EP0000896A2 - Propenyl amines, processes for their production and pharmaceutical compositions containing them - Google Patents

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

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EP0000896A2
EP0000896A2 EP78100611A EP78100611A EP0000896A2 EP 0000896 A2 EP0000896 A2 EP 0000896A2 EP 78100611 A EP78100611 A EP 78100611A EP 78100611 A EP78100611 A EP 78100611A EP 0000896 A2 EP0000896 A2 EP 0000896A2
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formula
radical
hydrogen
compound
lower alkyl
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German (de)
French (fr)
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EP0000896B1 (en
EP0000896A3 (en
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Helmut Dr. Hamberger
Adrian Dr. Stephen
Anton Dr. Stütz
Peter Dr. Stütz
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Sandoz AG
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Sandoz AG
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Priority claimed from CH1020377A external-priority patent/CH632251A5/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms

Definitions

  • This invention relates to propenyl-amines, processes for their production and pharmaceutical compositions containing them.
  • the present invention provides a compound of formula I,
  • 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.
  • 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 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.
  • R 4 is cycloalkylalkyl this is especially cyclopentyl alkyl or cyclohexylalkyl.
  • R 10 is cycloalkylalkyl this is especially cyclopropylalkyl or cyclobutylalkyl.
  • R 7 and R 8 are identical and are both hydrogen.
  • R 9 is hydrogen or halogen.
  • IIb and IIc the bond to the carbon atom to which R 2 and R 3 are attached is conveniently attached meta to X and para to the ring nitrogen, respectively.
  • X is conveniently sulphur, imino or lower alkylamino.
  • R 1 is preferably a radical of formula IIb, IIc or IId or especially IIa.
  • R 2 is preferably hydrogen.
  • R 3 is preferably hydrogen and R 4 is conveniently alkyl.
  • R 5 is conveniently hydrogen.
  • R 6 when it is a heterocycleconveniently contains one oxygen or sulphur atom or one or two nitrogen atoms.
  • the bond linking R 6 to the vinylene moiety is attached to a ring carbon atom adjacent to a ring heteroatom.
  • the ring is unsubstituted or substituted by lower alkyl.
  • R 10 is conveniently phenylalkoxy. IIa is conveniently optionally substituted 2 or 4-pyridyl.
  • IIIc is preferably a cycloalk-1-en-1-yl radical.
  • R 11 to R 13 are hydrogen.
  • q is conveniently 0 or 1.
  • R 14 is conveniently alkoxy (C 1-8 ) carbonyl, phenyl or alkyl or phenalkyl.
  • R 17 is conveniently halogen and R 18 is conveniently hydrogen.
  • R 6 is conveniently IIIc.
  • u is conveniently 3, 4 or 5, more conveniently 4.
  • m, n, p, q, s, t and v are conveniently chosen to produce a five or six-membered ring.
  • the double bond between R 6 and the nitrogen atom preferably has the trans configuration.
  • Halogen is conveniently fluorine, or preferably bromine or chlorine.
  • R 1 is IIb or IIe and R 6 is IIIa it is to be appreciated that the two radicals R 9 may be the same or different.
  • the present invention also provides a process for the production of a compound of formula I, which comprises
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 BaSO 4 or CaC0 3 .
  • 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.
  • 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.
  • 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.
  • an appropriate sensitizer such as eosine or a catalyst such as diphenyldisulphide may be present.
  • 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. NaBH 4 or LiAlH 4 .
  • a complex metal hydride reducing agent e.g. NaBH 4 or LiAlH 4 .
  • 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.
  • 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 R 4 or R 6 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.
  • 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.
  • 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
  • the compounds of formula VI are new and may be made by reacting an appropriate amine of formula IV with compounds of formulae R 5 -CHO and HC ⁇ CR under Mannich reaction conditions.
  • the title compound may also be made in analogous manner to Examples 3, 4 and 5.
  • the title compound may also be made in analogous manner to Examples 1 and 5.
  • the title compound may also be prepared by following Examplesl, 4 and 5.
  • the title compound may also be prepared by following Examples 1, 3 and 5.
  • the title compound may also be prepared in analogous manner to Examples 1, 3 and 4.
  • NMR data on the above-mentioned compounds of formula I, obtained as oils, are given in the following table.
  • the compounds of formula I exhibit chemotherapeutic activity.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 %.
  • a compound with particularly interesting activity is the compound of Example 4.
  • One group of compounds has a formula Ig,
  • Another group of compounds comprises those of formula Ih,
  • a further group of formula I compounds comprises compounds of formula Ii, wherein R III 1 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 R 2 , R 3 , R 4 , R 5 and R 9 are as defined above, with the proviso that R 3 and R 4 are other than -(CH 2 ) 11 -, is as defined above for R 6 with respect to formula I, with the following provisos

