketones embraced by the general formula II, which are obtained by the aforementioned processes or by other processes - 20 known per se, are optionally converted in a manner known per se into their lower alkyl enol ethers or into their di-loweralkyl ketals, i.e. into compounds of the general formula II with lower alkoxy as X, and an additional bond as Y.-b Y„, or ί. X Z. lower alkoxy as Y^ and hydrogen as Yy. For example, there are obtained by reaction oi the aforementioned ketones with triethyloxonium-tetrafluoroborate in an inert organic solvent, such as methylene chloride, and in the cold state, starting materials or the general formula II wherein X^ represents ethoxy and and Y^ together represent an additional bond. The tecrafluorc-borates initially obtained from this reaction can, as already mentioned, be reacted directly with starting materials of the general formula III.

Some representatives of the starting materials of the general formula IV for the process b) are known, and others can be produced by methods analogous to those for producing tha known starting materials. Also of the starting materials of the general formula V, some are known and others are obtainable analogously, e.g. by reaction of corresponding ketones with amines corresponding to the definition for R^, particularly in the presence of an acid catalyst, such as a catalytic amount of p-toluenesulphonic acid, preferably in a solvent azeotropically distilling with water, such as in toluene, at the boiling temperature thereof with continuous removal of the liberated water.

Starting materials for the process c), which are embraced by the general formula I, can be produced for example by che process a) or b). Corresponding starting materials having a hydrogen atom instead of R^ are obtained for example analogously to the process a) if anhydrous ammonia is used In place of a compound of the general formula III; for example, the tetrafluoroborate of a compound of the general formula II wherein X^ represents lower alkoxy, especially ethoxy, and Y, and Y^ as well as Y,. £nd Y4 together represent in each case an additional bond, and R^, 4, 2, n^ and n., have the meanings given under the formula I, is reacted with anhydrous ammonia in anhydrous methanol at room temperature or at a moderately elevated 'temperature, and the formed tetraflueroborafce of the imino compound is deprotonised, e.g., with 15 potassium-tert.-butoxide in tert.-butanol at modej:ately elevated temperature, e.g. at about 60°C [see Helv. Chim. Acta 54, 710-734, especially 722-723 (1971)3.

If the required starting materials are optically active, both the racemates and the isolated antipodes can be used, or in the case of diastereomeric compounds, it is possible to use mixtures of racemates or specific racemates, or likewise isolated antipodes. Such starting materials can also be used, if required, in the form of salts.

There are preferably used such starting materials of the general formula II and III or IV and V which yield the compounds of the general formula I which have bean particularly emphasised in the foregoing.

If the final materials are obtained as racemates or as mixtures of racemates, these can within the scope of the present invention be, if required, separated and resolved into their antipodes.

The compounds of the general formula I which are obtained by the process according to the invention are optionally converted, in the customary manner, into their addition salts with inorganic and organic acids. For example, the acid desired as salt component is added to a solution of a compound of the general formula I in an organic solvent. There are preferablyused for the reaction organic solvents in which the formed salt is difficultly soluble, so that it can be separated by filtration.

The crystallisation of the salt is if necessary effected or completed by the addition of a second solvent. Such solvents or mixtures are, e.g., ethyl acetate, methanol, ethanol, isopropanol, ether, acetone, methyl ethyl ketone, acetone/ether, acetone/ - 23 ethanol, methano1/ether or ethanol/ether.

It is possible to use as pharmaceutical active substances, instead of free bases, pharmaceutically acceptable acid addition salts, i.e. salts with acids of which the anions are not toxic in the dosage amounts concerned. Furthermore, it is of advantage if the salts to he used as pharmaceutical active substances readily crystallise and are not, or only slightly, hygroscopic. For salt formation with compounds of the general formula 1, it'is possible to use, e.g., hydrochloric acid, hydi*obroaic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicyclic acid, phenylacetic acid, mandelic acid or embonic acid.

The imino compounds of the general formula I and their pharmaceutically acceptable acid addition salts are preferablyadministered orally. The dally doses vary between 0.5 and 30 mg/kg for mammals; and for manuals of about 70 kg in weight, depending on the individual condition and age, the daily doses are between 50 and 1000 mg, especially between 150 and 500 mg. Suitable oral dosage units, e.g. dragees or tablets or capsules, preferably contain 50 to 500 mg, particularly 50 to 250 mg, of an active substance according to the invention, i.e. of a compound of the general formula I or of a pharmaceutically - 24 acceptable acid addition salt thereof, together with pharmaceutical carrier substances. These dosage units are produced by combining the active substance with, e.g., solid pulverulent carriers such as lactose, saccharose, sorbitol or mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatins, optionally with the addition of lubricants, such as· magnesium, cr calcium stearate cr polyethylene glycols, to form tablets or dragee cores. The dragee cores are coated, for example, with concentrated sugar solutions which can also contain, e.g., gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in readily volatile organic solvents or solvent mixtures. Dyestuffs nay be added to these coatings, e.g. for identification of the various dosage amounts. Further suitable oral dosage units are hard gelatine capsules, as well as soft closed capsules made from gelatine and a softener such as glycerin. The hard gelatine capsules contain the active substance preferably as a granulate, e.g. in admixture with lubricants such as talcum or magnesium stearate, and optionally stabilisers such as sodium metabisulphite or ascorbic acid.

Also applicable are oral preparations which are not divided into dosage units, such as syrups or shakes, which likewise can be produced by combination with pharmaceutical carriers in the usual manner. - 25 The following instructions are intended ro further illustrate the production of tablets: 500.0 g of 2-[2-(cyclohexylimino)-2-phenyl-ethylidene]pyrrolidine-(l:l)-fumarate is mixed with 500 g of lactose and 340 g of potato starch; the mixture is moistened v/ith an alcoholic solution of 10 g of gelatine and is then granulated through a sieve. After drying of the granulate, 60 g of potato starch, 60 g of talcum, 10 g of magnesium stearate and 20 g of highly dispersed silicon dioxide are mixed in, and tha mixture is subsequently pressed to form. 10,000 tablets each weighing 150 mg and each containing 50 mg of active substance; the tablets can be provided with grooves to effect a more precise adjustment of the dosage amount.

In place of the aforementioned active substance, it is also possible to use, e.g., 500.0 g of 2-[2-(cis-2-cyelohexylcyclopentylimino)-2-phenyl-ethylidene]-pyrrolidinemethanesulphonate-(1:1).

The following Examples further illustrate the production of the compounds of the general formula I and of starting materials not hitherto known; but in no way are they intended to limit the scope of the invention. The temperatures are given in degrees Centigrade. - 26 4 4 7 Ο 5 Example 1 9.1 g (0.03 mole) of 2-(2-ethcxy-2-phenyl-£thenyi)-1pyrroline-tetrsfluoroborata is dissolved in 30 ml of cyclonexylamine, and the clear solution is heated at 105° for 6 5 hours. The excess cyclohexylamine is subsequently distilled off as far as possible in a rotary evaporator; the residue is dissolved in methylene chloride; and rhe solution, with the addition of ice, is repeatedly extracted with i;< sodium hydroxide solution for liberation of the bases and removal of the tetra10 fluorcborcn hydride. The organic phase is dried over sodium sulphate, concentrated by evaporation, and tha residue Is concentrated twice with toluene in vacuo to remove the residual cyclohexylamina. The oil remaining is taken up in isopropanol, and a warm solution of 3 g of fumaric acid in 30 ml of isopropsnol I5 is added. The formed salt is filtered off, and recrystallised from ethanol to obtain 2-(2-(cyclohexylimino)-2-phenyl-ethylidene]pyrrolidine-(1:1)-fumarate, m.p. 202-203°.

