CA1136635A - Basic ethers, pharmaceutical preparation thereof and processes for preparing them - Google Patents

Basic ethers, pharmaceutical preparation thereof and processes for preparing them

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Publication number
CA1136635A
CA1136635A CA000336319A CA336319A CA1136635A CA 1136635 A CA1136635 A CA 1136635A CA 000336319 A CA000336319 A CA 000336319A CA 336319 A CA336319 A CA 336319A CA 1136635 A CA1136635 A CA 1136635A
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Prior art keywords
methyl
phenyl
imidazolyl
formula
chlorophenoxy
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Joachim Gante
Hans-Adolf Kurmeier
Dieter Orth
Helmut Prucher
Volkmar Rudolf
Helmut Wahlig
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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  • Pain & Pain Management (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

ABSTRACT OF THE DISCLOSURE

Ethers of the formula wherein G is an unsubstituted phenyl or benzyl group, a phenyl or benzyl group which is monosubstituted or disubstituted by halogen, or alkyl of 1 - 6 C atoms; Z is 1-imidazolyl or 2-methyl-1-imidazolyl;
A is -CH=CR -, -CO-CHR1 -, -CHOH-CHR1 - or CH2-CHR2 -; n is 1, 2 or 3; R1 is H or alkyl of 1 - 4 C atoms; and, R2 is alkyl of 1 - 4 C atoms, and the physiologically acceptable acid addition salts thereof have valuable pharmacological properties.

Description

1136~

The present invention relates to the preparation of new basic ethers having valuable pharmacological properties, and to the basic ethers so produced.
Similar compounds have been disclosed in German Offenlegungs-schrift 2,510,781.
It is an object of one aspect of this invention to provide novel compounds which can be used for the preparation of medicaments, e.g., having anti-mycotic properties.
By one aspect of this invention, new compounds are provided of formula (I):

G-O ~ A-tCH2) -Z

wherein G is an unsubstituted phenyl or benzyl group, a phenyl or benzyl group which is monosubstituted or disubstituted by halogen, or alkyl of 1 - 6 C atoms; Z is l-imidazolyl or 2-methyl-1-imidazolyl; A is -CH=CRl-, -CO-CHR , -CHOH-CHR - or CH2-CHR -; n is 1, 2 or 3; R is H or alkyl of 1 - 4 C atoms; and R2 is alkyl of 1 - 4 C atoms, and the physiologically acceptable acid addition salts thereof.
For all of the aforementioned radicals, alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, , . -- 1 --~ 3 1~3~35 -preferably methyl or ethyl. Furthermore, in the group G, alkyl can also be, for example: 1-, 2- or 3-pentyl, 2-methyl-1-butyl, isopentyl (3-methyl-1-butyl), 3-methyl-2-butyl, tert.-pentyl, neopentyl, 1-, 2- or 3-hexyl, 2-methyl-1,-2-or -3-pentyl, isohexyl (4-methyl-1-pentyl), 4-methyl-2-pentyl, 3-methyl-1-, -2- or -3-pentyl, 2-ethyl-1-butyl, 2,3-dimethyl-1- or -2-butyl, 2,2-dimethyl-l-butyl or 3,3-dimethyl-1- or -2-butyl.
Halogen is understood to mean preferably chlorine but it can also be fluorine, bromine or iodine.

In particular, Rl is preferably H or methyl and R2 is preferably methyl.
G is preferably an unsubstituted phenyl or benzyl group or a phenyl or benzyl group which is monosubstituted or disubstituted by halogen, especially chlorine. Specifically, G is preferably phenyl, p-chlorophenyl or 2,4-dichlorophenyl, or also benzyl, p-chlorobenzyl or 2,4-dichlorobenzyl or, furthermore, G can be, for example, o-, m- or p-fluorophenyl, o- or m-chlorophenyl, o-, m-or p-bromophenyl, o-, m- or p-iodophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,S-difluorophenyl, 2,3-, 2,5-, 2,6-, 3,4- or 3,5-dichloro-phenyl, dibromophenyl, e. g.. 2,4-dibromophenyl, diiodophenyl, e- g., 2,4-diiodophenyl, chloro-fluorophenyl, e. g., 2-fluoro-4-chlorophenyl or 2-chloro-4-fluoro-phenyl, o-, m- or p-fluorobenzyl, o- or m-chlorobenzyl, o-, m- or p-bromobenzyl, o-, m- or p-iodobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorobenzyl,
2,3-, 2,5-, 2,6-, 3,4- or 3,5-dichlorobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromobenzyl, dilodobenzyl, e. g-, 2,4-diiodo-benzyl, chloro-fluoro-benzyl, e- g-, 2-fluoro-4-chloro-benzyl or 2-chloro-4-fluoro-benzyl, or bromo-chlorobenzyl, e- g., 2-bromo-4-chloro-benzyl or 2-chloro-4-bromo-benzyl. Generall~
the substitution on the phenyl or benzyl group ls preferably in the p-position(s). G is also preferably methyl, ethyl or `` ~136635 branched alkyl, e. g. ~ isopropyl, isobutyl, most preferably iso~entyl or isohexyl.
A is preferably -cH=CRl or -cH2-cHR2- and specifically is in particular the following:
-CH=CH-, -CH=C(CH3)-, -CO-CH2-, -CO-CH(CH3)-, -CHOH-CH2-, -CHOH-CH(CH3)- or -CH2-CH(CH3)-.
The parameter n preferably has a..value of 1 or 2, most preferably 1.
Accordingly, the invention relates in particular to those compounds of the formula (I) in which at least one of G, A and Z
and/or the parameter n has one of the preferred meanings indicated above. Some of the preferred groups of compounds can be expressed by the following partial formulae Ia - Ih, which correspond to formula (I) and in which the residues which are not specified in detail have the meaning indicated above under formula (I), but wherein:
in Ia, G is phenyl, chlorophenyl or alkyl of 1 - 6 C atoms, n is 1 and Rl and R2 are each alkyl of 1 - 4 C atoms;
in Ib, G is phenyl or chlorophenyl, n is 1 and Rl and R2 are the same and each is alkyl of 1 - 4 C atoms;
in Ic, G is alkyl of 1 - 6 C atoms, n is 1 and Rl and R2 are the same and each is alkyl of 1 - 4 C atoms;
in Id, G is phenyl, chlorophenyl, dichlorophenyl, dichloro-benzyl or alkyl of 1 - 6 C atoms, n is 1 or 2 and Rl and R2 are the same and each is alkyl of 1 - 4 C atoms;
in Ie, G is phenyl, p-chlorophenyl, 2,4-dichlorophenyl;

:

2,4-dichlorobenzyl or alkyl of 1 - 5 C atoms, n is 1 or 2, Rl is H or methyl and R is methyl;
in If, Z is 2-methyl-1-imidazolyl;
in Ig, G is phenyl, p-chlorophenyl or isopentyl, A is -CH=CH-, -CH=C(CH3)-, -CO-CH2-, -CO-CH(CH3)-, -CHOH-CH2-, -CHOH-CH(CH3)- or -CH2-CH(CH3), Z is l-imidazolyl or 2-methyl-1-imidazolyl and n is 1; and in Ih, G is phenyl or p-chlorophenyl, A is -CH=CH-, -CH=C(CH3)- or -CH2CH(CH3)-, Z is l-imidazolyl and n is 1.
The invention in another aspect also relates to a process for the preparation of compounds of formula (I) and their physiologically acceptable acid addition salts, comprising:
(a) reducing a compound of the formula G_~A (CH2)n-1 CO Z

wherein G, Z, A and n are as above;
(b) solvolyzing a compound of the formula G--O~C~ (CH2 )~!1--Z

wherein L is OLi, OMgBr, ONgCl or OAc, Ac is alkanoyl, aroyl, alkylsulfonyl or arylsulfonyl of up to 10 carbon atoms each and G, Z, n and Rl are as above;
(c) reacting a compound of the formula G-O~A-(C~I2)n-X

wherein X is Cl, Br, I or OH and G, A and n are as above with an imidazole of the formula H - Z
wherein Z is as above;
(d) dehydrating a compound obtained by any of (a) to (c) of the formula 1~36635 G-O~CHOH-~ 2)n~Z

wherein G, Z, n and R are as above;
(e) reducing a compound obtained by any of (a) to (d) of the formula G_~A (~H2)n Z

wherein A' is -CH=CR -, -CO-CHRl- or -CHOH-CHRl- and G, Z, n and R are as above; and (f) converting a base obtained by any of (a) to (e) to one of its physiologically acceptable acid addition salts by treatment with an acid.
Such preparations of the compounds of formula (I) are carried out by procedures which are known in the art, e.g., as are descrlbed in the literature ~for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), George-Thieme-Verlag, Stuttgart~ and in particular under the reaction conditions which are known and suitable for these reactions. Use can also be made of well-known variants which are not mentioned in any greater detailherein.
In all of the formulae in this specification, G, Z, A~
n Rl and R2, Q and X are as defined in formulae (I) to (III), unless expressly stated otherwise.
Some of the starting materials for the preparation of the compounds of formula (I~ are known. They can be prepared by processes which are known in the art. If desired, the starting materials can also be formed in situ, in such a way that they .

are not isolated from the reaction mixture but are immediately further reacted to give the compounds of formula (1).
The compounds of formula (I) are obtainable, for example, by reduction of the compounds of formula (Il). In particular, the secondary alcohols of formula (I) (A = -CHOH-CHR -) can advantageously be prepared in this manner.

