Propenyl amines, processes for their production and pharmaceutical compositions containing them

Abstract

 The present invention provides propenylamines useful as anti-mycotic agents.

Description

[0001] This invention relates to propenyl-amines, processes for their production and pharmaceutical compositions containing them.

[0002] The present invention provides a compound of formula I,

wherein a)(i) R₁ is a radical of formula IIa,

wherein R₇ and R₈, independently, are hydrogen, halogen of atomic number from 9 to 53,trifluoromethyl, hydroxy, nitro, lower alkyl or lower alkoxy, or a radical of formula IIb, IIc, IId, IIe,



wherein R₉ is hydrogen, halogen of atomic number from 9 to 53, hydroxy, lower alkyl or lower alkoxy, X is oxygen, sulphur, imino, lower alkylimino or a radical of formula -(_CH2)_r- wherein r is 1, 2 or 3, s is 3, 4 or 5, and t is 2, 3 or 4, and R₂ is hydrogen or lower alkyl, or

(ii) R₁ and R₂ together with the carbon atom to which they are bound form a radical of formula IIf or IIg,

wherein p is 1, 2 or 3, R₃ and R₅, independently, are hydrogen or lower alkyl, R₄ is alkyl (C_1-6), alkenyl (C_3-12)' alkynyl (C₃_₁₂) or cycloalkyl (C_3-8)-alkyl (C_1-6); and R₆ is (i) an aromatic, five-membered heterocycle containing one oxygen, sulphur or nitrogen hetero-ring atom and optionally an additional one or two nitrogen hetero-ring atoms and being optionally substituted on a carbon ring atom by halogen of atomic number from 9 to 53, hydroxy, lower alkyl or lower alkoxy, and any nitrogen ring atom present being optionally substituted when possible, by lower alkyl, (ii) a radical of formula IIIa,

wherein R₉ is as defined above,

(iii) a radical of formula IIIb,

wherein R₁₀ is alkyl (C_1-12), alkenyl (C_3-12), alkynyl (C_3-12) cycloalkyl (C_3-8) alkyl (C_1-6), phenyl-alkyl (C_7-12), phenyl, phenylalkoxy (C_7-16), or aminoalkyl (C_1-12);

(iv) a radical of formula IIIc, IIId or IIIe,

wherein R¹¹, R₁₂ and R₁₃, independently, are hydrogen or lower alkyl, m is a whole number from 0 to 4, n is a whole number from 0 to 3, and v is a whole number from 0 to 5, (v) a radical of formula IIIf,

wherein _R14 is lower alkyl, al^ko^xy (C_1-12)-carbonyl, alkenyl (C_3-12), alkynyl (C_3-12), phenylalkyl (C_7-12) or phenyl, R₁₅ and R₁₆, independently, are hydrogen or lower alkyl, and q is a whole number from 0 to 5, or (vi) a radical of formula IIIg

wherein R₁₇ and R₁₈₁ independently, are hydrogen, halogen of atomic number from 9 to 53, trifluoromethyl, hydroxy, nitro, lower alkyl or lower alkoxy, with the proviso that one of R₁₇ and R₁₈ is other than hydrogen, and with the general proviso that R₁ is not a radical of formula IIa when R₆ is a radical of formula IIIg or phenyl, R₂ is hydrogen and R₃ is hydrogen or lower alkyl,

b) R₁ is a radical of formula IIa to IIe, as defined above, R₂, R₅ and R₆ are as defined above, and R₃ and R₄ together are -(CH₂)_u- whereinu is a whole number from 1 to 8.

[0003] Any lower alkyl or lower alkoxy radical has preferably 1 to 4 carbon atoms, especially 2 or 1 carbon atoms. Any alkyl(C_1-12) moiety is preferably alkyl(C2-8); phenyl- alkyl or phenylalkoxy has preferably 7 carbon atoms. Any alkenyl or alkynyl radical has preferably 3 to 6 carbon atoms, especially 3 or 4 carbon atoms. Preferably the multiple bond is in other than the a, ß position and is conveniently in the remote terminal position. An example of an alkenyl group is allyl. An example of an alkynyl group is propinyl Cycloalkylalkyl has preferably an alkyl moiety of 1 to 4 carbon atoms, especially 2 or 1 carbon atoms, and a cycloalkyl moiety preferably of 3 to 6 carbon atoms. When R₄ is cycloalkylalkyl this is especially cyclopentyl alkyl or cyclohexylalkyl. When R₁₀ is cycloalkylalkyl this is especially cyclopropylalkyl or cyclobutylalkyl.