The 2-(2-ethoxy-2-phenyl-ethenyl)-l-pyrroline-tetra£luoroborate used as starting material is produced as follows: a) 101.2 g (1.0 mole) of 2-pyrrolidinethione is dissolved in 300 ml of chloroform. A solution of 210 g (1.05 moles) of 2-bromoacetophenone in 400 ml of chloroform is slowly added dropwise with ice cooling. There is scon formed a thick crystal sludge, which Is stirred overnight at room temperature. It is then cooled again in the ice bach; che hydrobromide of the reaction, product, which has crystallised out, is filtered off and the filter residue is washed with a chlaroform/hexane mixture 1:3. To liberate the 2-((l-pyrrolin-2-yl)-thioJacetophenone, the hydrobromide is dissolved in about 1000 ml 5 of ice water; the solution is stirred with 100 ml of methylene chloride, and saturated sodium bicarbonate solution is added until the aqueous phase permanently shows an alkaline reaction The organic phase is separated; the aqueous phase is extracted twice with methylene chloride, and each organic phase is 1° washed once with saturated sodium chloride solution. The organic phases are subsequently combined, dried over sodium sulphate and concentrated at about 40° in a rotary evaporator, whereupon the crude 2-((1-pyrrolin-2-yl)-thio J-acetophenone remains behind in the form of yellow oil. This is then dried for about 30 minutes at room temperature under high vacuum. b) The crude product obtained according to a) is dissolved in a mixture of 1000 ml of toluene and 190 ml of triethylphosphite, and the mixture is heated under nitrogen at 60° for 16 hours. The dark solution is concentrated as far as possible in the rotary evaporator, and the residue is stirred at room temperature with 350 ml of ether. The suspension is filtered; the residue is washed with ether and subsequently recrystallised from acetone to obtain 2-(2-pyrrolidinylidene)acetophenone, m.p. 115-116°. - 28 4 4 7 0 5 c) 62.7 g (0.33 mole) of triethyloxonium-tetrafluoroborate is dissolved in 120 ml of methylene chloride, and the solution is cooled in an ice bath. In the course of about 30 minutes, a second solution of 56.2 g (0.3 mole) of 2-(2-pyrrolidinylidene)acetophenone in 150 ml of methylene chloride is added dropwise.

The reaction mixture is stirred ac 0' for 3 hours. Approximately half of the solvent is subsequently distilled off ia the rotary evaporator. On addition of 400 ml of ethyl acetate co the resulting concentrate, the crude 2-(2-3thoxy~2-phenyl-3thenyljl-pyrroline-tetrafluorobcrafca, m.p. 122-123“, precipitates.

After drying in vacuo at 60°, the product is further employed without additional purification.

Example 2 62.7 g (0.33 mole) of triethyloxoniumtetrafluoroborate is dissolved in 120 ml of methylene chloride, and the solution is cooled in an ice bath. A solution of 66.5 g (0.3 mole) of p-chloro-2-(2-pyrrolidinylldene)-acetophenone in 300 ml of methylene chloride is added dropwise within 30 minutes . The reaction mixture is stirred at 0° for 3 hours; the methylene chloride is subsequently evaporated off at 30° in a rotary evaporator, and the oily residue is dried at room temperature under high vacuum. The resulting crude 2-[2-(p-chlorophenyl)-2ethoxy-ethenyl]-1-pyrrolidine-tetrafluoroborate is directly dissolved in 200 ml of cyclohexylsmine. The brown solution is - 29 £47 05 heated for 2 1/2 hours at 100°, and the excess cyclohexylamine is subsequently evaporated off in the rotary evaporator. The salt mixture remaining behind is taken up in methylene chloride and the solution, vzith the addition of ice, is repeatedly extracted with IN sodium hydroxide solution. The organic phase is dried over sodium sulphate, concentrated by evaporation, and the residue is repeatedly concentrated vzith a small amount of toluene in vacuo in c-rder to remove the residual eyclohaxylamine. The oil remaining behind is dried under high vacuum and subsequently dissolved in ethanol, and a hot solution of about 25 g of fumaric acid in ethanol is added. The resulting salt is filtered off and recrystallised from isopropanol to yield 2-[2-(4-chlorophenyl)-2-(cyclohaxylimino)-athyli.dene]pyrrolidine-fumarate, m.p. 209-210° (decomposition).

With the use of 76.8 g (0.3 mole) of 3',4-dichloro-2-(2pyrrolidinylidene)-acetophenone, there is obtained in an analogous manner 2-[2-(3,4-dichlorophenyl)-2-(cyclohexylimino)-ethylidene]pyrrolidine-(1:1)-fumarate, m.p. 208-209° (from isopropanol/ether) The p-chloro-2-(2-pyrrolidinylidene)-acetophenone used as starting material is produced as follows: a) A solution of 73.5 g (0.315 mole) of 2-bromo-p-chloroacetophenone in 350 ml of chloroform is slowly added dropwise, vzith ice cooling, to a solution of 30.4 g (0.3 mole) of 2pyrrolidinethione in 100 ml of chloroform. There is formed a thick crystal slurry, which is stirred for a further 4 hours at - 304-1705 room temperature. The reaction mixture is cooled afresh in the ice bath; the hydrobromide of the reaction product is filtered off and the residue is washed with a chlcroform/hexane mixture 1:3. In order co liberate the p-chloro-2-ί(l-pyrrolin-2-yl)-thio] acetophenone, the crystalline residue is suspended in about 500 al of ice water; it is stirred with 300 ml of methylene chloride, and saturated sodium bicarbonate solutic: .2 X.S until the aqueous phase permanently shows an alkaline reaction. The aqueous phase is separated and extracted twice with methylene chloride. The organic phases are combined, washed once with saturated sodium chloride solution, dried over sodium sulphate and concentrated at about 40° in the rotary evaporator, whereupon the crude, gradually crystallising p-chloro-2-ί(l-pyrrclin-2-yl)thio]-acetophenone remains behind. It is subsequently dried at room temperature under high vacuum. b) The reaction product obtained according to a) is dissolved in 120 ml of triethylphosphite, and the solution is heated at 60° for 40 minutes, with the reaction product commencing to precipitate already after 10 minutes. After completion of the reaction, the reaction mixture is cooled in an ice bath; it is then filtered and the residue is washed with ether. Recrystallisation of the residue from isopropanoi yields p-chloro-2-(2pyrrolidinylidene)-acetophenone, m.p. 146-147°C. 3^4LDiehloro-2-(2-pyrrolidinylidene)-acetophenone, m.p. 148149°, is obtained analogously to a) and b). - 31 E?;ample 3 By refluxi.ng the solution of 9.1 g (0.03 mole) of 2-(2ethoxy-2-phenyl-ethenyl)-l-pyrroline-tetrafluoroborate in 30 ml of isopropylamine for one hour and processing analogously to Example 1, there is obtained crude 2-[2-(Isopropylimino)-2phenylethylidene]-pyrrolidine. The crude base is dissolved in isopropanol, and 2.8 g of methanesulphonic acid is added, whereupon 2-[2-(isopropylimino)-2-phenyl-ethylidenej-pyrrolidine(1:1)-methanesulphonate, m.p. 175-176° (decomposition) lo crystallises out.