- 5a -.~ .

Thus, in the compounds~ of formula (II), the residue Q
preferably is the group -A-(CH2)n-1~Y, wherein Y is CN, CONR R2, CH2NO2, CH2N3, CH2NRl-`W (wherein W is a benzyl group or another hydrogenolytically detachable radical), CH2N(W)2, CH-NOH, CHOH-NRlR , CH=NRl, CH2NR5 (wherein R5 is an alkylidene group with 1 - 4 C atoms) or another residue which can be reduced to the CH2NRlR group.
The residue Q can also be, for example: -CH2CR -R7 Lwherein R6 is an alkylidene group of 1 ~ 4 C atoms or H and an alkenyl group of up to 4 C atoms, and R7 is -tCH2)n_l'Y or -(CH2)n-Z)~, -CHoH-CR6-R7 or -CH2-CR4=CH-(CH2)n l-Z
~ As a rule, the starting materials of formula (II) are new; however, they can be prepared analogously to known processes.

Thus ketonitriles of the formula R-Co-CHR3-CN are obtain-able, for example, by Friedel-Crafts acylation of the.ethers of the formula R-H with acid chlorides of the formula Cl-CO-CH2R3 to give ketones of the formula R-Co-CH2R3 followed by subsequent bromination and reaction with KCN. Reduction of these ketonitriles with NaBH4 yields. the.hydroxynitriles of the formula R-CHOH-CHR -CN, from which, by dehydration, there can be obtained the unsaturated nitriles of the formula R-CH=CR3- CN, and by means of hydrolysis, there can be obtained the hydroxyacids. of the formula R-CHoH-CHR3-COOH; by dehydration of the hydroxyacids there can be obtained the unsaturated acids of the formula R-CH_CR3-CooH and by re-duction of these unsaturated acids, in which R3 = R4, there canbe obtained the saturated acids of the formula R-CH2-CHR4-CooH.
Ketones of the formula R-Co-CHR3-(CH2) -Cl can be prepared, for example, by Friedel-Crafts acylation of the ethers of the formula R-H with acid chlorides of the formula Cl-CO-CHR3-(CH2) -Cl.

.. ~ -6~

Acid amides of the formula R-CHoH-CHR3-Co-Z are obtainable~ for example, by Friedel-Crafts ac~lation or by Gattermann or Vils-meier reaction of the ethers of.the formula R-H to giye aldehydes of the formula R-CHO, subsequent Reformatski reaction wi.th es.ters of the formula Br-CHR3~COOC2H.5 to give hydroxy-es.ters of the formula R-CHOH-CHR -COOC2H5 and.then by the reaction of the latter with.bases of the formula HZ. The elimination of water results in unsaturated amides of.the formula R-CH-CR3-Co-Z and reduction (if R3 = R4) results in saturated amides of the formula R-CH2CHR4-Co-z. Reduction of the sai.d hydroxyesters (if R3 = R4) with HI results in acids of the formula R-CH2-CHR -COOH, saponification taking place at the same time., and these acids can be converted to th.e corresponding alcohols of the formula R-CH2-CHR -CH2OH using LiAlH4. Diols of the formula R-CHoH-CHR3-CH20H are obtainable by reduction of the afore-mentioned hydroxy-es.ters.with LiAlH4 and alcohols of the formula R-CH=CR3-CH20H are obtainable by dehydration and by sub.sequent reduction of the hydroxy-esters. The corresponding halides. can be prepared from these alcohols in a conventional manner~ for example using SOC12 or PBr3~ and these halides - like the above-mentioned ketones of the formula R-Co-CHR3-(CH2) -Cl- also can be converted to the corresponding nitro compounds of the formula R-A-CH2NO2 using alkali metal nitrites; to the azides of the formula R-A-CH2N3 using alkali metal azides; or to the amines of the formula R-A-CH2-NH-W or R-A-CH2N(W)2 using amines of the formula W-NH2 (for example benzylamine). or (W)2NH. Oxidation of the alcohols results in the corresponding aldehydes of the formula R-A-CHO, which can be converted to the corresponding oximes of the formula R~A-CH=NOH using hydroxylamine and to t-he corresponding aldehyde-ammonias of the formula R-A-CHOH-Z~ or imines of the formula R-A-CH=NR , using bases of the formula HZ. Unsaturated nitriles of the formula R-CH=CH-CN can also be prepared from the mentioned a.ldehydes of the formula R-CHO
and cyanoacetic acid. Reduction of the aldehydes yields the 5 corresponding alcohols of the formula R-CH2OH, which can be converted easily to the nitriles. of the formula R-~CH2-CN via the correspondlng bromides of the formula R-CH2Br. Reaction with organometallic compounds of the formula CH3M (wherein M
is Li, MgBr or MgCl) and hydrolysis of the reaction products yields ketones of the formula R CH2CO-CH3~ which can be converted to the aminoketones of the formula R~CH2-CO-CH2-Z by bromina-tion and subsequent reaction with a base of the formula H-Z.
These aminoketones can be converted to compounds of the formula R-CH=CH-CH2-z by reduction~ with the elimination of water.
Of the starting materials of formula (II)~ the ami.des of the formula R-A-CO-Z and the nitriles of the formula R-A-CN
are preferred.
The starting materials of formula (II) can~ for example, be converted to the compounds. of formula (I) by catalytic hydrogenation, with nascent hydrogen, with.complex metal hydrides or with help of other chemical reducing agents. The methods of reduction which are most suitable for the individual starting materials generally depend on the nature of the functional group Y
and are well known to those skilled in the art, from the.data given in the literature. Thus~ for example, nitri.les, amines of h formulae R-A-tCH2)n-NH-W or R-A (CH2)n 2 aldehyde-ammonias can preferably be hydrogenated catalytically.
Reduction of the acid amides~ on the other hand~ is preferably carried out with complex metal hydrides or with diborane.
Suitable catalysts for catalytic hydrogenation reacti.ons are, for example, noble metal, nickel or cobalt catalysts~ and 113f~63S

also mixed catalysts, such.as copper/chromium oxide. Noble metals whieh ean be used are in partieular platinum and palladium whieh ean be used on eatalyst earriers (for example~
on ehareoal, calcium carbonate or strontium carbonate), in the form of oxides (for example platinum oxide) or in finely divided form. Nickel and cobalt catalysts are preferably used in the form of Raney metals. The hydrogenation can preferably be earried out under pressures of between . 1 and 200 atmos-pheres and at temperatures of between -80 and ~150, most preferably between 20 and 100. The hydrogenation is earried out in the presenee of an lnert solvent, for example an aleohol~
e- g., methanol, ethanol or isopropanol; a earboxylic ~cid~
e. g., acetic acid; an ester~ e- g-, ethyl acetate; o.r of an ether, e- g-~ tetrahydrofuran (THF) or dioxane. Solvent mixtures can also be used~ for example, water-containing mixtures.
Furthermore, it can be advantageous to add a base, e. g., sodium hydroxide or potassium hydroxide or ammonia, during the hydro-genation reaetion, for example, durin~ the hydrogenation of nitriles.
Further reduein~ agents whieh ean be employed are complex metal hydrides, e-g-, LiAlH4~ NaBH4, or NaAl-(OcH2cH2Oc}~3) and also diborane, if desired, with the addition of catalysts e- g-- BF3, AlC13 or LiBr. Suitable solvents for this reaetion are in partieular ethers, e- g., diethyl ether~ THF, dioxane, 1,2-dimethoxyethane.or diglyme; and hydroearbons, e- 8-. benzene.
The reduetion of ketones is preferably earried out with NaBH4;
suitable solvents for this reaetion are, in partieular~ alcohols, e- g - methanol or ethanol~ or mixtures of these alcohols with THF. Using this procedure, the reduction is preferably carried out 1~36635 at temperatures between -80 and +150, and preferably between 20 and 120.
A further suitable method of reduction is the reaction with nascent hydrogen. This can be produced~ for example~ by treating metals with acids or bases. Thus~ for example, the systems zinc/acid, zinc/alkali metal hydroxide solution~ iron( acid or tin/acid can be used. Suitable acids are, for example, hydrochloric acid or acetic acid. An alkali metal, e- g., sodium, in an alcohol, e- g-, e,hanol, isopropanol~ n-butanol, amyl alcohol or isoamyl alcohol, or in phenol can also be used as the reducing agent~ and further reducing agents which can be used are, for example, an aluminum/nickel alloy in aqueous alkaline solution or aqueous-alcoholic alkaline solution~ and also sodium amalgam or aluminum amalgam in aqueous-alcoholic or aqueous solution. The reaction temperatures are between 0 and 150, preferabiy between 20 and 120.
The starting compounds of formula (II) can also be con-yerted to compounds of formula (Il by cathodic reductionr preferably in aqueous-alcoholic or aqueous-acetic acid medium.
Further suitable reducing agents are, for example, sodium dithionite in aqueous-alcoholic or alkaline solution and also iron-II hydroxide, tin-II chloride, hydrogen disulfide~ hydrogen sulfides, sulfides~ polysulfides and hydrazine, all of which are used in accordance with the conditions given in the literature for such reductions.
Selectiye reductions can also be effected by suitable choice of the reagents and reaction conditions. Thus, e.g., Schiff's bases R-CH=CR3-CH=NRl or R-CH=CR3-(CH2) -N=alkylidene (wherein the alkylidene group has 1 ~ 4 C atoms) can be reduced to the corresponding unsaturated amines using LiAlH4, -lQ- ~