[0004] Conveniently R₇ and R₈ are identical and are both hydrogen. Conveniently R₉ is hydrogen or halogen. In IIb and IIc the bond to the carbon atom to which R₂ and R₃ are attached is conveniently attached meta to X and para to the ring nitrogen, respectively. X is conveniently sulphur, imino or lower alkylamino. R₁ is preferably a radical of formula IIb, IIc or IId or especially IIa.

[0005] R₂ is preferably hydrogen. R₃ is preferably hydrogen and R₄ is conveniently alkyl. R₅ is conveniently hydrogen. R₆, when it is a heterocycleconveniently contains one oxygen or sulphur atom or one or two nitrogen atoms. Preferably the bond linking R₆ to the vinylene moiety is attached to a ring carbon atom adjacent to a ring heteroatom. Conveniently the ring is unsubstituted or substituted by lower alkyl. R₁₀ is conveniently phenylalkoxy. IIa is conveniently optionally substituted 2 or 4-pyridyl. In IIIc, IIId, IIIe it is to be appreciated that the bond linking R₆ to the vinylene moiety and R₁₁ to ^R₁₃ may be attached to any of the ring carbon atoms present. IIIc is preferably a cycloalk-1-en-1-yl radical. Preferably ^R₁₁ to ^R₁₃ are hydrogen. q is conveniently 0 or 1.

[0006] Any double bond in IIIf is conveniently trans. R₁₄ is conveniently alkoxy (C_1-8) carbonyl, phenyl or alkyl or phenalkyl. R₁₇ is conveniently halogen and R₁₈ is conveniently hydrogen. R₆ is conveniently IIIc. u is conveniently 3, 4 or 5, more conveniently 4.

[0007] The values m, n, p, q, s, t and v are conveniently chosen to produce a five or six-membered ring.

[0008] The double bond between R₆ and the nitrogen atom preferably has the trans configuration.

[0009] Halogen is conveniently fluorine, or preferably bromine or chlorine.

[0010] When R₁ is IIb or IIe and R₆ is IIIa it is to be appreciated that the two radicals R₉ may be the same or different.

[0011] The present invention also provides a process for the production of a compound of formula I, which comprises

a) reacting a compound of formula IV,

wherein R₁ to R₄ are as defined above, with a compound of formula V,

wherein A is a leaving group, and R₅ and R₆ are as defined above, or

b) producing a compound of formula Ia,

wherein R₁ to R₃ and R₅ are as defined above, and

and

are as defined above for R₄ and R₆ respectively, with the proviso that they each are other than alkynyl, by reducing a compound of formula VI,

wherein R₁ to R₃,

R₅ and

are as defined above, or

c) producing a compound of formula Ib,

wherein R₁ to R₆ are as defined above, by iscmerising photochemically a compound of formula Ic,

wherein R₁ to R₆ are as defined above, or

d) producing a compound of formula Id,

wherein ^R₁, ^R₂, R₅ and R₆ are as defined above,

is hydrogen or lower alkyl,

is alkyl (C_1-6), alkenyl (C_3-12), alkynyl (C_3-12) or cycloalkyl(C_3-8)alkyl (C_1-6); by introducing the group

into a compound of formula VII,

wherein R₁, R₂,

R₅ and R₆ are as defined above.

[0012] Process a) may be effected in conventional manner for the production of tertiary amines by condensation from analogous starting materials. The process may be effected in an inert solvent such as a lower alkanol, e.g. ethanol, optionally in aqueous admixture, an aromatic hydrocarbon solvent, e.g. benzene or toluene, a cyclic ether, e.g. dioxane or a carboxylic acid dialkylamide solvent, e.g: dimethylformamide. The reaction temperature is conveniently from room temperature to the boiling temperature of the reaction mixture, preferably room temperature. The reaction is conveniently effected in the presence of an acid binding agent, such as an alkali metal carbonate, e.g. sodium carbonate. The leaving group A is conveniently iodine or preferably chlorine or bromine, or an organic sulphonyloxy group having 1 to 10 carbon atoms, e.g. alkylsulphonyloxy, preferably having 1 to 4 carbon atoms such as mesyloxy, or alkylphenylsulphonyloxy preferably having 7 to 10 carbon atoms such as tosyloxy.