Example 4 By heating the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy2-phenyl-ethenyl)-l-pyrroline-tetratiuoroborate in 50 ml of tert.-butylamine in a closed tube at 105° for 18 hours and processing analogously to Example 1, there is obtained crude 2- [j2-phenyl-2- (tert. -butylimino) -ethylidenej-pyrrolidine. The crude base is dissolved in ether, and 2.8 g of methanesulphonic acid is added, whereupon 2-[2-phenyl-2-(tert.-butylimino)ethylidene]-pyrrolidine-(1:1)-methanesulphonate crystallises out. It melts at 208-209° (decomposition) after reerystallisation from ethyl acetate.

Example 5 By heating the solution of 9.1 g (0.03 mole) of 2-(2ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 25 ml - 32 4 7 0 5 of aniline for one hour at 80° and precessing analogously to Example I, there is obtained crude 2-^-phenyl^-Cphenylimino) -ethylidene]-pyrrolidine. An addition of 2.3 g of methanesulphonic acid is made to a solution of the crude base in ethyl acetate and the resulting crystals are filtered off.

The product thus obtained is 2-[phenyl-2-(phenylimino)ethylideaci-?yrrolidine-(l:l)-methanesulphonat6j m.p. 193-194° (decomposition), Example 6 The solution of 9.1 g (0.03 mole) of 2-;2-etboxy-2~phenylechenyl)-l-pyrroline-tetrafluoroborace in 25 mi of diethyiamine is refluxed for 12 hours; it is then processed analogously to Example 1 to yield crude 2-(2-(diethylanino)-2-phenyl-ethenyij1-pyrroline. By the addition of 2.8 g of methanesulphonic acid to the solution of the crude base in isopropanol, removal of the crystals by filtration and recrystallisation from isopropanol, there is obtained 2-i2-(diethylamino)-2-phenyl-ethenyl]-lpyrroline-(l:l)-methanesulnhonate, m.p. 143-145° (decomposition).

Example 7 9.1 g (0.03 mole) of 2-[2-ethoxy-2-phenyl-ethenyl)-lpyrroline-tetrafluoroborate is dissolved in 11.2 g (0.06 mole) of 1,1-diphenylmethylamine, and the solution is heated at 110° for 30 minutes, whereupon the tetrafluoroborate of the reaction product precipitates directly. The reaction mixture is cooled, - 33 diluted with ethyl acetate and filtered. The crystallised filter residue is suspended in methylene chloride; and for liberation of the base and removal of the tetrafluoroborcu hydride it is repeatedly extracted with IN sodium hydroxide- solution. The crude 2-(2-((diphenylmethyl)-imino]-2-phenyiethylidene]pyrrolidine remaining after the methylene chloride has been evaporated off is dissolved in ethyl acetate, and 2.8 g of methanesulphonic acid is added. The salt precipitating in crystalline form is purified by recrystallisation from isopropanol to yield 2-(2-((diphenylmethyl)-iminoj-2-phenylethylidene]pyrrolidine-(1:1)-methanesulphonate, m.p. 212-213° (decomposition).

Example 8 9.9 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyI)-4,5,6,7tetrahydro-3H-azepine-tetrafluoroborate is dissolved in 50 ml of isopropylamine, and the solution is refluxed for 18 hours.

The excess isopropylamine is then distilled off, the residue is dissolved in methylene chloride, and the solution, with the addition of ice, is extracted twice with IN sodium hydroxide solution and washed once with water. The organic phase is dried over sodium sulphate and concentrated by evaporation. The crude 2-[2-(isoprcpylimino)-2-phenylethylidene]-hexahydro-lH-azepine remaining behind as oil is dissolved in ethyl acetate. The salt, precipitated after the addition of 2.8 g of methanesulphonic acid, is purified by recrystallisation from acetone to obtain 2-(2-(isopropylimino)-2-phenyl-ethylidene]-hexahydro-lH-azepine- 34 « 4 7 Ο 5 (l:l)-mefcnanesulphonate, m.p. 155-157° (decomposition).

The 2-{2-ethoxy-2-phenyl—athenyl)-4,5,6,7-tetrahydro-3Hazepine-tetrafluoroborate used as starting material is produced as follows: a) A solution of 21 g (0.105 mole) of 2-bromoacetophenone in 50 ml of methylene chloride is slowly added dropwise at room temperature tc a solution of 10.1 g (0.1 mole) of hexahydro 2H-azepine-2-thione in 100 ml of methylene chloride. The solution is stirred for 18 hours at room temperature; ice is subsequently added and the solution is washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution; it is subsequently dried over sodium sulphate and filtered. The filtrate is allowed to stand for 4 hours at room temperature, during which time the colour changes from yellow to red, and the splitting-off of sulphur from the initially formed 2-(4,5,6,7 tetrahycto-3H-azepin-2-yl)-thio]acetophenone becomes completed. The solvent is then evaporated off in vacuo; the residue is taken up in ether; the solution is stirred twice in succession with active charcoal, filtered and the filtrate is concentrated by evaporation to approximately 100 ml. On cooling of this solution in an ice/sodium chloride bath, 2-(hexahydro-2Il-azepin-2-ylidene)-acetophenone crystallises out. After reerystallisation from ether/hexane, it melts at 73-74°. - 35 447 OS b) 60 g (0.315 mole) of triethyloxonium-fcetrafluoroborate end 64.8 g (0.30 mole) of 2-(hexahydro-2R-asepin-2-ylidene)acetophenone are dissolved in 500 ml of methylene chloride.

The reaction mixture is allowed to stand for 48 hours at room temperature; it is subsequently concentrated by evaporation to a small volume and ethyl acetate is added to the oil remaining, whereupon crude 2-(2-ethoxy-2-phenyl-ethenyl)4,5,6,7-tetrahydro-3H-azepine-tetrafluoroborate5 m.p. 136138° (decomposition), crystallises out. After drying at 50° in vacuo, this product can be further used directly.