- 1~3663S

The compounds of formula (I) are also obtainable by solvolysis, preferably hydrolysis, of starting materials which correspond to formula (I) but in which the amino group and/or the hydroxyl group is present in a functionally modified form.
The starting materials for the solvolysis reaction are as a rule new, but they can be prepared analogously to methods which are known in the art.
Such s.tarting materials include., for example~ acyl deri-vati~yes of the amines of formula (I), particularly the amides of the formula R-A-(CH2).n NR ~Ac (wherein Ac is any desired acyl radical, the nature of which.is not critical since it is detached during the solvolysis, but which preferably has 1 - 10 C atoms, for example alkanoylr aroyl~ alkylsulfonyl or arylsul-fonyl each with. up to 1~ C atoms, for example acetyl~ benzoyl~
meth~ulfonyl or p-toluenesulfonyl) e These amides are obtain-able, for example, by Friedel-Crafts alkylation of the ethers of the formula R-H with.halogeno-amides of the formula Cl-A-(CH2) -NRl-Ac or Br-A-(CH2)-n~NR -Ac.
Preferred starting materials, for the solvolysis reaction, in which the OH group is functionally modified~ correspond~ for example, to the general formula ~V) R-CHL-CHR -(CH2)n~Z IV
wherein L is a functi.onally mQdified OH group, expecially OM
or OAc.
These compounds.are~ for example, the correspondin~ alcoho-lates, especially the magnesium alcoholates or lithium alcoholates~
e. g. . are formed as reaction products in Grignard reactions or in reactions with organo-lithium compounds; and the esters (for example, the carboxylic acid esters~ in which the carboxylic acid radical preferably has. up to 7 C atoms, for example~ acetyl or --11-- ' 1~36635 benzoyl, or the alkyl- or aryl-sulfonic acid esters, in which the alkyl radical preferably contains 1-6 C atoms and the aryl radical preferably contains 6-10 C atoms); and also the ethers (for example the alkyl ethers, in which the alkyl group preferably contains up to 6 C atoms, the aryl ethers, in which the aryl group preferably contains 6-10 C atoms, and the aralkyl ethers, in which the aralkyl group preferably contains 7-11 C atoms); and the boric acid esters, which are formed as intermediates during oxidative hydroborination. Furthermore, a chlorine, bromine or iodine atom can be present in place of the hydroxyl group;
the compounds are then the corresponding hydrogen halide acid esters.
The above-mentioned magnesium alcoholates or lithium alcoholates are obtainable, for example, by reacting organo-metallic compounds of the formula R-M with aldehydes of the formula H-CO-CHR -(CH2)n~Z or by reacting aldehydes of the formula R-CHO
with organometallic compounds of the formula M-CHR -(CH2)n-Z, preferably in an ether, e- g-. diethyl ether or THF, as the solvent. Halides of the formulae R-CHCl-CHR -(CH2)n~Z or R-CHBr-CHR (CH2)n-Z can be prepared, for example, by halogenation of acid amides of the formula R-CH2-CHR -(CH2)n l-CO-Z and subsequent reduction with LiAlH4. The corresponding esters of the formula R-CH(OAc)-CHR3-(CH2)n~Z can be prepared from the halides by reaction with potassium acylates, for example, potas-sium acetate.
Solvolysis of these compounds is preferably effectedby the action of a solvent, e- g - water (hydrolysis) or an .alcohol with preferably 1-4 C atoms (alcoholysis), in the ,j : .
,: ,. ~ 1 .

presence of an acid or basic catalyst, for example, a mineral ~ . .
acid, e- g-, sulphuric acid or hydrochloric acid, a metal " ,~
hydroxide, e g~ ~ sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lead hydroxide or silver hydroxide, or a metal salt or ammonium salt, e- g~ ~ sodium carbonate or potassium carbonate, or ammonium chloride. The alcohols used are preferably methanol, ethanol or isopropanol and it is also possible to use mixtures of water with one of these alcohols. The solvolysis is preferably effected at temperatures between 0 and about 120.
Specifically, the above-mentioned amides are preferably hydrolyzed by boiling for several hours with aqueous, aqueous-alcoholic or alcoholic hydrochloric acid,sulphuric acid, sodium hyd~oxide solution or potassium hydroxide solution. The above-mentioned magnesium alcoholates are preferably~not isolatedbut, after they have been formed by the Grignard reaction, are.
hydrolyzed in situ with dilute acids, for example, sulphuric acid or hydrochloric acid, or with aqueous ammonium chloride solution. The above-mentioned halides and esters are preferably saponified in aqueous or aqueous-alcoholicsolution. or suspension, in which reaction, if desired, a solubilizing agent can be present, forexample, an alcohol, glycol or glycol ether. The saponify-ing agents used are preferably alkalis, e- g~ ~ NaOH or KOH.
The compounds of formula (I) are;also obtainable by reaction of a compound of the formula R-A-(CH2)n-X (III) with a compound of the formula H-Z or with a reactive derivative of such a compound. The starting materials of the formula(II~
include, for example, the above-mentioned ketones of the~formula R-CO-CHR -(CH2) -Cl. Other starting materials of the formula(II~

.

' can be prepared, for example, by reduction of these ketones to carbinols of the formula R-CHOH-CHR3-(CH2)n-Cl and, if desired, subsequent dehydration and/or reduction. The starting materials of the formula H-Z are known.
The reaction of compounds of formula(III)with compounds of the formula H-Z i5 carried out at temperatures between 0 and 250, preferably between 50 and 120, and under pressures of between 1 and 50 atmospheres. The reaction can be carried out in the presence of an inert solvent, for example, an alcohol, e. g-, methanol, ethanol, isopropanol or n-butanol; an ether, e. g-, diethyl ether, diisopropyl ether, THF or dioxane; a hydrocarbon, e g- ~ benzene, toluene or xylene;
an amide, e- g- ; dimethylformamide (DMF); or a sulfoxide, e- 8- ~
dimethylsulfoxide. If desired, a catalyst can be present, for example, sodium amide, which can also be produced in situ from sodium and liquid ammonia, and also bases, e. g-, sodium car-bonate, potassium carbonate, sodium bicarbonate or potassium bi-carbonate. It is also possible to use an excess of the compound of the formula H-Z as the solvent, preferably at the boiling tem-perature. X is preferably Cl, Br or I. If X is a reactivelyfunctionally modified OH group, it is preferably an alkyl- or aryl-sulfonyloxy group with in particular of up to 10 C atoms.
Secondary amines of the formula R-A-(CH2)n-NHRl (wherein Rl is alkyl with 1-4 C atoms) can also be prepared by heating alcohols of the formula R-A-(CH2)n-OH with alkylamines of the formula R -NH2 in the presence of Raney nickel.
If desired, a resulting hydroxy compound of the formula R-CHoH-CHR3-(CH2)n-Z can be dehydrated to the corres--ponding unsaturated compound of the formula R-CH=CR3-(CH2)n-Z, preferably by the action of an acid catalyst, e. 8-- hydro-1~36635 chloric acid, sulphuric acid or a sulfonic acid, e- g-, p-toluenesulfonic acid, in an inert solvent, for example, a hydrocarbon, e . g . ~ benzene or toluene, at temperatures between 0 and 150, preferably between 80 and 110. Dilute aqueous-ethanolic hydrochloric acid at 70-80C is preferably used for the dehydration of secondary alcohols; for the dehydra-tion of tertiary alcohols, on the other hand, 20% aqueous hydro-chloric acid, also with the addition of dioxane, is used, at 90-100. As a rule, the (more stable) trans forms (or E-forms) of the compounds of the formula I (A= -CH=CR3-) are formed in dehydration reaction.
- Resulting keto compounds of the formula R-CO-CHR -(CH2)n~Z can, if desired, be reduced to the corresponding hydroxy compounds of the formula R-CHOH-CHR3-(CH2)n-Z,~preferably using NaBH4 under the conditions indicated above.
Furthermore, if desired, resulting unsaturated compounds of the formula R-CH=CR3-(CH2)n~Z, keto compounds of the formula R-Co-CHR3-(CH2)n-Z or hydroxy compounds of the formula R-CHoH-CHR3-(CH2)n-Z, (wherein R3 = R4 in each case) can be reduced to the saturated compounds of the formula R-CH2-CHR -(CH2)n~Z. The reduction of the hydroxy compounds is effected, for example, with hydroiodic acid, preferably in acetic acid at temperatures between 20 and the boiling tem-perature, preferably at the boiling temperature. The keto compounds and the unsaturated compounds can preferably be hydrogenated catalytically under the conditions indicated a~ove, for example, in the presence of a noble metal cata-lyst, e. g. ~ palladium-on-charcoal, at room tcmperature and under normal pressure.