[0013] Process b) may be effected in conventional manner for catalytic hydrogenation in order to produce a compound of formula Ia wherein the double bond adjacent to

has the cis configuration. Alternatively, the process may be effected in conventional manner for a complex metal hydride reduction in order to produce a-compound of formula Ia wherein the double bond has the trans configuration.

[0014] The catalytic hydrogenation may be effected in a solvent, e.g. methanol, ethanol, methylene chloride, pyridine or ethyl acetate. The catalyst is preferably palladium on a carrier material such as BaSO₄ or CaC0₃. The catalyst may be pretreated, e.g. with a lead salt, so as to be partially poisoned (e.g. a Lindlar catalyst). The hydrogenation may be effected at room temperature and at normal pressure.

[0015] The metal hydride reduction may be effected in conventional manner for a lithium aluminium hydride or a diisobutylaluminium hydride reduction. The reduction is conveniently effected in an inert solvent such as toluene or benzene. The reaction is conveniently effected at room temperature.

[0016] Process c) may be effected in conventional manner for a photochemical isomerisation of a cis alkene. The reaction may be effected in a solvent such as benzene, petroleum ether, ethanol, or preferably cyclohexane. The solution is conveniently irradiated with light from a mercury high or low pressure lamp. The reaction is conveniently effected at room temperature. If desired, an appropriate sensitizer such as eosine or a catalyst such as diphenyldisulphide may be present.

[0017] Process d) may be effected in manner conventional for the "alkylation" of secondary amines (the term "alkylation" being used here to denote introduction of any of the hydrocarbyl groups RQ^I), for example by direct "alkylation" with an "alkylating" agent, for example a. halide or sulphate, or by reductive alkylation, in particular by reaction with an appropriate aldehyde and subsequent or simultaneous reduction. Reductive "alkylation" is suitably effected in an inert organic solvent, such as a lower alkanol, e.g. methanol, and at an elevated temperature, in particular at the boiling temperature of the reaction medium. The subsequent reduction may be effected with, for example, a complex metal hydride reducing agent, e.g. NaBH₄ or LiAlH₄. The reduction may also be effected simultaneously to the alkylation, for example by use of formic acid which may serve both as reducing agent and as a reaction medium.

[0018] It is to be appreciated that in any of the above processes, side reactions may occur, e.g. reduction of halogen to hydrogen, reduction of a nitro group to an amino group, reduction of an alkenyl moiety to an alkyl moiety and/or reduction of a keto moiety to a carbinol moiety in processes b) or process d) when reductive alkylation is used, or simultaneous cis/trans isomerisation of any double bond present in R₄ or R₆ when process c) is used. The reaction conditions should be chosen to avoid such side reactions, and the desired final product isolated using conventional purification techniques, e.g. thin layer chromatography.

[0019] Free base forms of the compounds of formula I may be converted into salt forms and vice versa. Suitable acids for acid addition salt formation include hydrochloric acid, fumaric acid and naphthalene-l,5-disulphonic acid.

[0020] The starting materials are either known or may be made in conventional manner. For example non-cyclic amines of formula IV may be made by condensing a compound of. formula VIII,

or the corresponding iodide or chloride, with a compound of formula

[0021] The cyclic amines of formula IV may be made as follows:-

wherein Alk = lower alkyl.

[0022] The compounds of formula VI are new and may be made by reacting an appropriate amine of formula IV with compounds of formulae R₅-CHO and HC≡CR

under Mannich reaction conditions.

[0023] The compounds of formula VII are also new and may be made as follows:-

[0024] In the following Examples all temperatures are uncorrected and in degrees Centigrade.

[0025] In the tables hereinafter, the following indications are used:-

1) All double bonds have the trans configuration; all alkyl groups are unbranched unless stated otherwise.

2) If no melting point is given, the free base form of the compound is obtained and this is an oil. Melting points are for the free base form unless specified otherwise.

3) Monohydrochloride salt form.

4) Dihydrochloride salt form.