Example 9 8.8 g (0.03 mole) of 2-[2-ethoxy-2-(2-thienyl)-ethenyl3-lpyrroline-tetrafluoroborate is dissolved in 30 ml of isopropylamine. The solution is refluxed for 18 hours, and the excess isopropylamine is thereupon evaporated off in a rotary evaporator. Tha brown residue is dissolved in methylene chloride, ice is added, the solution is extracted twice with IN sodium hydroxide solution, dried over sodium sulphate and concentrated by evaporation. The crude 2-[2-(isopropylimino)-2-(2-thienyl)ethylidene]-pyrrolidine, which is obtained as gradually crystallising oil, is dissolved in ethyl acetate, and to the solution is added 2.8 g of methanesulphonic acid. The precipitated salt is filtered off and recrystallised from isopropanol/ether to obtain 2-ί2-(iSopropylimino)-2-(2-thienyl)-ethylidene]-pyrrolidine- 36 4 4 7 0 5 (l:l)-methanesulphonate, m.p. 144-146° (decomposition). The 2-|2-ethoxy-2-(2~thienyl-ethanyl]-l-pyrroline used as starting material is produced as follows: a) To a solution of 30.3 g (0.3 mole; of 2-pyrrolidinethione in 200 ml of methylene chloride, there is slowly added dropwise in the course cf 30 minutes, with ice cooling, a solution cf g (0.76 mole) of freshly prepared 2-(brcnoacetyl)-thiophene [J.Amer.Chem.Soc. 71, 10 (1949); see also Houben-Weyl 4th edition, vol. 5/4, page 182] in 100 ml of carbon tetrachloride, whereupon a light-brown precipitate immediately forms. The reaction mixture is stirred at room temperature for a further 20 minutes, and the precipitate is subsequently filtered off and washed with methylene chloride. In order to liberate the base, the crude hydrobromide is suspended in methylene chloride, ice is added, and the suspension is stirred with saturated sodium bicarbonate solution being slowly added until the water phase shows a permanent alkaline reaction. The organic phase is subsequently separated, dried over sodium sulphate and concentrated at about 40° in the rotary evaporator, whereupon 2-[[2-(l-pyrrolin-2-yl)-thio]-acetyl]-thiophene remains behind in the form of brown oil. b) The crude product obtained according to a) is dissolved in a mixture of 250 ml of toluene and 30 ml of triethylphosphite and the solution is heated at 80° for 2 1/2 hours. By the - 37 44705 cooling of the reaction mixture In an Ice bath, the reaction product is caused to crystallise out; it is subsequentlyfiltered off and washed with ether. Reerystallisation from ethyl acetate/hexane yields 2-i2-(2-pyrrolIdinylidene)-acetylIthiophene, m.p. 149-150°. c) 5.5 g (0.03 mole) of 2-[2-(2-pyrrolidinylidene)-acetyl]thiophene and 6.26 g (0.033 mole) of triethyloxonium-tetraborofluorate are dissolved together in 30 ml of methylene chloride, and the solution is stirred at room temperature for 2 1/2 hours. The reaction product is then precipitated by the addition of about 100 ml of ethyl acetate; It is filtered off and washed with ethyl acetate. Reerystallisation from acetone/ hexane yields 2-[2-ethoxy-2-(2-thienyl)-efchenyl1-1-pyrrolinetefcrafluoroborate, m.p. 148-151° (decomposition), which, after drying at 50° in vacuo, is further used directly.

Example 10 Crude 2-[2-(1-piparidyl)-2-phenyl-ethenyl]-l-pyrroiine is produced by refluxing for 12 hours the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 25 ml of piperidine, and processing the reaction mixture analogously to Example 1. By the addition of 2.8 g of methanesulphonic acid to the solution of the crude base in isopropanol, concentration of this solution in the rotary evaporator and reerystallisation of the residue from acetone/ - 38 4 4 7 0 3 hexane, there is obtained 2-]2-(l-piperidyl)-2-phenylefchenylj1-pyrroliae-(1:1)-raethaaesulphoaate, m.p. 123-124°.

Example 11 Crude 2-ί 2-(N-inethylcyclohexylamino)-phenylethenyl1-1pyrroline is produced by heating the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-etaenyl·)-1-pyrrolinatetrafluoroborate in 20 ml of N-methyi-cycIchexylamine for 2 hours at 100’, and processing the reaction mixture analogously to Example 1. By addition of 2.8 g of methanesulphonic acid to the solution of the crude base in isopropanoi, evaporation of this solution in the rotary evaporator and recrystallisation of the residue from ethyl acetate, there is obtained 2-(2(N-methyl-cyclohexylamino)-phenylethenylj-1-pyrroline-(1:1)methanesulphonate, m.p. 163-164.

Example 12 62.7 g (0.33 mole) of triethyloxonium-tetrafluoroborate is dissolved in 120 ml of methylene chloride, and the solution is cooled in an ice bath. A solution of 65.1 g (0.3 mole) of p-methoxy-2-(2-pyrrolidinylidene)-acetophenone, m.p. 134-135°, produced completely analogously to Example 2 a) and 2b), in 450 ml of methylene chloride is added dropwise within 30 minutes. The reaction mixture is stirred at 0° for 3 hours; the methylene chloride is subsequently evaporated off at 30° in the rotary evaporator, and the oily brown residue is dried at room temperature under high vacuum.

The crude 2-(2-(p-methoxyphenyl-2-ethoxy-ethenyl]-lpyrroline-tetrafluoroborate obtained in this manner is directly dissolved in 180 ml of cyclohexylamine, and the brown solution is heated at 100° for 2 1/2 hours. Processing is carried out analogously to Example 2, whereby to the crude oily 2-[2-(pmethoxyphenyl)-2-(cyclohexylimino)-ethylidene]-pyrrolidine dissolved in 300 ml of isopropanol there is added a solution of 18.6 g of fumaric acid in isopropanol, and crystallisation is effected by the addition of acetone. After recrystallisation from an acetone/water mixture (6:1), the resulting 2-(2-(pmethoxyphenyl)-2-(cyclohexylimino)-ethylidene j-pyrrolidine-(1:1)fumarate melts at 192-193° (decomposition).

In an analogous manner are obtained, starting with 65.1 g (0.3 mole) of m-methoxy-2-(2-pyrrolidinylidene)-acetophenone, m.p. 93-94°, the crude 2-[2-(cyclohexylimino)-2-(m-methoxyphenyl)ethylidene]-pyrrolidine and from that its (1:1)-methanesulphonate, m.p. 137-138° (from isopropanol/acetone).

Likewise in an analogous manner is obtained, starting with 65.1 g (0.3 mole) of o-methoxy-2-(2-pyrrolidinylidene)-acetophenone, m.p. 100°, 2-[2-(o-methoxyphenyl)-2-(cyclohexylimino)ethylidenej-pyrrolidine, which melts at 91-92° after recrystallisation from ligroin. - 40 Example 13 9.5 g (0.03 mole) of 2-[2-(n-methylphenyl)-2-ethoxy-ethsnylj1-pyrroline-tetrafluoroboraue is dissolved in 20 mi of cyclohexylamine, and the solution is heated ar 100° fcr 2 1/2 hours. Processing is carried out analogously co Example 2, whereby the crude crystallising 2- (2- (p-methyIpheuy 1, -2- (cyclchexylimi.no) ethylidene}-pyrrolidine is dissolved in ethanol, and to the solution is added a hot ethanolic solution of 3 g of fumaric acid. The formed salt is filtered off, and recrystallised from isopropanol to obtain 2-i2-(p-methylphenyl)-2-(cyclohexyliroino)ethylidenei-pyrrolidine-(l:l)-fumarate, m.p. 201-202° (decomposition) .

The starting material is produced as follows: a) 62.7 g (0.33 mole) of triethyloxonium-tetrafluoroborate is dissolved in 120 ml of methylene chloride and the solution is cooled to 0°. Within 30 minutes is added dropwise a solution of 60.3 g (0.3 mole) of p-methyl-2-(2-pyrrolidinylidene)acetophenone, m.p. 143-144°, produced analogously to Examples 2a) and 2b), in 370 ml of methylene chloride. The reaction mixture is stirred at 0° for 3 hours; the methylene chloride is subsequently evaporated off at about 30° in a rotary evaporator and the yellow oily residue is crystallised from ethyl acetate. The product is filtered off, washed with ethyl acetate, dried at 50° in vacuo, and further employed without additional purification.