A resulting ba~e of formula (I) can be converted to the corresponding acid addition salt with an acid in the conventional manner. Acids suitable for this reaction are those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example, sulphuric acid, hydrogen halide acids, e- g-, hydrochloric or hydrobromic acid, phos-phoric acids, e g, orthophosphoric acid, nitric acid or sulfamic acid; or organic acids, specifically aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulphuric acids, e~ g- ~ formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- and ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxy-ethanesulfonic acid, benzenesulfonic acid, p-toluene-sulfonic acid, naphthalene-mono- and -disulfonic acids or laurylsulfuric acid.
If desired, the free bases of formula ~)can be libera-ted from their salts by treatment with strong bases such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate.
The compounds of formula (I) can contain one or more centers of asymmetry. In such case, they are usually present in racemic form. Resulting racemates can be resolved by methods which are known in the art, mechanically ~f~ ~

.

1~36635 or chemically, into their optical antipodes. Preferably, diastereomers are formed from the racemic mixture by reaction with an optically active separating agent. Suitable separating agents are, for example, optically active acids, e-g-, the D-and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyl-tartaric acid, mandelic acid, malic acid and lactic acid or the various optically active camphorsulfonic acids, e- g., B-camphorsulfonic acid.

Of course, it is a~so possible to obtain optically active compounds of formula (I) by the methods described above by using starting materials which are already optically active.
It has been found that the compounds of formula (I) possess valuable pharmacological properties coupled with good tolerances. In particular, they have anti-mycotic and anti-bacterial properties, for example, against Microsporum audouini, dermatophytes, e. g., Trichophyton rubrum and Trichophyton mentagrophytes, Histoplasma capsulatum, Aspergillus fumigatus, yeasts, e~ g , Candida albicans, Nocardia asteroides, Staphyl-ococcus aureus, Streptococcus pyogenes, Proteus vulgaris, Pseudomonas aeruginosa, Mycobacterium tuberculosis typus humanus, Mycobacterium ranae and/or Escherichia coli. The compounds are also effective against systemic mycoses, and against protozoa and especially against Trichomonadidae. These activities can be determined, for example, by the conventional agar dilution method in vitro, but also in vivo, for example, on mice, rats or rabbits.

1~36635 Furthermore, the compounds also exhibit antiphlo-gistic activity which can be demonstrated, for example, on rats in the adjuvant arthritis test by the method of Newbould (Brit. J. Pharmacol. 21, (1963) pages 127-136). The compounds also have an anti-arteriosclerotic activity, cholesterol ~13~635 level-lowering effects (which can be demonstrated in the serum of rats by the method of Levine et al, Automation in Analytical Chemistry, Technicon Symposium 1967, Mediad, New York, pages 25-28), and triglyceride level-lowering effects (which can be demonstrated by the method of Noble and Campbell, Clin.
Chem. 16 ~1970) pages 166-170). Furthermore, analgesic, anti-pyretic, enzyme-inducing, fibrinolytic and thrombocyte aggregation-inhibiting activities can be demonstrated by the methods commonly used for this purpose.
The compounds of formula (I) and their physiologically acceptable acid addition salts can therefore be used as medicinally active compounds and also as intermediate products for the pre-paration of other medicinally active compounds.
The invention also teaches the use of the novel compounds of formula (I) and of their physiologically acceptable acid addition salts for the preparation of pharmaceutical formu-lations, especially by a non-chemical route. For this purpose, the compounds can be brought, together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, optionally, in combination with one or more further active compounds, into a suitable dosage form.

The invention also provides agents, especially pharmaceutical formulations, containing a compound of formula (I) and/or one of its physiologically acceptable acid addition salts.

These formulations can be used as medicaments in human medicine and in veterinary medicine. Excipients which can be used are organic or inorganic substances which are suitable, in particular, for topical application, but also for enteral (for example oral) or parenteral administration, and do not react with the new compounds, for example, water, vegetable oils, hydrocarbons, e g-, alkylated naphthalenes, halogenated hydrocarbons, e - g. , CF2C12 (for example, for aerosols), benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, e. g., lactose or starch, magnesium stearate, talc and petroleum jelly. Formulations used for oral adminis-tration are in particular tablets, dragees, capsules, syrups, juices or drops; for rectal administration are suppositories;
for intravaginal administration are ovula; for parenteral admin-istration are solutions, preferably oily or aqueous solutions,and also suspensions, emulsions or implants; and for topical application are solutions, lotions, emulsions, sprays (aerosols), ointments, creams, pastes or powders. The new compounds can also be lyophilized and the resulting lyophilizates can be used, for example, to prepare injection preparations. The formulations mentioned can be sterilized and/or contain auxiliaries, e . g., lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs, flavorings and/or aroma substances. If des~red, they can also contain one or more further active in-gredients, for example, one or more antibiotics, vitamins and/or other anti-mycotic agents.

.:

~` 1136635 The new compounds are as a rule administered analo-gously to known, commercially available anti-mycotic agents, for example, clotrimazole or miconazole. In the case of the preferred topical application in combination with excipients suitable for this purpose, a high activity over a wide dilution range can be determined. For example, concentrations of the active ingredient of between 0.1 and 10 percent by weight, based on the weight of the preparation used, prove effective for combating fungi or bacteria. Concentrations of to 3 percent by weight are preferred. When applled orally or parenterally as anti-mycotic agents, the preferred dosages of the new compounds are between O.l and 2 g per dosage unit.

If the new compounds are used as antiphlogistic agents or agents for lowering the lipid level, they are 15 preferably administered perorally. They are then as a rule administered analogously to known antiphlogistic agents (for example, indometacin) or agents for lowering the lipid level (for example clofibrate), preferably in dosages of between about 5 and 500 mg and especially of between 20 and 200 mg per dosage 20 unit. The daily dose is preferably between 0.2 and 20 mg/kg of body weight. However, the specific dose for each patient depends on various conventionally known factors, for example, on the activity of the particular compound employed, 25 on the age, the body weight, the general state of health, on the sex, on the diet, on the time and route of administration and on the rate of excretion, the combination of medicinal sub-stances and on the severity of the particular disease. Thus, in individual cases concentrations or dosages which are higher 30 or lower than those indicated above, can also be used.

Each of the compounds of formula (I) named in the exam-ples which follow is particularly suitable for the preparation of pharmaceutical formulations.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative. In the following examples, all temperatures are set forth uncorrected in degrees 10 Celsius; unless otherwise indicated, all parts and percentages are by weight.
In the examples which follow, "customary working up"
denotes: water or dilute sodium hydroxide solution is added if necessary, the mixture is extracted with an organic solvent which 15 is immiscible with water (for example, benzene, chloroform or methylene chloride) the phases are separated, the organic phase is dried over sodium sulfate, filtered and evaporated and the product is purified by chromatography and/or crystallization.
The product can also be purified by crystallization of one of its 20 acid addition salts.