EXAMPLE 1: 4-[N-methyl-N-(1-naphthylmethyl))aminocrotonic acid ethyl ester [process a)]

[0026] 1.9 g of bromocrotonic acid ethyl ester are added dropwise to a mixture of 1.7 g of N-methyl-N-(1-naphthylmethyl)amine, 1.4 g of K₂CO₃ and 10 ml dimethylformamide. After the mixture is stirred for 18 hours at room temperature, it is filtered and evaporated under a vacuum. The residue is chromatographed on silica-gel using benzene/ethyl acetate (1:1) as solvent to yield the title compound in free base form, as an oil,after evaporating the appropriate fractions.

[0027] The title compound may also be made in analogous manner to Examples 3, 4 and 5.

EXAMPLE 2: N-(3-cyclohex-1-en-1-yl-2-cis-propenyl)-N-methyl-N-(1-nanhthylmethyl)amine [process b)]

[0028] 5 g of N-(3-cyclohex-l-en-l-yl-propynyl)-N-methyl-N-(l-naphthylmethyl)amine are hydrogenated in absolute pyridine using 750 mg Pd/BaS0₄ as catalyst at room temperature and normal pressure, until the calculated amount of hydrogen is taken up. The reaction mixture is filtered and the pyridine removed in a vacuum. The residue is chromatographed on silica-gel using benzene/ethylacetate (9_:1) to yield the title compound in free base form as an oil after evaporating the appropriate fractions, m.p. (hydrochloride) 184-188°.

[0029] The title compound may also be made in analogous manner to Examples 1 and 5.

EXAMPLE 3: N-(3-cyclohexyl-2-trans-propenyl)-N-methyl-N-(1-naphthylmethyl)amine [process b)]

[0030] 28 ml of a 1.2 molar solution of diisobutylaluminium hydride in toluene are added to 5 g of N-(3-cyclohexyl- propynyl)-N-methyl-N-(1-naphthylmethyl)amine in absolute benzene. After the mixture is stirred for 3 hours at 40°, water is carefully added. The organic phase is separated off, dried and evaporated to yield the title compound in free base form, as an oil.

[0031] The title compound may also be prepared by following Examplesl, 4 and 5.

EXAMPLE 4: N-(3-cyclohex-1-en-1-yl-2-trans-propenyl)-N-methyl-N-(1-nanhthylmethyl)amine [process c)]

[0032] 1.2 g of N-(3-cyclohex-1-en-1-yl-2-cis-propenyl)-N-methyl-N-(1-naphthylmethyl)amine are irradiated for 3 hours with a Hg high pressure lamp (λ) 300 nm) in 1 litre cyclohexane in the presence of 50 mg diphenyldisulphide at room temperature under an inert gas atmosphere. After the solvent is evaporated, the title compound is obtained in free base form and converted into the hydrochloride, m.p. 184-188°

[0033] The title compound may also be prepared by following Examples 1, 3 and 5.

EXAMPLE 5: N-methyl-N-[3-(5'-methyl-2'-thienyl)-2-trans- propenyl)-N-(1-naphthylmethyl)amine [process d)]

[0034] 

a) 15.2 g of 3-(5'-methyl-2'-thienyl)prop-2-enal and 15.7 g of 1-aminomethylnaphthalene in 350 ml benzene are boiled under reflux until the calculated amount of water has boiled off. 3.6 g of the resulting Schiff base in 100 ml methanol are boiled under reflux with 5 g NaBH₄ for 30 minutes to yield N-[3-(5'-methyl-2'-thienyl)-2-trans-propenyl)]-N-(l-naphthylmethyl)amine, which is used directly in the next stage. [To isolate this intermediate the reaction mixture is evaporated in a vacuum; the residue is partitioned between aqueous sodium carbonate solution and diethyl ether and the organic phase is evaporated].

b) The crude reaction mixture obtained in step a) is treated with 20 ml 37% aqueous formaldehyde solution. The mixture is boiled under reflux for 60 minutes, subjected to ice-cooling, treated with 9 g NaBH₄ and stirred for another 60 minutes at room temperature. The mixture is evaporated in a vacuum to a residue which is partitioned between aqueous NaHC0₃ and diethyl ether. The organic phase is dried and evaporated to yield the title compound in free base form as an oil, m.p. (hydrochloride) 140-156°.

[0035] The title compound may also be prepared in analogous manner to Examples 1, 3 and 4.