Example 14 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyi-ethenyl)-2imidazoline-tetrafluoroborate is dissolved in 30 ml of cyclopentylamine, and the solution is heaced under nitrogen at 100° for 18 hours. The excess cyclopentylamine is subsequently distilled off as far as possible in the rotary evaporator; the residue is dissolved in methylene chloride, and the solution, with the addition of ice, is repeatedly extracted with IN sodium hydroxide solution for liberation of the bases and removal of the tetrafluoroboron hydride. The organic phase is dried over sodium sulphate, concentrated by evaporation, snd the residue is concentrated twice with toluene in vacuo to effect the removal of the residual cyclopentylamine. The oil remaining behind is taken up in isopropanol, and 3 g of methanesulphonic acid is added. The salt is precipitated by the addition of ethyl acetate, and subsequently recrystallised from pure isopropanol to obtain 2-[2-phenyl-2-(cyclopentylamino)-ethenyl]2-imidasoline-(1:1)-methanesulphonate, m.p. 184-186°.

•The 2-(2-ethoxy-2-phenyi-ethenyl)-2-imidazoline-tetrafluoroborate is produced as follows: g (0.105 mole) of triethyloxonium-tetrafluoroborate is dissolved in 200 ml of methylene chloride. To the solution is added 18.8 g (0.1 mole) of crystalline 2-(2-imidazolidinylidene)acetophenone [m.p. 211-212°, see J. Klosa, Arch.Pharmaz. 286, 397 (1953)]. After the slightly exothermic reaction has subsided, - 42 £4705 the reaction mixture, a clear yellow solution, is stirred for 16 hours at rocci temperature: it is subsequently concentrated to dryness in the rotary evaporator; and ths crystallising residue Is suspended in 300 mi of ethyl acetate. The suspension is cooled to 5°, and the crystals are filtered off with suction to obtain 2-(2-echoxy-2-pheayl-ethenyl)-2-iaic.azoline-fcetrafluorobcrate, m.p. 151-152°. After drying at 50 in vacuo, the product is further employed without additional purification.

Example 15 g (0.105 mole) of triethyloxoaium-tetrafluoroborate is dissolved in 100 ml of methylene chloride, and the solution is cooled in an ice bath. A solution of 22.9 g (0.1 mole) of 1phenyl-2-(2-pyrrolidinylidene)-l,3-bjtanadioae in 70 ml of methylene chloride is added dropwise in the course of 30 minutes.

The reaction mixture is subsequently stirred for 4 hours at room temperature; the methylene chloride Is evaporated off at 30° in the rotary evaporator; and the oily residue is dried under high vacuum at room temperature, The resulting crude 3-ethoxy-lphenyl-2-(l-pyrrolin-2-yl)-2-buten-I-oae-tctrafluorofcorate is dissolved directly in 30 ml of cyclohexylamine, whereupon the reaction mixture heats up. It is allowed to stand for about 15 hours at room temperature, and the excess cyclohexylainine is then evaporated off in the rotary evaporator. The salt mixture remaining behind is taken up In methylene chloride, and the solution, with the addition of ice, is repeatedly extracted with - 43 IN sodium hydroxide solution. The organic phase is dried over sodium sulphate, concentrated by evaporation, and the residue is repeatedly concentrated with a small amount of toluene in vacuo in order to remove the residual cyclohexylamine. The oil remaining is dried under high vacuum, and subsequently chromatographed on a silica-gel column with ethyl acetate as the eluant. The main fractions are combined, dissolved in isopropanol, and a hot solution of about 6 g of fumaric acid in ethanol is added. The resulting salt is filtered off and recrystallised from isopropanol. There is obtained 3-(cyclohexylamino)-l-phenyl-2-(l-pyrrolin-2-yl)-2-buten-l-one-(l:1)fumarate, m.p. 170-172°.

The starting material is produced as follows: a) 9.9 g (0.1 mole) of 2-methoxy-l-pyrroline and 24.4 g (0.15 mole) of l-phenyl-l,3-butanedione are mixed together and, in a nitrogen atmosphere, heated with stirring for 18 hours In an oil bath at 100° . The dark reaction mixture is cooled to 60° and 500 ml of hexane is added. Upon further cooling to room temperature, the reaction product crystallises out. Reerystallisation from ethyl acetate/hexane yields l-phenyl-2(2-pyrrolidinylidene)-l,3-butanedione, m.p. 106-108°. - 44 Example 16 9.1 g (0,03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1pyrroline-tetrafluoroborate is heated in 12.5 g (0.1 sols) of 3-azabjcycloJ3.2.2i nonane at 110° for 30 minutes, during which the tetrafluoroborate of the reaction, product precipitates out directly.

The reaction, mixture is cooled, diluted with isopropanol and filtered. The crystallised filter residue is suspended in methylene chloride and, for liberation of the base and removal of the tetraflucroboron hydride, repeatedly extracted with IK sodium hydroxide solution. The crude 2-i2-(3-azabicyclo(3.2.2j noa-3-yl)-2-phenylethenyi]-l-pyrroline, remaining behind after the methylene chloride has been evaporated off, is dissolved in acetone and to the solution is added 2.8 g of methanesulphonic acid. The salt precipitating on addition of hexane is purified by recrystallisation from acetone/hexane to yield 2-I2-(3-azabicyclo(3.2.2]non-3-yl)-2-phenyl-ethenyll-l-pyrrolins(1:1)-methanesulphonate, m.p. 172-173° (decomposition).

Example 17 A mixture of 11.3 g (0.04 mole) of 2-[2-(cyclohexylimino)-2phenyl)-ethylidenej-pyrrolidine (liberated from the fumarate obtained according to Example 1) and 30 ml of methyl iodide is stirred for 15 hours at room temperature. The formed yellow crystals are filtered off and subsequently washed with ether. - 45 ¢4705 The filter residue is thereupon suspended in 200 ml of methylene chloride and, for liberation of the base and removal of the hydrogen iodide, extracted three times with 100 ml of IN sodium hydroxide solution each time. The organic phase is then concentrated by evaporation, whereupon the crude base remains behind in the form of yellow oil. This oil is dissolved in methanol; to the solution is added a methanolic solution of 2.2 g of fumaric acid, and the mixture is concentrated in vacuo in the rotary evaporator. The residue is recrystallised from isopropanol to obtain 1-methyl-2-[2(cyclohexylimino)-2-phenyl-ethylideneI-pyrrolidine-fumarate(1:1), m.p. 182-183°.

Example 18 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1pyrroline-tetrafluoroborate and 5.0 g (0.03 mole) of eis-2cyclohexylcyclopentyfamine [for production see J. Martin Grisar et al., J. Med. Chem. 16, 683, (1973)] are heated together at 100° for 2 hours. The melt is subsequently cooled, taken up in methylene chloride, and this solution is then extracted once in each case with IN sodium hydroxide solution, with 2N potassium carbonate solution and with water. The organic phase is dried over sodium sulphate and concentrated by evaporation, and the crystallising reddish residue is briefly dried under high vacuum. The crude base is recrystallised once from isopropanol, subsequently dissolved warm in ethyl acetate, and - 46 1,5 2 of methan'-sulphonic acid is added. After cooling, the precipitated salt is filtered off and recrystallised from methylene chloride/ethyl acetate. The resulting 2-(2-(cis-2cyelohexyleyclopentylimino)-2-phenyi-ethylidene]-pyrrolidine5 methanesulphonate-(l:i) melts at 179-180°.