A solution of 25.5 g. of 2-methyl-3-p-phenoxyphenyl-propionamide (obtainable by Friedel-Crafts acylation of di-phenyl ether to p-phenoxy-propiophenone; bromination to a-bromo-phenoxypropiophenone; reaction with KCN in dimethyl formamide (DMF) to give a-cyano-p-phenoxy-propiophenone;
reduction with NaBH4 to 2-methyl-3-p-phenoxyphenyl-3-hydroxy-propionitrile; hydrolysis with the simultaneous elimination of water to give a-methyl-p-phenoxy-cinnamic acid; reduction with Na-amalgam to 2-methyl-3-p-phenoxyphenyl-propionic acid; re-action with SOC12 to give the chloride; and, reaction of the latter with NH3) in 500 ml. of THF is added dropwise to a suspension of 7.6 g. of LiAlH4 in 250 ml. of absolute THF, while stirring, the mixture is boiled for 16 hours; ethyl acetate and then 32~ sodium hydroxide solution are added, with cooling, the reaction mixture is worked up in the customary manner and 2-methyl-3-p-phenoxyphenyl-propylamine is obtained.

A solution of 2.53 g. of 2-methyl-3-p-phenoxy-phenyl-
3-hydroxy-propionitrile in 30 ml. of absolute THF is added dropwise to a mixture of 0.76g. of LiAlH4 in 30 ml. of absolute THF, while stirring and passing N2 through the mixture. The resulting mixture is stirred for an additional 30 minutes at 20, aqueous sodium sulfate solution is added and the reaction mixture is worked up in the customary manner and 2-methyl-3-p-phenoxyphenyl-3-hydroxy-propylamine is obtained.

A solution of 2.53 g. of 2-methyl-3-p-phenoxy-ci-nnamic acid amide (which can be prepared from the acid via the chloride in 30 ml. of benzene is added dropwise to a suspension of 5 g of sodium aluminum bis-(2-methoxyethoxy)-dihydride in 30 ml of benzene, with constant stirring. The reaction mixture is boiled up in the customary manner and 2-methyl-3-p-phenoxy-phenyl-2-propen-1-amine is obtained.

A solution of 26.9 g of 2-methyl-3-p-benzyloxy-phenyl-propionamide [obtainable from phenyl benzyl ether via p-benzyl-oxy-propiophenone, ~-bromo-p-benzyloxy-propiophenone, ~-cyano-p-benzyloxy-propiophenone, 2-methyl-3-p-benzyloxy-phenyl-3-hydroxy-propionitrile, ~-methyl-p-benzyloxy-cinnamic acid and 2-methyl-3-p-benzyloxy-phenyl-propionic acid] in 300 ml of THF
is added dropwise to a solution of 4.6 g of diborane in 50 ml of THF, while stirring. The resulting mixture is boiled for two hours, cooled and 25% hydrochloric acid is added. The reaction mixture is then poured into water and worked up with sodium hydroxide solution and ethyl acetate and 2-methyl-3-p-benzyloxy-phenyl-propylamine is obtained.

A solution of 23.7 g of 2-methyl-3-p-phenoxyphenyl-propionitrile ~obtainable from the amide using p-toluene-sulfonyl chloride/pyridine) in 250 ml of methanol is hydrogenated with the addition of 8 g of KOH and 12 g of Raney nickel catalyst under about 80 atmospheres and at 80 for 3 hours and filtered, the filtrate is evaporated and the residue is worked up with water and methylene chloride. After drying and evaporating the organic phase, 2-methyl-3-p-phenoxy-phenyl-propylamine is obtained.

25.5 g of 2-methyl-3-p-phenoxyphenyl-propanaldoxime (obtainable by a Rosenmund reduction of the corresponding acid to the aldehyde and reaction of the latter with hydroxylamine) is dissolved in 500 ml of ethanol and hydrogenated on 3 g of Pto2 at 20 and under normal pressure until the reaction has stopped. The reaction mixture is filtered, the filtrate is evaporated and 2-methyl-3-p-phenoxyphenyl-propylamine is obtained.

23.5 g of 2-methyl-3-p-phenoxyphenyl-propenonitrile (obtainable from p-phenoxybenzaldehyde and cyanoacetic acid) is dissolved in 150 ml of isopropanol, 15 g of liquid NH3 and 3 g of isopropanol-moist Raney Ni is added and the hydrogena-tion is carried out at 80 and under 80 atmospheres for 4 hours.
After filtering and evaporating the filtrate, 2-methyl-3-p-phenoxyphenyl-propylamine is obtained.

A solution of 33.1 g of N-benzyl~N-(2-methyl-3-p-phenoxyphenyl-propyl)-amine (obtainable by reacting 2-methyl-3-p-phenoxyphenyl-propanol with SOC12 to give 1-chloro-2-methyl-3-p-phenoxyphenyl-propane and reacting the latter with benzylamine) in 500 ml of methanol is hydrogenated on 8 g of 5% Pd-on-charcoal at 20 and under normal pressure. After filtering and evaporating the filtrate, 2-methyl-3-p-phenoxy-phenyl-propylamine is obtained.
The same product is obtainable analogously from N-benzylidene-N-(2-methyl-3-p-phenoxyphenyl-propyl)-amine.

A solution of 2.95 g of 1-isobutylideneamino-2-methyl-3-p-phenoxyphenyl-propane (obtainable by boiling 2-methyl-3-p-phenoxyphenyl-propylamine with isobutyraldehyde in benzene for 5 hours) in 75 ml of methanol is hydrogenated, after adding 0.3 g of PtO2, at 20 and under normal pressure until the 1~3~635 absorption of hydrogen has ceased. The reaction mixture is filtered and worked up in the customary manner and 1-iso-butylamino-2-methyl-3-p-phenoxyphenyl-propane is obtained.
4.21 g of 1-p-phenoxyphenyl-2-methyl-3-dibenzyl-amino-propane (obtainable by reacting 1-p-phenoxyphenyl-2-methyl-3-chloro-propane with dibenzylamine) is dissolved in 50 ml of ethyl acetate and hydrogenated on 0.5 g of 10~ Pd-C
at 20 and under 1 atmosphere until the reaction has ceased.
The reaction mixture is filtered and the filtrate is evaporated and 2-methyl-3-p-phenoxyphenyl-propylamine is obtained.

100 ml of a 1 molar solution of 2-(1-imidazolyl)-ethyl-lithium in ether is added dropwise to a boiling solution 15 of 21.7 g of 4-p-chlorophenoxy-benzaldehyde in 350 ml of ether, under N2 and while stirring, the mixture is stirred for an additional one hour at 25 and for 2.5 hours at 35 and the lithium l-(4-p-chlorophenoxyphenyl)-3-(1-imidazolyl)-propan-1-olate which has formed is decomposed by adding 200 ml of saturated NH4Cl solution, with ice-cooling. After customary working up, l-(4-p-chlorophenoxy-phenyl)-3-(1-imidazolyl)-propan-l-ol with a m.p. of 102-103 is obtained.

12.4 g of 3-(1-imidazolyl)-propanal (obtainable by reacting 3-chloropropanal diethyl acetal with imidazole and subsequently hydrolyzing the reaction product) in 400 ml of ether is added dropwise to a Grignard solution of 24.9 g of p-bromodiphenyl ether and 2.43 g of magnesium in 1,000 ml of ether, at 20, while stirring. The reaction mixture is stirred for an additional two hours, the resulting alcoholate is decomposed with diluted su~huric acid, the mixture is worked up in the customary manner and l-p-phenoxy-phenyl-3-(l-imidazolyl)-propan-l-ol is obtained.

A solution of 31.2 g of 1-(4-p-chlorophenoxyphenyl)-2-methyl-3-chloro-propan-1-ol (obtainable by a Friedel-Crafts reaction of 4-chloro-biphenyl ether with 2-methyl-3-chloro-propionyl chloride to give l-(4-p-chlorophenoxyphenyl)-2-methyl-3-chloro-propan-1-one and a Meerwein-Ponndorf reduction of the latter) in 150 ml of absolute ethanol is added dropwise at 0 to a solution of 10 g of NH3 in 150 ml of absolute ethanol. The mixture is stirred for an additional 2 hours at 20, the solution is concentrated and worked up with aqueous sodium hydroxide solution and with ether and 2-methyl-3-(4-p-chlorophenoxyphenyl)-3-hydroxy-propylamine is obtained.

-A solution of 2.77 g of 1-p-phenoxyphenyl-2-methyl-3-chloropropan-l-ol and 30 g of methylamine in 100 ml of methanol is heated at 120 for 2 hours in an autoclave. After cooling and the customary working up, 1-p-phenoxy-phenyl-2-methyl-3-methylamino-propan-l-ol is obtained.

2.39 g of 1-p-isopentoxyphenyl-3-chloro-propene (obtainable from p-isopentoxy-cinnamyl alcohol and SOC12) is heated with 3 ml of diethylamine and 50 ml of ethanol for 15 hours at 40 in an autoclave, the reaction mixture is cooled and worked up in the customary manner to give l-p-iso-pentoxyphenyl-3-diethylamino-propene, hydrochloride, m.p~
134-135.