[0036] In analogous manner to that described in Examples 1, 3, 4 and 5, the following trans compounds of formula Ie may be produced:

wherein R₁ and R₆ are as follows:

[0037] In analogous manner to that described above for Examples 1, 3 and 4 there may be produced the following trans compounds of formula If,

wherein R₁, R₆ and u are as follows:

EXAMPLE 42:

[0038] In analogous manner to that described in Examples 1 and 2, the following cis compound of formula I may be produced:

aa) N-(3-cyclohex-1-en-1-yl-2-cis-propenyl)-2-(1'-naphthyl)-piperidine ; free base-oil.

EXAMPLES 43-47:

[0039] In analogous manner to that described in Examples 1, 3, 4 and 5, the following compounds of formula I may be produced:

43) N-cinnamyl-N-methyl-N-[2-(1'-naphthyl)-2-propyl)amine; free base-oil;

44) N-(1-acenaphthenyl)-N-methyl-N-(3-phenyl-2-trans- propenyl)amine, m.p. (hydrochloride) 210-216°;

45) N-(l-acenaphthenyl)-N-methyl-N-[3-(5'-methyl-2'-thienyl)-2-trans-propenyl)amine, free base-oil;

46) N-(6,7,8,8a-tetrahydro-1-acenaphthenyl)-N-methyl-N-(3-phenyl-2-trans-propenyl)amine, m.p. (hydrochloride) 185-192°;

47) N-methyl-N-(2,3-dihydro-l-phenalenyl)-N-(3-phenyl-2- trans-propenyl), free base-oil.

[0040] NMR data on the above-mentioned compounds of formula I, obtained as oils, are given in the following table. The data comprises peak position in ppm relative to TMS as standard in CDC1₃; type of peak (D = doublet; DD = double doublet; DT = double triplet; M = multiplet; Q = quartet; S = singlet; T = triplet) and in parentheses the corresponding number of hydrogen atoms.

[0041] The compounds of formula I exhibit chemotherapeutic activity. In particular, they exhibit antimycotic activity, as indicated in vitro with tests against various families and types of mycetes, including Trichophton quinkeanum, Aspergillus fumigatus, Microsporum canis, Sporotrychium schenkii and Candida albicans, at concentrations of, for example 0.1 to 100 pg/ml, and in vivo in the experimental skin mycosis model in guinea pigs. In the latter model, guinea pigs are infected by cutaneous application of Trichophyton quinkeanum. The test substance is administered daily for 7 days beginning 24 hours after the infection by local application by rubbing the test substance (taken up in polyethylene glycol) on the skin surface, or perorally, the test substance being administered as a suspension. The activity is shown on local application at concentrations of from example 0.1 to 2%, in particular 0.1 to 0.6%. The oral activity is shown at dosages of, for example, 50 to 100 mg/kg.

[0042] The compounds are therefore indicated for use as anti-mycotic agents. An indicated daily dose is from 500 to 2000 mg. If desired, this may be administered in divided doses 2 to 4 times a day in unit dosage form containing from about 125 mg to about 1000 mg or in sustained release form.

[0043] The compounds may be used in free base form or in the form of chemotherapeutically acceptable acid addition salts. Such salt forms exhibit the same order of activity as the free base forms.

[0044] The compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and, optionally, other excipients and administered in such forms as tablets or capsules. The compounds may alternatively be administered topically in such conventional forms as ointments or creams. The concentration of the active substance in such topical application forms will of course vary depending on the compound employed, the treatment desired and the nature of the form etc. In general, however, satisfactory results are obtained at concentrations of from 0.05 to ₃, in particular 0.1 to 1 wt %.

[0045] A compound with particularly interesting activity is the compound of Example 4.

[0046] One group of compounds has a formula Ig,

wherein

is 1-naphthyl, optionally mono-substituted by lower alkyl or alkoxy,

u is a whole number from 1 to 8,

is of formula







wherein R₁₉ is hydrogen, hydroxy, lower alkoxy or lower alkyl, or of formula

wherein R₂₀ is alkyl (C_1-12) or phenylalkyl-(C_7-12) or of formula

or

wherein m, n and v are as defined above.