There are obtained in an analogous manner, starting with 9.1 g (0.03 mole) of 2-(2-etfaoxy-2-ph=nyl-ethsnyl)-i-pyrrolidin tetrafluoroborate and 4.25 g cf 2-eyclohexyl-l-mechylefchyias;ine 2-[2-(2-cyclohexyl-I-me snylethyl)-imino]-2-phenyl-echylidene]10 pyrrolidine and from that its (l:l)-methanesulnhcnate having a melting point of 191 - 192°.

Example 19 by a process analogous to that described in Example IS, there is obtained, from 14.5 g (0.0478 mole) of 2-(2-ethoxy-215 phsnyl-ethenyl)-1-pyrroline-tetrafluoroborate and 7.3 g (0 .044 mole) of trans-2-cyclohexylcyclopentylamine, crude {2- ]2~ (trans-2-cyelohe;-;ylcyclopentyIimino)-2-phenyl-ethyIidene] pyrrolidine]. The crude base is chromatographed on a short silica-gel column with methanol as the eluant. The main fractions are combined, dissolved in methanol, and to this solution is added a solution of the equimolar amount of fumaric acid in methanol. The methanolic solution is concentrated by evaporation, and the residue remaining behind is triturated with ether to obtain 2-[2-(trans-2-cyclohexylcyclopentylimino)- 47 2-phenyl-ethylidene]-pyrrolidine-fumarate-(l:1), m.p. 157 158° (with decomposition).

Example 2(3 By the process described in Example 18, there is produced, from 4.0 g (0.013 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1pyrroline-tetrafluorohorate and 2.25 g (0.013 mole) of 1eyclohexyl-2-amino-pencane, 2-[2-[1-(cyclohexylmethyl)-butylimino J-2-phenyl-ethylidene]-pyrrolidine-fumarate-(1:1). In the melting point tube, the slightly yellowish, hygroscopic crystals commence foaming at about 85°.

The l-cyclohexyi-2-amino-pentane, used as starting material, can be obtained by hydrogenation of 3.7 g of l-phenyl-2-aminopentane hydrochloride, dissolved in 100 ml of water. The catalyst used is 1.4 g of 5% rhodium-charcoal. Hydrogenation ceases after about 4 1/2 hours at 70° and 4 bars hydrogen pressure. The resulting l-cyclohexyl-2-amino-pentane hydrochloride melts at 130-131°.

Example 21 By the process described in Example 18, there is produced, from 10.4 g (0.034 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-lpyrroline-tetrafluoroborate and 6.2 g (0.034 mole) of trans4-cyclohexylcyclohexylamine [for production see D.V. Nightingale et al., J. Org. Chem. 17, 1017 (1952)], 2-[2-(trans-4-cyclohexylcyclohexyl-imino)-2-phenyl-ethylidene]-pyrrolidine. The - 48 crude base is chromatographed on a short silica-gel column with a chloroform/methanol mixture (volume ratio 9:1) as the eluant. The main fractions are cambinad and dissolved in ethanolic hydrochloric acid; the solution is concentrated by evaporation, and the residue remaining is triturated with ethyl acetate. There is obtained 2-i2-(trans-4-cyclohexyleyclohexylimiao)-2-phenyl-ethylideneΪ-pyrrolidine hydrochloriae(1:1), m.p. 243-244°.

Example 22 Analogously to Example 1, there is obtained, starting with 9.5 g of 2-(2-ethoy.y-2-phenyl-£thenyI)-3,4,5,6-tetriihydropyridine-tetrafluoroboraca and 30 ml of cyclohexylamine, 2((2-pheny1-2-(cyclohexylami.no)-athenylj-3,4,5,6-tetrahydropyridine, and from this its (I:1)-methanesulphonate, m.p. 172173’; and starting with 9.5 g of 2-(2-ethoxy-2-phenyi-ethenyl)3.4.5.6- tetrahydropyridine-tetrafluoroborate and 30 ml of diethylamine, is obtained 2-[2-phenyl-2-(diethylamino)-ethenyl 3.4.5.6- tetrahydropyridine, and from this its (1:1)-fumarate, m.p. 169-170° (from isopropanoi).

The 2-(2-ethoxy-2-phenyl-ethenyl)-3,4,5,6-tetrahydropyridinetetrafluoroborate required as starting material is produced as follows : a) 12.7- g (0.1 mole) of 2-ethoxy-3,4,5,6-tetrahydropyridine and 24.4 g (0.15 mole) of l-phenyl-l,3-butanedione are mixed and heated together in a nitrogen atmosphere, with stirring, for 32 hours in an. oil bath at 100°. The reaction mixture is cooled, and subsequently chromatographed on silica gel with an ethyl acetate/hexane mixture as the eluant. The main fractions are combined and crystallised from ether to obtain l-phenyl-2(2-piperidinylidene)-l,3-butanedione in the form of yellow crystals, m.p. 80-81°. b) 12.15 g (0.05 mole) of l-phenyl-2-(2-piperidinyIidene)-1,3butanedione are introduced into a prepared solution of 3.5 g of sodium in 120 ml of ethanol. The reaction mixture is then refluxed for 40 minutes. After cooling, it is neutralised with glacial acetic acid, and filtered off from the sodium acetate. The filtrate is concentrated in the rotary evaporator, and the residue is dissolved in methylene chloride. The solution is repeatedly extracted with water; the organic phase is dried over sodium sulphate, and the solvent is evaporated off in the rotary evaporator. The oily residue is crystallised from ether/ hexane to yield 2-(2-piperidinylidene)-acetophenone, m.p. 59-60° c) 4.1 g (0.022 mole) of triethyloxonium-tetrafluoroborate is dissolved in 50 ml of methylene chloride, and the solution is cooled in an ice bath. Within about 15 minutes, there is added dropwise a solution of 4.2 g (0.02 mole) of 2-(2-piperidinylidene)-acetophenone in 20 ml of methylene chloride. The reaction mixture is subsequently stirred for 15 hours at room temperature. The yellow reaction solution is concentrated in ths rotary evaporator to a small volume, and caused to crystallise - 50 Ί 4 7 :.j ρ by the addition of ethyl acetate. The precipitated crude 2-(2-e thoxy-2-pheny 1-e thienyl)-3,4,5,6-tecrahydropyridinetetrafluoroborate, m.p, 143-144°. is dried at 60° in vacuo and subsequently further used without additional purification.

Example 23 Analogously to Example I there is obtained, from 7.2 g (0.03 mole) of 2-(2-etho::y-l-propenyi)-l-pyrrolidine-tetrafluoroborate (see nelv. Chim. Acta 54, 722 - 3 (1971)j and 30 ml of tert.-butylamine, 2-12-(tert.-butylimino)-propylidene]-pyrrolidine, and from this its (1:1)-methanesulphonate, m.p. 154 - 155° (from ethyl acetate/aeetonitrile); and starting with 7.2 g (0.03 molt) of 2-(2-erhoxy-l-prcpenyl-]-pyrroline-tetrafluoroborate and 20 ml of N-methyi-cyclohexylanine, is obtained 2i2-(N-methyl-cyclohexylamino)-1-propenyll-l-pyrroline, and from this its (1:1)-fumarate, m.p. 152-1533 (from isopropanol).