EXAMPLES 16 to 43 The following compounds are obtained analo~ously to Example 15 from the correspondiny chlorine or bromine compounds with dimethylamine or diethylamine:

16. 1-p-Phenoxyphenyl-3-dimethylamino-propan-1-one.
17. 1-(4-p-Chlorophenoxy-phenyl)-3-dimethylamino-1-propan-l-one.
18. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-dimethyl~mino-propan-l-one.
19. 1-p-Isopentoxyphenyl-3-dimethylamino-propan-1-one.
20. 1-p-Phenoxyphenyl-2-methyl-3-dimethylamino-propan-1-one.
21. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-dimethylamino-propan-l-one.
22. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-dimethyl-amino-pr~pan-l-one.
23. 1-Benzyloxyphenyl-2-methyl-3-dimethylamino-propan-1-one.
24. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-dimethylamino-propan-l-one.
25. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-dimethylamino-propan-l-one.
26. 1-p-Methoxyphenyl-2-methyl-3-dimethylamino-propan-1-one.
27. 1-~p-Isopentoxyphenyl-2-methyl-3-dimethylamino-propan-1-one.
28. 1-p-Phenoxyphenyl-4-dimethylamino-butan-1-one.
25 29. 1-(4-p-Chlorophenoxyphenyl)-4-dimethylamino-butan-1-one.
30. 1-p-Phenoxyphenyl-3-diethylamino-propan-1-one.

31. 1-(4-p-Chlorophenoxy-phenyl)-3-diethylamino-propan-1-one.
32. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-diethylamino-propan-l-one.
33. 1-p-Isopentoxyphenyl-3-diethylamino-propan-1-one.
34. 1-p-Phenoxyphenyl-2-methyl-3-diethylamino-propan-1-one.
35. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-diethylamino-propan-1-one.
36. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-diethylamino-propan-l-one~
37. 1-p-Benzyloxyphenyl-2-methyl-3-diethylamino-propan-l-one.
38. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-diethylamino-propan-l-one.
39. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-diethylamino-propan-l-one.
40. 1-p-Methoxyphenyl-2-methyl-3-diethylamino-propan-1-one.
41. 1-p-Isopentoxyphenyl-2-methyl-3-diethylamino-propan-1-one.
42. 1-p-Phenoxyphenyl-4-diethylamino-butan-1-one.
43. 1-(4-p-Chlorophenoxyphenyl)-4-diethylamino-butan-1-one.

A mixture of 2.75 g of l-p-phenoxyphenyl-2-methyl-3-chloro-propan-l-one (obtainable by a Friedel-Crafts reaction of diphenyl ether with 2-methyl-3-chloropropionyl chloride) and 1.36 g of imidazole i8 heated at 140 for : ' 3~

3 hours. After cooling and customary working up, there is obtained l-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-one, hydrochloride, m.p. 149-151.
EXAMPLES 45 to 83 The following compounds are obtained analogously to Example 44 from the corresponding chloro- or bromo-ketones with di-n-butylamine, imidazole or 2-methylimidazole:
45. 1-p-Phenoxyphenyl-2-methyl-3-di-n-butylamino-propan-1-one.
46. 1-p-Phenox~ ellyl-3-(1-imidazolyl)-propan-1-one.
47. 1-(4-p-Chlorophenoxy-phenyl)-3-(1-imidazolyl)-propan-l-one, hydrochloride, m.p. 157-159.
48. 1-[4-(2,4-Dichlorophcnoxy)-phenyl]-3-(1-imidazolyl)-propan-l-one.
49. 1-p-Isopento~yphenyl-3-(1-imidazolyl)-propan-1-one.
50. 1-(4-p-Fluoropheno~y-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-one.
51. 1-(4-o-Chloropheno~y-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-one.
52. 1-(4-m-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-one.
53. 1-(4-p-Chloropheno~y-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-one .
54. 1_(4-p-Bromophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-one.
55. 1-(4-p-Iodophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-one.
56. 1 [4-(2,4-Dichloropheno~y)-pllenyl]-2-methyl-3-(1-imidaz-oly~propan-l-one.
57. 1-p-Benzyloxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-one.

58. 1-(4-p-Chlo~obenzyloxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-one.
59. 1-[4-(2,4-Dichlorobenzyloxy}phenyl]-2-methyl-3-(1-imi-- dazolyl)-propan-l-one.
60. 1-p-Methoxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-one.

61. l-p-Isopentoxyphenyl-2-met};yl-3-(l-i3Y3idazolyl)-propan~
l-one.
62. l-p-Isohexylox~phenyl-2-3~3ethyl-3-(l-imidazolyl)-propan-l-one.
63. 1-p-Phenoxyphenyl-2-n-butyl-3-(1-imidazolyl)-propan-l-one.
64. 1-p-Phenoxyphenyl-4-(1-imidazolyl)-butan-1-one.
65. 1-(4-p-Chlorophenoxy-phenyl)-4-(l-i~3nidazolyl)-butan-l-one.
66. 1-p-Phenoxyphenyl-2-methyl-4-(1-imidazolyl)-butan-l-one.
67. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-4-(1-imidazolyl)-butan-l-one.
68. 1-p-Phenoxyphenyl-5-(1-imidazolyl)-pentan-1-one.
69. 1-(4-p-Chloropheno~y-phenyl)-5-(1-imidazolyl)-pentan-l-one.
70. 1-p-Phenoxyphenyl-3-(2-methyl-1-imidazolyl)-propan-l-one.
71. 1-(4-p-Chlorophenoxy-phenyl)-3-(2-methyl-1-imidazolyl)-propan-l-one .
72. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-(2-methyl-1- ~
imidazolyl)-propan-l-one.

73. 1-p-Isopentoxyphenyl-3-(2-methyl-1-imidazolyl)-propan-1-one.
74. 1-p-Phenoxyphenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propan-l-one.
75. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)-propan-l-one.
76. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-(2-methyl-1-imidazolyl)-propan-l-one.
77. 1-p-Benzyloxyphenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propan-l-one.
78. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)-propan-l-one.
79. 1-[4-(2,4,Dichlorobenzyloxy)-phenyl]-3-(2-methyl-1-imidazolyl)-propan-l-one.
80. 1-p-Methoxyphenyl-3-(2-methyl-1-imidazolyl)-propan-1-one.
81. 1-p-Isopentoxyphenyl-3-(2-methyl-1-imidazolyl)-propan-1-one.
82. 1-p-Phenoxyphenyl-4-(2-methyl-1-imidazolyl)-butan-1-one.
83. 1-(4-p-Chlorophenoxyphenyl)-4-(2-methyl-1-imidazolyl)-butan-l-one.

2.42 g of 2-methyl-3-p-phenoxyphenyl-propan-1-ol i6 dissolved in 10 ml oE isopropylamine and, after adding 0.5 g of Raney nickel, the solution is shaken for 15 hours at 160 in a tube. After cooling, filtering off the catalyst and evaporating the filtrate, l-p-phenoxy-phenyl-2-methyl-3-isopropylamino-propane is obtained.

1136fi;~5 A mixture of 3.06 g of 1-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propan-1-one, 1.5 g of KOH, 2.5 ml of 85%
hydrazine and 25 ml of diethylene glycol is warmed at 100 for 1 hour. The temperature is raised slowly until the hydrazone has decomposed and the mixture is boiled for a further 4 hours, cooled and worked up in the customary manner to give l-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propane, hydrochloride, m.p. 146-148.

4.15 g of NaB~4 are added in portions to a solution of 30.6 g of 1-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-one in 160 ml of methanol and 160 ml of THF, while stirring, the mixture is stirred for an additional 1 hour at 20, diluted with ice-water and worked up~in the customary manner and l-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-ol is obtained.
EXAMPLES 87 to 1 _ The following compounds are obtained analogously to Example 86 from the corresponding ketones with NaBH4:
87. 1-p-Phenoxyphenyl-3-dimethylamino-propan-1-ol.
88. 1-(4-p-Chlorophenoxy-phenyl)-3-dimethylamino-propan-l-ol.
89. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-dimethylamino-^ propan-l-ol.
9O. l-p-Isopentoxyphenyl-3-dimethylamino-propan-1-ol.
91. 1-p-Phenoxyphenyl-2-methyl-3-dimethylamino-propan-1-ol.