[0047] Another group of compounds comprises those of formula Ih,

wherein

is a radical of formula IIa, IIb wherein X is oxygen or sulphur, IIc, IId wherein s is 4, IIe wherein t is 3 or a radical of formula

wherein R₉ is as defined above,

R₂ and R₅ are independently hydrogen or lower alkyl,

^u is a whole number from 1 to 8,

is as defined above for R₆,

with the following provisos,

(a) R₁₀ is other than phenyl or phenylalkoxy, and

(b) when

is 1-naphthyl optionally mono-substituted by lower alkyl or alkoxy and R₂ and R₅ are each hydrogen, R^III₆ is other than

(i) a radical of formula IIIa, IIIb or IIIf,

(ii) a radical of formula IIIc, IIId or IIIe, wherein R₁₁, R₁₂ and R₁₃ are each hydrogen, or

(iii) a radical of formula IIIg wherein one of R₁₇ and R₁₈ is hydrogen and the other is hydroxy, lower alkyl or lower alkoxy, or

(iv) an optionally substituted thiophen or furan radical.

[0048] A further group of formula I compounds comprises compounds of formula Ii,

wherein R^III₁ is a radical of formula IIa, IIb wherein X is oxygen or sulphur, IIc, IId wherein s is 4, IIe wherein t is 3, or a radical of formula

^R₂, R₃, R₄, R₅ and R₉ are as defined above, with the proviso that R₃ and R₄ are other than -(CH₂)₁₁-,

is as defined above for R₆ with respect to formula I, with the following provisos

(i) R₁₀ is other than phenyl or phenylalkoxy and

(ii) when R₁ is a radical of formula IIa,

is other than a radical of formula IIIg, or phenyl.

Claims

1. A compound of formula I,

wherein a)(i) R₁ is a radical of formula IIa,

wherein R₇ and R₈, independently, are hydrogen, halogen of atomic number from 9 to 53,trifluoromethyl, hydroxy, nitrc, lower alkyl or lower alkoxy, or a radical of formula IIb, IIc, IId, IIe,



wherein R₉ is hydrogen, halogen of atomic number from 9 to 53, hydroxy, lower alkyl or lower alkoxy, X is oxygen, sulphur, imino, lower alkylimino or a radical of formula -(CH₂)_r- wherein r is 1, 2 or 3, s is 3, 4 or 5, and t is 2, 3 or 4, and R₂ is hydrogen or lower alkyl, or

(ii) R₁ and R₂ together with the carbon atom to which they are bound form a radical of formula IIf or IIg,

wherein p is 1, 2 or 3, R₃ and R₅, independently, are hydrogen or lower alkyl, R₄ is alkyl (C_1-6), alkenyl (C_3-12), alkynyl (C_3-12) or cycloalkyl (C_3-8)-alkyl (C_1-6) ; and R₆ is (i) an aromatic, five-membered heterocycle containing one oxygen, sulphur or nitrogen hetero-ring atom and optionally an additional one or two nitrogen hetero-ring atoms and being optionally substituted on a carbon ring atom by halogen of atomic number from 9 to 53, hydroxy, lower alkyl or lower alkoxy, and any nitrogen ring atom present being optionally substituted when possible, by lower alkyl, (ii) a radical of formula IIIa,

wherein R₉ is as defined above, (iii) a radical of formula IIIb,

wherein R₁₀ is alkyl (C_1-12), alkenyl (C_3-12),-alkynyl (C_3-12) cycloalkyl (C_3-8)-alkyl (C_1-6), phenyl-alkyl (C_7-12), phenyl, phenylalkoxy (C_7-16), or aminoalkyl (C_1-12); (iv) a radical of formula IIIc, IIId or IIIe,

wherein R₁₁, R₁₂ and R₁₃, independently, are hydrogen or lower alkyl, m is a whole number from 0 to 4, n is a whole number from 0 to 3, and v is a whole number from 0 to 5, (v) a radical of formula IIIf,

wherein R₁₄ is lower alkyl, alkox^y (C_1-12)-carbonyl, alkenyl (C_3-12), alkynyl (C_3-12), phenylalkyl (C_7-12) or phenyl, ^R₁₅ and R₁₆, independently, are hydrogen or lower alkyl, and q is a whole number from 0 to 5, or (vi) a radical of formula IIIg

wherein R₁₇ and R₁₈, independently, are hydrogen, halogen of atomic number from 9 to 53, trifluoromethyl, hydroxy, nitro, lower alkyl or lower alkoxy, with the proviso that one of R₁₇ and R₁₈ is other than hydrogen, and with the general proviso that R₁ is not a radical of formula IIa when R₆ is a radical of formula IIIg or phenyl, R₂ is hydrogen and R₃ is hydrogen or lower alkyl,

b) R₁ is a radical of formula IIa to IIe, as defined above,
R₂, R₅ and R₆ are as defined above, and R₃ and R₄ together are -(CH₂)_u - wherein u is a whole number from 1 to 8, or an acid addition salt thereof.