Example 24 Analogously to Example 8 there is obtained, starting with 9.9 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-4,5,6,7fcetrahydro-3H~azepine~ietrafiurnn'borace and 20 ml of cyclohexylamine, 2-[2-(cyclohexylimino)-2-pheayl-ethylidenej-hexahydro-lH-azepine, and from this its (1:1)-fumarate, m.p. 169-170° (from isopropanol); and starting with 9.9 g (0.03 mole) of 2(2-ethoxy-2-phenyl-ethenyl)-4,5,6,7-tetrahydro-3H-azepinetetrafluoroborate and 40 ml of diethylamine, 2-[2-(diethylami.no) - 51 -2-phenyl-ethenyl]-4,5,6,7-tetrahydro-3H-azepine, and from this its (l:l)-methanesulphonate, m.p. 122-124° (from isopropanol).

Example 25 Analogously to Example 14 there is obtained, starting with 9.1 g (0.03 mole) of 2-(2-ethoxy-2-ph2nyl-ethenyl)-2-imidasolinetetrafluoroborate and 45 g of 2,6-dichloroaniline, crude 2-[2-phenyl-2-(2,δ-dichloroanilino)-ethenyl]-2-iinidazoline, and from this its (1:1)-fumarate, m.p. 207-203° (from ethanol/ ether).

Example 26 Analogously to Example 15 there is obtained, starting with 34.5 g (0.1 mole) of crude 3~ethoxy-l-phenyl“2-(l-pyrrolin-2-yl)buten-l-one-tetrafluoroborate and 80 ml of diethyiamine, 315 (diethylamino)-l-phenyl-2-(l-pyrrolin-2-yl)-2-buten-l-one, and from this its (1:1)-fumarate.

Example 27 By the process described in Example 18, there is produced, from 5.4 g (0.0167 mole) of 2-(l-methyl-2-ethoxy-2-phenyl20 ethenyl)-1-pyrroline-tetrafluoroborate and 5 ml of cyclohexylamine, 2-[l-methyl-2-(cyclohexylimino)-2-phenyl-ethylidene]pyrrolidine. The crude base is chromatographed on a short column of silica gel. Elution is performed firstly with chloroform and then with a chloroform/methanol mixture (volume ratio 9:1). - 52 The main fractions are combined and dissolved in ethanolic hydrochloric acid, the solution is concentrated by evaporation and the residue remaining is triturated with ethyl acetate.

The crude hydrochloride obtained is recrystallised from an ethyl acetate/isc-propanol mixture to obtain 2-{I-methyl-2(cyciohexylimino)-2-phenyl-ethylidenei-pyrrolidine hydrochloride, m.p. 264-265° (slight decomposition).

The starting material is produced as follows: a) 17.0 g of a-(2“pyrrolidinylid2ae~aeetophenone ano 11.3 g ic of potassium-tert.-butoxide are dissolved in a mixture of 8 ml of dimethylformamide and 170 ml of benzene. A solution of 25 g of methyl iodide in 25 ml of benzene is added dropwise xvithin 30 minutes. The reaction mixture heats up to 38°. It is stirred for 2 hours ac room temperature; to the reaction mixture is then added a further 2.5 g of potassium tert.-butoxide and it is subsequently stirred for 15 hours at room temperature. The cloudy reaction mixture is filtered clear with the aid of diatomaceous earth; it is concentrated by evaporation and the evaporation residue is chromatographed on a silica-gel column with an ethyl acetate/hexane mixture (volume ratio 1:1). There is obtained 2-methyl-2-(2-pyrrolidi.nylidene)-acetophenone, m.p. 91-92° (from cyclohexane). b) By the process described in Example 1 there is obtained, from 32,5 g of 2-methyl-2-(2-pyrrolidiaylidene)-acetophenone and 33.3 g of triethyloxonium-tetrafluoroborate, crude 2-(125 methyl-2ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate. This is a viscous oil which can be reacted with cyclohexylamine without further purification.

Example 28 g (0.025 mole) of N-(α-methylbenzylidene)-cyclohexylamine, .6 g (0.05 mole) of 2-athoxy—1-pyrroline and 2.4 g (0.025 mole) of methanesulphonic acid are neated together for 2 hours at 100° with stirring. The reaction mixture is then cooled, diluted with ethyl acetate and, after commencing crystallisation, cooled with ice. The formed salt is filtered off and recrystallised from isopropanol/ether to obtain 2-[2-(cyclohexylimino)2-phenyl-ethylidene]-pyrrolidine-methanesulphonate-(1:1), m.p. 186-187°, The N-(a-methylbenzyildene)-cyclohexylamine used as starting material is produced as follows: g (0.1 mole) of acetophenone and 12 g (0.12 mole) of cyclohexylamine are dissolved in 200 ml of toluene. 0.1 g of p-toluenesulphonic acid is added, and the solution is refluxed for 15 hours, with the reaction water being separated by means of a water separator. The toluene is subsequently evaporated off in the rotary evaporator, and the residue is distilled under high vacuum, whereupon N-(a-methylbenzylidene)-cyclohexylamine passes over at 99-101° / 0.001 mm Hg.

Claims (26)

1. CLAIMS:I. Imino compounds of chs general formula I > z)n 2 (CSJr., 5 \. wherein 5 R represents an alipnatic or cycloaliphatic hydrocarbon radical, an option ally substituted phenyl, or an optionally ring-substituted mono- or diphenyl-lower-alkyl I?2 represents optionally substituted phenyl, optionally substituted monocyclic heteroaryl or lower alkyl, or 10 o-phenylene linked with a carbonyl group R^, R. represents hydrogen, lower alkyl, a carbonyl group linked with an o-phenylene radical R,, to form an o-benzoylene radical, cr the group R^-CO wherein R represents lower alkyl or optionally substituted phenyl, 15 R ; , represents, if present, hydrogen or lower alkyl, or together with R^ a saturated bivalent aliphatic or cycloaliphatic radical having a minimum of 4 and a cf 6 carbon atoms between the two linkage points maximum - oo 4 47 OS and a total of 4 to 12 carbon atoms, a K-lower alkyl-ethylene imino ethylene cr the ethyleneoxyethylene radical. Rg represents, if present, hydrogen or lower alkyl, A represents an optionally branched-chain lower alkylene having 2 to chain members between the two linkage points, Z represents epoxy, epithio, imino or lower alkylimino , and uh and rs?2 represent 0 or 1 and together always represent 1, n-j. represents 1 or, if Z represents imino or lower alkylimino and represents 1, can also represent 0, n-2 represents 0 or 1, and wherein two additional bonds, either corresponding to the dashed lines or corresponding to the dotted lines, are present, with m 1 representing 0 in the former case and representing 0 in the latter case, and their acid addition salts.

2. Imino compounds of the general formula I given in Claim 1, wherein R^ represents an aliphatic or cycloaliphatic hydrocarbon radical having a maximum of 12 carbon atoms, R 2 represents a phenyl or thienyl radical optionally substituted by lower alkyl, lower alkoxy, halogen up to atomic number 35 and/or trifluoromethyl, Rg represents hydrogen or lower alkyl, R^, if present, represents lower alkyl, or together with R^ a saturated bivalent aliphatic or cycloaliphatic hydrocarbon radical having a minimum of 4 and a miximum of 6 carbon atoms between the two linkage points and a total or 4 to 12 carbon atoms, or the ethyleneoxyethylene radical, R_, if present, □ 56 represents hydro gen or lower alkyl, and Α,Ζ,η, and r_ 2 have the meanings given in Claim 1, and their pharmaceutically acceptable acid addition salts.