92. 1 (4-p-Chlorophenoxy-phenyl)-2-methyl-3-dimethylamino-propan-l-ol.
93. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-dimethyl-amino-propan-l-ol.
94. 1-p-Benzyloxyphenyl-2-methyl-3-dimethylamino-propan-l-ol.
95. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-dimethyl-amino-propan-l-ol.
96. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-di-methylamino-propan-l-ol.
97. 1-p-Methoxyphenyl-2-methyl-3-dimethylamino-propan-l-ol.
98. 1-p-Isopentoxyphenyl-2-methyl-3-dimethylamino-propan-l-ol.
99. 1-p-Phenoxyphenyl-4-dimethylamino-butan-1-ol.
100. 1-(4-p-Chlorophenoxy-phenyl)-4-dimethylamino-butan-l-ol.
101. 1-p-Phenoxyphenyl-3-diethylamino-propan-1-ol.
102. 1-(4-p-Chloropheno~y-phenyl)-3-diethylamino-propan-l-ol.
103. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-diethylamino-propan-l-ol.
104. 1-p-Isopentoxyphenyl-3-diethylamino-propan-1-ol.
105. 1-p-Phenoxyphenyl-2-methyl-3-diethylamino-propan-1-ol.
106. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-diethylamino-propan-l-ol.
107. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-diethyl-amino-propan-l-ol.
108. 1-p-Benzyloxyphenyl-2-methyl-3-diethylamino-propan-l-ol.

109. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-diethyl-amino-propan-l-ol.
110. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-diethylamino-propan-l-ol.
111. 1-p-Methoxyphenyl-2-methyl-3-diethylamino-propan-l-ol.
112. 1-p-Isopentoxyphenyl-2-methyl-3-diethylamino-propan-l-ol.
113. 1-p-Phenoxyphenyl-4-diethylamino-butan-1-ol.

114. 1-(4-p-Chlorophenoxy-phenyl)-4-diethylamino-butan-l-ol.
115. 1-p-PheIloxyphenyl-2-methyl-3-di-n-butylamino-propan-l-ol.
116. 1-p-Phenoxypllenyl-3-(1-imidazolyl)-propan-1-ol.
117. 1-(4-p-Chlorophenoxy-phenyl)-3-(1-imidazolyl)-propan-l-ol, m.p. 102 - 103.
118. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-(1-imidazolyl)-propan-l-ol.
119. 1-p-Isopentoxyphenyl-3-(1-imidazolyl)-propan-1-ol.
20 120. 1-(4-p-Fluorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-ol.
121. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(l-imidazolyl) propan-l-ol .
122. 1-(4-m-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-ol.
123. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-ol, m.p. 159 - 162.

1:136635 124. 1-(4-p-Bromophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-ol.
125. 1-(4-p-Iodophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-ol.
126. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-(l-imidazolyl)-propan-l-ol.
127. 1-p-Benzyloxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-ol.
128. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-(1-imidazo-lyl)-propan-l-ol.
129. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-(l-imidazolyl)-propan-l-ol.
130. 1-p-Methoxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-ol.
131. 1-p-Isopentoxyphenyl-2-methyl-3-(l-imidazolyl) propan-l-ol .
132. 1-p-Isohexyloxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-ol.
133. 1-p-Phenoxyphenyl-2-n-butyl-3-(1-imidazolyl)-propan-l-ol.
134. 1-p-Phenoxyphenyl-4-(1-imidazolyl)-butan-1-ol.
135. 1-(4-p-Chlorophenoxy-phenyl)-4-(1-imidazolyl)-butan-l-ol.
136. 1-p-Phenoxyphenyl-2-methyl-4-(1-imidazolyl)-butan-1-ol.
137. 1-(4-p-chlorophenoxy-phenyl)-2-meth~l-4-(l-imidazolyl) butan-l-ol.
138. 1-p-Phenoxyphenyl-5-(1-imidazolyl)-pentan-1-ol.
139. 1-(4-p-Chlorophenoxy-phenyl)-5-(1-imidazolyl)-pentan-1-ol.

1~36635 140. 1-p-Phenoxyphenyl-3-(2-methyl-1-imidazolyl)-propan-l-ol.
141. 1-(4-p-Chlorophenoxy-phenyl)-3-(2-methyl-1-imidazolyl)-propan-l-ol.
5142. 1-(4-(2,4-Dichlorophenoxy)-phenyl]-3-(2-methyl-1-imidazolyl)-propan-l-ol.
143. 1-p-Isopentoxyphenyl - 3-(2-methyl-1-imidazolyl)-propan-l-ol.
144. 1-p-Phenoxyphenyl-2-methyl-3-(2-methyl-1-imidazolyl)-10 propan-l-ol.
145. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)-propan-l-ol, fumarate, m.p. 175 - 177.
146. 1-~4-(2,4-Dichlorophenoxy)-phenyll-2-methyl-3-(2-me-thyl-l-imidazolyl)-propan-l-ol.
15147. 1-p-Benzyloxyphenyl-2-methyl-3-(.2-methyl-1-imidazolyl)-propan-l-ol.
148. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-(2-methyl-l-imidazolyl)-propan-l-ol.
149. 1-~4-(2,4-Dichlorobenzyloxy)-phenyl~-2-methyl-3-20(2-methyl-1-imidazolyl)-propan-1-ol.
150. 1-p-Methoxyphenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propan-l-ol.
151. 1-p-Isopentoxyphenyl-2-methyl-3-(2-methyl-1-imidaz-olyl)-propan-l-ol.
25152. 1-p-Phenoxyphenyl-4--(2-methyl-1-imidazolyl)-butan-l-ol.
153. 1-(4-p-Chlorophenoxy-phenyl)-4-(2-methyl-1-imidaz-olyl) -butan-l-ol.

29.4 g of 1-p-phenoxyphenyl-3-(1-imidazolyl)-propan-l-ol is boiled with 10 g of p-toluenesulfonic acid in 500 ml of toluene for 2 hours under a water separator and the mixture is cooled and worked up with sodium hydroxide solution to give l-p-phenoxyphenyl-3-(1-imidazolyl)-propene, hydrochloride, m.p. 148-151.

A mixture of 3.43 g of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-1-ol, 0.1 g of benzene-sulfonic acid and 80 ml of benzene is boiled for 24 hours under a water separator. After the customary working up, there is obtained l-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(l-imidazolyl)-propene, hydrochloride, m.p. 131-133; 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propene, methanesulfonate, m.p. 153-155.

.
32.9 g of 1-(4-p-chlorophenoxy-phenyl)-3-(1-imidazolyl) propan-l-ol is dissolved in 240 ml of ethanol, 30 ml of 37%
aqueous hydrochloric acid is added and the mixture is boiled for 1 hour and evaporated. After the customary working up, there is obtained l-(4-p-chlorophenoxy-phenyl)-3-(1-imidazolyl)-propene, hydrochloride, m.p. 147-149.

30.8 g of 1-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propan-l-ol is heated with 325 ml of 20% aqueous hydrochloric acid at 100 for 45 minutes and the mixture is evaporated and worked up in the customary manner to give l-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propene, hydrochloride, m.p. 160-162.

EXAMPLES 158 to 221 The following alkenes are obtained from the corre-sponding alcohols, analogously to Example 154, 155, 156 or 157 (a little dioxane can also be added in order to improve dissolu-tion):

158. 1-p-Phenoxyphenyl-3-dimethylamino-propene.
159. 1-(4-p-Chlorophenoxy-phenyl)-3-dimethylamino-propene.
160. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-dimethylamino-propene.
161. 1-p-lsopentox~phenyl-3-dimethylamino-propene.
162. 1-p-Phenoxyphenyl-2-methyl-3-dimethy~amino-propene.
163. 1-(4-p-Chlorophenoxy-phellyl)-2-metllyl-3-dimethyl-amino-propene.

164. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-dimethyl-amino-propene.
165. 1-p-Benzyloxyphenyl-2-methyl-3-dimethylamino-propene.
166. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-dimethyl-amino-propene.
167. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl~-2-methyl-3-dimethylamino-propene.
168. 1-p-Metho}~phenyl-2-methyl-3-dimethylamino-propene.
169. 1-p-Isopentoxyphenyl-2-methyl-3-dimethylamino-propene.
170. 1-p-Phenoxyphenyl-4-dimethylamino-butene.
- 171. 1-(4-p-Chlorophenoxy-phenyl)-4-dimethylamino-butene.

172. 1-p-Phenoxyphenyl-3-diethylamino-propene, hydro-chloride, m.p. 127-128 (decomposition).
173. 1-(4-p-Chlorophenoxy-phenyl)-3-diethylamino-propene, hydrochloride, m . p . 179-180.

174. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-diethylamino-propene.
175. 1-p-Isopentoxyphenyl-3-diethylamino-propene, hydro-chloride, m.p. 134 - 136.
176. 1-p-Phenoxyphenyl-2-methyl-3-diethylamino-propene.
177. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-diethylamino-propene.
178. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-diethyl-almino-propene .
179. 1-p-Benzyloxyphenyl-2-methyl-3-diethylamino-propene.
180. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-diethyl-amino-propene.
181. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-diethylamino-propene.
182. 1-p-Methoxyphenyl-2-methyl-3-diethylamino-propene.
183. 1-p-Isopentoxyphenyl-2-methyl-3-diethylamino-propene.