2. A process for the production of a compound as claimed in Claim 1, which comprises

a) reacting a compound of formula IV,

wherein R₁ to R₄ are as defined above, with a compound of formula V,

wherein A is a leaving group, and R₅ and R₆ are as defined above, or

b) producing a compound of formula Ia,

wherein R₁ to R₃ and R₅ are as defined above, and

and

are as defined above for R₄ and R₆ respectively, with the proviso that they each are other than alkynyl, by reducing a compound of formula VI,

wherein R₁ to R₃,

R₅ and

are as defined above, or

c) producing a compound of formula Ib,

wherein R₁ to R₆ are as defined above, by isomerising photochemically a compound of formula Ic,

wherein R₁ to R₆ are as defined above, or

d) producing a compound of formula Id,

wherein R₁, R₂, R₅ and R₆ are as defined above,

is hydrogen or lower alkyl,

is alkyl(C_1-6), alkenyl(C_3-12), alkynyl (C_3-12) or cycloalkyl (C_3-8) alkyl( C_1-6); by introducing the group

into a compound of formula VII,

wherein R₁, R₂,

R₅ and R₆ are as defined above.

3. A compound of Claim 1, having the formula Ig,

wherein

is 1-naphthyl, optionally mono-substituted by lower alkyl or alkoxy, u is a whole number from 1 to 8,

is of formula







wherein R₁₉ is hydrogen, hydroxy, lower alkoxy or lower alkyl, or of formula

wherein R₂₀ is alkyl (C_1-12) or phenylalkyl-(C_7-12) or of formula

or

wherein m, n and v are as defined in Claim 1.

4. A compound of Claim 1, having the formula Ih,

wherein

is a radical of formula IIa, IIb wherein X is oxygen or sulphur, IIc, IId wherein s is 4, IIe wherein t is 3 or a radical of formula

wherein R₉ is as defined in Claim 1, R₂ and R₅are independently hydrogen or lower alkyl, u is a whole number from 1 to 8,

is as defined in Claim 1 for R₆, with the following provisos,

(a) R₁₀ is other than phenyl or phenylalkoxy, and

(b) when

is 1-naphthyl optionally mono-substituted by lower alkyl or alkoxy and R₂ and R₅ are each hydrogen,

is other than

(i) a radical of formula IIIa, IIIb or IIIf,

(ii) a radical of formula IIIc, IIId or IIIe, wherein R₁₁, R₁₂ and R₁₃ are each hydrogen, or

(iii) a radical of formula IIIg wherein one of R₁₇ and R₁₈ is hydrogen and the other is hydroxy, lower alkyl or lower alkoxy, or

(iv) an optionally substituted thiophen or furan radical.

5. A compound of Claim 1 having the formula Ii,

wherein

is a radical of formula IIa, IIb wherein X is oxygen or.sulphur, IIc, IId wherein s is 4, IIe wherein t is 3, or a radical of formula

R₂, R₃, _R4, R₅ and R₉ are as defined in Claim 1, with the proviso that R₃ and R₄ are other than -(CH₂)_u-,

is as defined in Claim 1 for R₆ with respect to formula I, with the following provisos

(i) R₁₀ is other than phenyl or phenylalkoxy and

(ii) when R₁ is a radical of formula I_Ia,

is other than a radical of formula IIIg, or phenyl.

6. A compound of Claim 1 which is N-(3-cyclohexyl-2-trans-propenyl)-N-methyl-N-(l-naphthylmethyl)amine.

7. A pharmaceutical composition comprising a compound of any one of Claims 1, and 3 to 6 in free base form or in chemotherapeutically acceptable acid addition salt form in association with a chemotherapeutically acceptable diluent or carrier.