3. Imino compounds of the general formula I given in Claim 1, wherein E.,R,,R., if present, and R-r if present, r C n t are as defined in claim 2, and and m 2 have the meanings given m Clai: represents snd n„ represents 0 and simultaneously k represents ethylene, trimethylene or tetramethylene, or n represents O, n 2 represents 1, Z represents imino or lower alkylimiao and simultaneously A represents ethylene, and their pharmaceutically acceptable addition salts,

4. Imino compounds of the general formula I given in Claim 1, wherein R represents an aliphatic hydrocarbon having a maximum of δ carbon atoms, or a cycloaliphatic hydrocarbon radical having a maximum of 12 carbon atoms, &2 represents a phenyl radical optionally substituted by lower alkyl, lower alkoxy, halogen up to atomic number 35 and/ or trifluoromethyl, or a thienyl radical optionally substituted by lower alkyl and or hy halogen up to atomic number 35, and R, represents hydrogen, R, and R-, if present, are as defined in claim 2, and and m 2 have the meanings given in Claim 1, A represents ethylene, trimethylene or tetramethylene, n^ represents I and s, represents 0 and hence Z is omitted, and their pharmaceutically acceptable acid addition salts.

5. Inir.o compounds of the general formula I given in Claim 1, wherein F/ and R^ are as defined in Claim 4, ? 2 represents a phenyl radical optionally substituted by methyl, methoxy or halogen up to atomic number 35, or a thienyl radical, R^, if present, represents lower alkyl, or together with R. tetra- to hexamethylane, if present, 5 represents hydrogen or lower alkyl and A represents ethylene, trimethylene or tetramethylene, and m? have the meanings given In Claim 1, n^ represents 1 and represents 0 and hence Z is omitted, and their pharmaceutically acceptable acid addition salts. 10

6. Imino compounds of the general formula 1 given in Claim 1, wherein R. represents a saturated aliphatic hydrocarbon radical which has a maximum of 8 carbon atoms and which is bound by way of a secondary or tertiary carbon atom, or a saturated cycloaliphatic hydrocarbon radical having 5 to 12 carbon atoms, 15 Rg represents a phenyl radical optionally substituted by methyl, methoxy or halogen up to atomic number 35, or a thienyl radical, Κ.^ represents hydrogen, R^, if present, represents lower alkyl and A represents ethylene, and mg have the meanings given in Claim 1, n^ represents 1 and Hg represents 0 and hence Z 20 is omitted, and their pharmaceutically acceptable acid addition salts.

7. The imino compounds described in the foregoing Examples and corresponding to the general formula I given in Claim 1. 44703

8. 2-[2-(Cyelohexyx-iaino)-2-phenyl-ethylidene]-pyrrolidine and ics pharmaceutically acceptable acid addition salts.

9. , 2- [2- (cis-?.- Cyclohexyl-cyclopentylimino) -2-phenylethylidene]-pyrrolidine and its pharmaceutically acceptable acid 5 addition salts. it). A process for the production of imino compounds of the general formula I given in Claim I, wherein R,, Rg’ ^3» R,, S.., A, 2, , r.v,, a, and n„ have the meanings given there, £φ J -£· «d X d, and double bonds are present as indicated there, and of their 10 acid addition salts, which process comprises a) -reacting a compound cf the general formula II wherein represents lower alkoxy or together with Y^ the oxo radical, Y^ represents lower alkoxy, together with Y2 an additional bond, or together with X^the oxo radical, and Yg represents hydrogen, or together with Y^ or Yg an additional bond, Yg represents together v/ith f or Y 4 an additional bond, and Y^ represents hydrogen, lov/er alkyl, or together with Yg an additional bond, and 5 R 2 ,Rg,A,Z,n^ and n 2 have the meanings given under formula- I, with a compound of the general formula III H—S (III) wherein has the meaning given for R. under the formula I,

10. But always represents hydrogen in the case where Υ Λ represents lower alkyl in the compound of the general formula II, and R^ has the meanings given under the formula I; or b) for the production of compounds of the general formula I -wherein Rg is hydrogen, m 1 is 0, and m 9 is 1 and therefore R^ is absent, and R^,R 2 ,Rg,A,Z,n^ and n 2 have the meanings given under the formula I reacting a compound of the t J general formula IV ,(Z)n (CH-)n n \ I 2 ' C5 X (IV) wherein f represents lov/er alkoxy, lower alkylthio or halogen, and Α,Ζ,η^ and n 2 have the meanings given under the formula I, or an acid addition salt thereof, v/ith a compound of the general formula V ί 4 7 Ο 5 wherein R., X,, and R, have, the raeanings given under the x L J formula I, or with an acid addition salt thereof; and/or c) replacing in a resulting compound .of the general formula Ϊ, 5 in which a hydrogen atom is present as .1,. or ft-, or in a compound corresponding thereto, which contains a hydrogen atom instead of the radical R,, the hydrogen atom, or the two said hydrogen atoms, by lower alkyl; and,optionally, converting a resulting compound of the general t.q formula I into an acid addition salt, or liberating the compound of the general formula 1 from an acid addition salt obtained. .

11. Process according no claim 10, wherein a starting material of the general’formula II or III is used in the the form of a salt. 5

12. Process according to Claim 10, wnerein an optionally active starting material is used in the form of the racemate 3 4705 or of the isolated antipode,or in the case of a diastereomeric compound, a mixture of racemates or a specific racemate, or likewise an isolated antipode is used, if required, in the form of a salt.

13. Process according to Claim 10, wherein a mixture of racemates obtained is separated in known manner into the pure racemates.

14. Process according to Claim 10, wherein a racemate obtained is resolved in known manner into the optical antipodes .

15. Pharmaceutical compositions which contain an imino compound according to Claim 1 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier.

16. Pharmaceutical compositions which contain an imino compound according to one of the Claims 2, 3, 4, 5 and 6 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier.

17. Pharmaceutical compositions which contain an imino compound according to one of Claims 7 and 8 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier. - 62

18. 2 f2- (4-Chlorc.phenyI)-2- (cyclohexylimino) -ethylidene J-pyrrolidine and its pharmaceutically acceptable acid addition salts.

19. 2-[2-Pfeenyl-2-(tert-bultvlimino)-ethylidene]pyrrolidine ar.d its pharmaceutically acceptable acid addition salts.

20. 2-[2-(Diethylamino)-2-Qhenyl-etheayi]-1pyrroline and its pharmaceutically acceptable acid addition salts.

21. 2-[2-(l-Piperidyl)-2-phsnyl-ethenyl]-1“ pyrroline and its pharmaceutically acceptable acid addition salts.

22. 2-!7~(p-Methoxyphenyl)-2-(cyclohexylimino)ethylidene]-pyrrolidine and its pharmaceutically acceptable acid addition salts.

23. 2- j_2- (Cycichezyiimino) -2-- (m^me thoxyphenyl) ethylidene)pyrrolidine and its pharmaceutically acceptable acid addition salts.

24. 2-^2-(p-MethvIphenyl)-2-(cyclohexylimino)ethylidenej-pyrrolidine and its pharmaceutically acceptable acid addition salts,

25. 2- {j2- (3-Acabicyclo ϊ.2.2.2] non-3-yl) -2-phenylethenylj-I-pyrroline and its pharmaceutically acceptable acid addition salts,

26. 2-[l-Methyl-2-(cyclohexylimino)-2-phenylethylidene J pyrrolidine and its pharmaceutically acceptable acid addition salts.