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Quinoline Compounds (AREA)
  • Furan Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

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

Description

  • This invention relates to propenyl-amines, processes for their production and pharmaceutical compositions containing them.
  • The present invention provides a compound of formula I,
    Figure imgb0001
    • wherein a)(i) R1 is a radical of formula IIa,
      Figure imgb0002
      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,
      Figure imgb0003
      Figure imgb0004
      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,
      Figure imgb0005
      wherein p is 1, 2 or 3, R3 and R5, independently, are hydrogen or lower alkyl, R4 is alkyl (C1-6), alkenyl (C3-12)' alkynyl (C3_12) or cycloalkyl (C3-8)-alkyl (C1-6); 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,
      Figure imgb0006
      wherein R9 is as defined above,
    • (iii) a radical of formula IIIb,
      Figure imgb0007
      wherein R10 is alkyl (C1-12), alkenyl (C3-12), alkynyl (C3-12) cycloalkyl (C3-8) alkyl (C1-6), phenyl-alkyl (C7-12), phenyl, phenylalkoxy (C7-16), or aminoalkyl (C1-12);
    • (iv) a radical of formula IIIc, IIId or IIIe,
      Figure imgb0008
      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,
      Figure imgb0009
      wherein R14 is lower alkyl, alkoxy (C1-12)-carbonyl, alkenyl (C3-12), alkynyl (C3-12), phenylalkyl (C7-12) 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
      Figure imgb0010
      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.
  • Any lower alkyl or lower alkoxy radical has preferably 1 to 4 carbon atoms, especially 2 or 1 carbon atoms. Any alkyl(C1-12) 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.
  • 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.
  • 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 R 13 may be attached to any of the ring carbon atoms present. IIIc is preferably a cycloalk-1-en-1-yl radical. Preferably R 11 to R 13 are hydrogen. q is conveniently 0 or 1.
  • Any double bond in IIIf is conveniently trans. R14 is conveniently alkoxy (C1-8) 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.
  • The values m, n, p, q, s, t and v are conveniently chosen to produce a five or six-membered ring.
  • The double bond between R6 and the nitrogen atom preferably has the trans configuration.
  • Halogen is conveniently fluorine, or preferably bromine or chlorine.
  • 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.
  • 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,
      Figure imgb0011
      wherein R1 to R4 are as defined above, with a compound of formula V,
      Figure imgb0012
      wherein A is a leaving group, and R5 and R6 are as defined above, or
    • b) producing a compound of formula Ia,
      Figure imgb0013
      wherein R1 to R3 and R5 are as defined above, and
      Figure imgb0014
       and
      Figure imgb0015
       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,
      Figure imgb0016
      wherein R1 to R3,
      Figure imgb0017
       R5 and
      Figure imgb0018
       are as defined above, or
    • c) producing a compound of formula Ib,
      Figure imgb0019
      wherein R1 to R6 are as defined above, by iscmerising photochemically a compound of formula Ic,
      Figure imgb0020
      wherein R1 to R6 are as defined above, or
    • d) producing a compound of formula Id,
      Figure imgb0021
      wherein R 1, R 2, R5 and R6 are as defined above,
      Figure imgb0022
       is hydrogen or lower alkyl,
      Figure imgb0023
       is alkyl (C1-6), alkenyl (C3-12), alkynyl (C3-12) or cycloalkyl(C3-8)alkyl (C1-6); by introducing the group
      Figure imgb0024
       into a compound of formula VII,
      Figure imgb0025
      wherein R1, R2,
      Figure imgb0026
       R5 and R6 are as defined above.
  • 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.
  • 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
    Figure imgb0027
    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.
  • 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.
  • 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.
  • 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.
  • 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 RQI), 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.
  • 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.
  • 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.
  • 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,
    Figure imgb0028
    or the corresponding iodide or chloride, with a compound of formula
    Figure imgb0029
  • The cyclic amines of formula IV may be made as follows:-
    Figure imgb0030
    wherein Alk = lower alkyl.
  • 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
    Figure imgb0031
     under Mannich reaction conditions.
  • The compounds of formula VII are also new and may be made as follows:-
    Figure imgb0032
  • In the following Examples all temperatures are uncorrected and in degrees Centigrade.
  • 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)]
  • 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.
  • 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)]
  • 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°.
  • 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)]
  • 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.
  • 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)]
  • 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°
  • 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)]
    • 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°.
  • The title compound may also be prepared in analogous manner to Examples 1, 3 and 4.
  • In analogous manner to that described in Examples 1, 3, 4 and 5, the following trans compounds of formula Ie may be produced:
    Figure imgb0033
    wherein R1 and R6 are as follows:
    Figure imgb0034
    Figure imgb0035
  • In analogous manner to that described above for Examples 1, 3 and 4 there may be produced the following trans compounds of formula If,
    Figure imgb0036
    wherein R1, R6 and u are as follows:
    Figure imgb0037
    • EXAMPLE 42:
  • 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:
  • 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.
  • 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.
    Figure imgb0038
    Figure imgb0039
    Figure imgb0040
    Figure imgb0041
  • 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.
  • 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.
  • 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.
  • 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 %.
  • A compound with particularly interesting activity is the compound of Example 4.
  • One group of compounds has a formula Ig,
    Figure imgb0042
    • wherein
      Figure imgb0043
       is 1-naphthyl, optionally mono-substituted by lower alkyl or alkoxy,
    • u is a whole number from 1 to 8,
    • Figure imgb0044
       is of formula
      Figure imgb0045
      Figure imgb0046
      Figure imgb0047
      Figure imgb0048
      wherein R19 is hydrogen, hydroxy, lower alkoxy or lower alkyl, or of formula
      Figure imgb0049
      wherein R20 is alkyl (C1-12) or phenylalkyl-(C7-12) or of formula
      Figure imgb0050
      or
      Figure imgb0051
      wherein m, n and v are as defined above.
  • Another group of compounds comprises those of formula Ih,
    Figure imgb0052
    • wherein
      Figure imgb0053
       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
      Figure imgb0054
      wherein R9 is as defined above,
    • R2 and R5 are independently hydrogen or lower alkyl,
    • u is a whole number from 1 to 8,
    • Figure imgb0055
       is as defined above for R6,
    • with the following provisos,
      • (a) R10 is other than phenyl or phenylalkoxy, and
      • (b) when
        Figure imgb0056
         is 1-naphthyl optionally mono-substituted by lower alkyl or alkoxy and R2 and R5 are each hydrogen, RIII 6 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.
  • A further group of formula I compounds comprises compounds of formula Ii,
    Figure imgb0057
    wherein RIII 1 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
    Figure imgb0058
     R 2, R3, R4, R5 and R9 are as defined above, with the proviso that R3 and R4 are other than -(CH2)11-,
    Figure imgb0059
     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,
      Figure imgb0060
       is other than a radical of formula IIIg, or phenyl.

Claims (7)

1. A compound of formula I,
Figure imgb0061
wherein a)(i) R1 is a radical of formula IIa,
Figure imgb0062
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,
Figure imgb0063
Figure imgb0064
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,
Figure imgb0065
wherein p is 1, 2 or 3, R3 and R5, independently, are hydrogen or lower alkyl, R4 is alkyl (C1-6), alkenyl (C3-12), alkynyl (C3-12) or cycloalkyl (C3-8)-alkyl (C1-6) ; 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,
Figure imgb0066
wherein R9 is as defined above, (iii) a radical of formula IIIb,
Figure imgb0067
wherein R10 is alkyl (C1-12), alkenyl (C3-12),-alkynyl (C3-12) cycloalkyl (C3-8)-alkyl (C1-6), phenyl-alkyl (C7-12), phenyl, phenylalkoxy (C7-16), or aminoalkyl (C1-12); (iv) a radical of formula IIIc, IIId or IIIe,
Figure imgb0068
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,
Figure imgb0069
wherein R14 is lower alkyl, alkoxy (C1-12)-carbonyl, alkenyl (C3-12), alkynyl (C3-12), phenylalkyl (C7-12) or phenyl, R 15 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
Figure imgb0070
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,
Figure imgb0071
wherein R1 to R4 are as defined above, with a compound of formula V,
Figure imgb0072
wherein A is a leaving group, and R5 and R6 are as defined above, or
b) producing a compound of formula Ia,
Figure imgb0073
wherein R1 to R3 and R5 are as defined above, and
Figure imgb0074
 and
Figure imgb0075
 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,
Figure imgb0076
 wherein R1 to R3,
Figure imgb0077
 R5 and
Figure imgb0078
 are as defined above, or
c) producing a compound of formula Ib,
Figure imgb0079
wherein R1 to R6 are as defined above, by isomerising photochemically a compound of formula Ic,
Figure imgb0080
wherein R1 to R6 are as defined above, or
d) producing a compound of formula Id,
Figure imgb0081
wherein R1, R2, R5 and R6 are as defined above,
Figure imgb0082
 is hydrogen or lower alkyl,
Figure imgb0083
 is alkyl(C1-6), alkenyl(C3-12), alkynyl (C3-12) or cycloalkyl (C3-8) alkyl( C1-6); by introducing the group
Figure imgb0084
 into a compound of formula VII,
Figure imgb0085
wherein R1, R2,
Figure imgb0086
 R5 and R6 are as defined above.
3. A compound of Claim 1, having the formula Ig,
Figure imgb0087
wherein
Figure imgb0088
 is 1-naphthyl, optionally mono-substituted by lower alkyl or alkoxy, u is a whole number from 1 to 8,
Figure imgb0089
 is of formula
Figure imgb0090
Figure imgb0091
Figure imgb0092
Figure imgb0093
 wherein R19 is hydrogen, hydroxy, lower alkoxy or lower alkyl, or of formula
Figure imgb0094
wherein R20 is alkyl (C1-12) or phenylalkyl-(C7-12) or of formula
Figure imgb0095
or
Figure imgb0096
wherein m, n and v are as defined in Claim 1.
4. A compound of Claim 1, having the formula Ih,
Figure imgb0097
wherein
Figure imgb0098
 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
Figure imgb0099
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,
Figure imgb0100
 is as defined in Claim 1 for R6, with the following provisos,
(a) R10 is other than phenyl or phenylalkoxy, and
(b) when
Figure imgb0101
 is 1-naphthyl optionally mono-substituted by lower alkyl or alkoxy and R2 and R5 are each hydrogen,
Figure imgb0102
 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,
Figure imgb0103
wherein
Figure imgb0104
 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
Figure imgb0105
R2, R3, R4, R5 and R9 are as defined in Claim 1, with the proviso that R3 and R4 are other than -(CH2)u-,
Figure imgb0106
 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 IIa,
Figure imgb0107
 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.
EP78100611A 1977-08-19 1978-08-07 Propenyl amines, processes for their production and pharmaceutical compositions containing them Expired EP0000896B1 (en)

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CH1020377A CH632251A5 (en) 1977-08-19 1977-08-19 Process for preparing novel 2-naphthyl-substituted, cyclic, N-allylamine derivatives
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EP0024587A1 (en) * 1979-08-22 1981-03-11 Sandoz Ag Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals
EP0041293A1 (en) * 1980-05-30 1981-12-09 Akzo N.V. Biologically-active tricyclic amines, methods for their preparation and pharmaceutical compositions containing same
FR2500823A1 (en) * 1981-03-02 1982-09-03 Abbott Lab 1-Aminoalkyl- tetra:hydro-naphthalene derivs. - useful as adrenergic and dopaminergic stimulants and inhibitors
FR2520741A1 (en) * 1982-02-03 1983-08-05 Sandoz Sa NOVEL BENZOTHIOPHENE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS
EP0164697A2 (en) * 1984-06-09 1985-12-18 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
EP0254677A1 (en) * 1986-07-08 1988-01-27 Sandoz Ag Antimycotic 6-phenyl-2-hexen-4-ynamines
US4822822A (en) * 1985-11-01 1989-04-18 Mitsui Toatsu Chemicals, Inc. Benzylamine derivatives, and use thereof
US5334628A (en) * 1984-06-09 1994-08-02 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
US5935998A (en) * 1995-07-06 1999-08-10 Novartis Ag Use of all allylamine derivatives such as terbinafine, in the manufacture of a medicament for the treatment of helicobacter pylori infection or associated diseases
AU723758B2 (en) * 1996-08-01 2000-09-07 Dow Agrosciences Llc 4-substituted quinoline derivatives having fungicidal activity

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JPH03105465U (en) * 1990-02-16 1991-10-31
US6117884A (en) * 1997-07-31 2000-09-12 Daeuble; John 4-substituted quinoline derivatives having fungicidal activity
JP4509327B2 (en) * 2000-08-03 2010-07-21 ダイセル化学工業株式会社 Process for producing N, N-disubstituted-4-aminocrotonic acid ester
WO2007014130A2 (en) * 2005-07-21 2007-02-01 Nomir Medical Technologies, Inc. Near infrared microbial elimination laser system (nimels)
US20050197512A1 (en) * 2003-08-29 2005-09-08 Ulrich Beutler Purification process
GB0320312D0 (en) 2003-08-29 2003-10-01 Novartis Ag Purification process
MXPA06014026A (en) * 2004-07-02 2007-02-08 Warner Lambert Co Compositions and methods for treating pathological infections.
US20090082469A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched terbinafine
WO2017132912A1 (en) * 2016-02-03 2017-08-10 华东理工大学 Alkylamine with benzoalicyclic substituent and application thereof
CN108084125B (en) * 2016-11-23 2020-08-18 华东理工大学 Benzoheterocyclylalkylamines and their use

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Cited By (19)

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FR2462426A1 (en) * 1979-06-08 1981-02-13 Sandoz Sa NOVEL DERIVATIVE OF 2- (1-NAPHTHYL) PIPERIDINE, ITS PREPARATION AND ITS APPLICATION AS A MEDICINAL PRODUCT
EP0024587A1 (en) * 1979-08-22 1981-03-11 Sandoz Ag Propenylamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals
US4755534A (en) * 1979-08-22 1988-07-05 Sandoz Ltd. Propenylamines, pharmaceutical compositions containing them and their use as pharmaceuticals
EP0041293A1 (en) * 1980-05-30 1981-12-09 Akzo N.V. Biologically-active tricyclic amines, methods for their preparation and pharmaceutical compositions containing same
WO1981003490A1 (en) * 1980-05-30 1981-12-10 Akzo Nv Biologically-active tricyclic amines,methods for their preparation and pharmaceutical compositions containing same
FR2500823A1 (en) * 1981-03-02 1982-09-03 Abbott Lab 1-Aminoalkyl- tetra:hydro-naphthalene derivs. - useful as adrenergic and dopaminergic stimulants and inhibitors
US4737516A (en) * 1982-02-03 1988-04-12 Sandoz Ltd. Benzothienylallylamines processes for their production and their use as pharmaceuticals
FR2520741A1 (en) * 1982-02-03 1983-08-05 Sandoz Sa NOVEL BENZOTHIOPHENE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS
US5021458A (en) * 1984-06-09 1991-06-04 Kaken Pharmaceutical Co., Ltd. Amine derivatives and fungicides containing the same
EP0164697A3 (en) * 1984-06-09 1987-04-29 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
EP0164697A2 (en) * 1984-06-09 1985-12-18 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
US5106866A (en) * 1984-06-09 1992-04-21 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
US5200423A (en) * 1984-06-09 1993-04-06 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
US5334628A (en) * 1984-06-09 1994-08-02 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
USRE34770E (en) * 1984-06-09 1994-11-01 Kaken Pharmaceutical Co., Ltd. Amine derivatives, processes for preparing the same and fungicides containing the same
US4822822A (en) * 1985-11-01 1989-04-18 Mitsui Toatsu Chemicals, Inc. Benzylamine derivatives, and use thereof
EP0254677A1 (en) * 1986-07-08 1988-01-27 Sandoz Ag Antimycotic 6-phenyl-2-hexen-4-ynamines
US5935998A (en) * 1995-07-06 1999-08-10 Novartis Ag Use of all allylamine derivatives such as terbinafine, in the manufacture of a medicament for the treatment of helicobacter pylori infection or associated diseases
AU723758B2 (en) * 1996-08-01 2000-09-07 Dow Agrosciences Llc 4-substituted quinoline derivatives having fungicidal activity

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FI782446A (en) 1979-02-20
NZ188170A (en) 1981-05-01
IL55382A (en) 1981-12-31
JPS5441855A (en) 1979-04-03
MY8500040A (en) 1985-12-31
CA1111852A (en) 1981-11-03
PT68448A (en) 1978-09-01
ES472641A1 (en) 1979-10-16
US4680291A (en) 1987-07-14
IT1098253B (en) 1985-09-07
DK152114B (en) 1988-02-01
IT7826835A0 (en) 1978-08-18
DE2862103D1 (en) 1982-11-18
IL55382A0 (en) 1978-10-31
IE47314B1 (en) 1984-02-22
FI65774B (en) 1984-03-30
IE781670L (en) 1979-02-19
JPS6317050B2 (en) 1988-04-12
FI65774C (en) 1984-07-10
EP0000896B1 (en) 1982-10-13
EP0000896A3 (en) 1979-05-30
DK354678A (en) 1979-02-20
DK152114C (en) 1988-06-20

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