184. 1-p-Pllenoxyphenyl-4-die-tllylamino-but-ene.
185. 1-(4-p-Chlorophenoxy-phenyl)-4-die-thylamino-butene.
186. 1-p-PhenQxyphenyl-2-methyl-3-di-n-butylamino-propene.
187. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-(1-imi~azolyl)-propene.

188. 1-p-Isopentoxyphenyl-3-(1-imidazolyl)-propene.
189. 1-(4-p-~luorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propene.
190. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propene.
191. 1-(4-m-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazo]yl)-propene.
192. 1-(4-p-Bromophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propene.
193. 1-(4-p-Iodophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propene.
194. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-(l-imidazolyl)-propene.
195. 1-p-Benzyloxyphenyl-2-methyl-3-(1-imidazolyl~propene.
196. 1-(4-p-Chlorobenzyloxy)-phenyl-2-methyl-3-(1-imidaz-olyl)-propene.
197. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-(l-imidazolyl)-propene.
198. 1-p-Methoxyphenyl-2-methyl-3-(1-imidazolyl)-propene.
199. 1-p-Isopentoxyphenyl-2-methyl-3-(1-imidazolyl)-propene.
200. 1-p-Isohexyloxyphenyl-2-methyl-3-(1-imidazolyl)-propene~
201. 1-p-Phenoxyphenyl-2-n-butyl-3-(1-imidazolyl)-propene.
- 202. 1-p-Phenoxyphenyl-4-(1-imidazolyl)-butene.

203. 1-(4-p-C]~loropheno~-phenyl)-4-(1-imidazolvl)-propene.
204. 1-p-Phenoxyphenyl-2-methyl-4-(1-imidazolyl)-butene.
205. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-4-(1-imidazolyl)-butene.
s 206. 1-p-Phenox~henyl-5-(1-imidazolyl)-pentene.
207. 1-(4-p-Chlorophenoxy-phenyl)-5-(1-imidazolyl)-pentene.
208. 1-p-Pheno~rphenyl-3-(2-methyl-1-imidazolyl)-propene.
209. 1-(4-p-Chlorophenoxy-phenyl)-3-(2-methyl-1-imidazolyl)-propene.
210. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-3-(2-methyl-1-imidazolyl)-propene.
211. 1-p-Isopentoxyphenyl-3-(2-me-thyl-1-imidaz~lyl)-propene.
212. 1-p-Phenox~phenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propene, hydrochloride, m.p. 179-1~ .
213. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-(2-methyl_l_ imidazolyl)-propene, hydrochloride, m.p. 17, - 17 8.
214. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-(2-methyl-l-imidazolyl)-propene.
215. 1-p-Benzylox~phenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propene.
216. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-(2-methyl-l-imidazolyl)-propene.
217. 1-C4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-(2-methyl-1-imidazolyl)-propene.
218. 1-p-Methoxyphenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propene.
219. 1-p-Isopentoxyphenyl-2-methyl-3-(2-m,ethyl-1-1midazolyl)-propene.
220. 1-p-Phenoxyphenyl-4-(2-methyl-1-imidazolyl)-butene.

221. 1-(4-p-Chlorophenoxy-phenyl)-4-(2-methyl-1-imidazolyl)-butene.

A mixture of 3.43 g of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-1-ol, 10 ml of 67% aqueous hydroiodic acid and 18 ml of acetic acid is heated at 150 for 1.5 hours. After cooling and the customary working up, there is obtained l-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(l-imidazolyl)-propane, m.p. 113-116; 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane, methanesulfonate, m.p. 123-125.
EXAMPLES 223 to 263 The follo~ing compounds are obtained analogrously to Example 222 by reduction of the corresponding hydroxy-amines:
223. 1-p-Phenoxyphenyl-2-methyl-3-dimethylamino-propane.
224. 1-(4-p-Chlorophenoxy-phellyl)-2-methyl-3-dimethyl-amino-propane.
225. 1-[4-(2,4-Dichlorophenoxy~phenyl]-2-methyl-3-dimethyl-amino-propane.
226. 1-p-Ben~yloxyphenyl-2-methyl-3-dimethylamino-prop~ne.
227. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-dimethyl-amino-propane.
228. 1-[4-(2,4-Dichlorobenzylo~y~phenyl]-2-methyl-3-dimethylamino-propane, 229. 1-p-Methoxyphenyl-2-methyl-3-dimethylamino-propane.
230. 1-p-Isopentoxyphenyl-2-methyl-3-dimethylamino-propane.
231. 1-p-Phenoxyphenyl-2-methyl-3-diethylamino-propane.
232. 1-(4-p-Chloropheno~y-phenyl)-2-methy,1-3-diethylamino-propane.
233. 1-[4-(2,4-Dichloropheno~y)-phenyl]-2-methyl-3-diethyl-amino-propane.
234. 1-p-Benzyloxyphenyl-2-methyl-3-diethylamino-propane.
235. l-(4-p-Clllorobenzyloxy-phenyl)-2-methyl-3-dieth)71-amino-propane.
236. 1-~4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-diethylamino-propane.
237. 1-p-Methoxyphenyl-2-meth~1-3-diethylamino-propane.
238. 1-p-Isopentoxyphenyl-2-methyl-3-diethylamirlo-propane.
239. 1-p-Phenoxypheny]-2-methyl-3-di-n-butylamino-propane.
240. 1-p-Phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propane, hydrochloride, m.p. 146 - 148.
241. 1-(4-p-Fluorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)_ propane.
242. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane.
243. 1-(4-m-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane.
244. 1-(4-p-Bromophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane.
245. 1-(-4-p-Iodophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane.
246. 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-(1-imi-dazolyl)-propane.
247. 1-p-Benzyloxyphenyl-2-methyl-3-(1-imidazolyl)-propane.
248. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-(1-imi-dazolyl)-propane.
249. 1-[4-(2,4-Dichlorobenzyloxy~phenyl]-2-methyl-3-(l-imidazolyl)-propane.
25C. l-p-Methox~phenyl-2-methyl-3-(1-imidazolyl)-propane.

-~4-~ , 251. 1-p-Isopentoxyphenyl-2-methyl-3-(~imidazolyl)-prop~ne, oil.
~ 252. 1-p-Isohe,yloxyphenyl-2-mcthyl-3-(1-imidazolyl)-propane.
253. l-p-Pheno~yphenyl-2-n-butyl-3-(l-imid2zolyl)-propane.
254. 1-p-Pheno}~phenyl-2-methyl-4-(1 imida 7 0 ly l)-butane.
255. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-4-(1-imida~ olyl ) butane.
256. 1-p-Pheno~yphenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propane, hydrochloride, m.p. 155-157.
257. 1-(4-p-Chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-l-imidazolyl)-propane, hydrochloride, m.p. 145 - 148.
258 1-[4-(2,4-Dichlorophenoxy)-phenyl]-2-methyl-3-(2-methyl-l-imidazolyl)-propane.
259. 1-p-Benzyloxyphenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propane.
260. 1-(4-p-Chlorobenzyloxy-phenyl)-2-methyl-3-(2-methyl-l-imidazolyl)-propane, 261. 1-[4-(2,4-Dichlorobenzyloxy)-phenyl]-2-methyl-3-(2-methyl-1-imidazolyl)-propane.
262. 1-p-Methoxyphenyl-2-methyl-3-(2-methyl-1-imidazolyl)-propane.
263. 1-p-Isopentoxyphenyl-2-methyl-3-(2-nethyl-1-imidazolyl)-propane.

1~36635 Example 264 A solution of 29 g of 1-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propene in 500 ml of methanol is hydrogenated on 10 g of 5~ Pd-C at 20 and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is filtered and the filtrate is evaporated to give l-p-phenoxy-phenyl-2-methyl-3-(1-imidazolyl)-propane, hydrochloride, m.p. 146-148.
Example 265 A solution of 2 41 g of 2-methyl-3-p-phenoxyphenyl-propylamine and 1.5 g of benzaldehyde in 25 ml of benzene is boiled for 2 hours under a water separator. The solution of the resulting l-benzylideneamino-2-methyl-3-p-phenoxyphenyl-propane is heated with 5 g of methyl iodide for 12 hours at 150 in a tube and the mixture is then evaporated. The~resulting quaternary salt is boiled in 90~ ethanol for 10 minutes. The mixture is ~ain evaporated, the residue is taken up in dilute hydrochloric acid and the benzaldehyde which has been split off is extracted with ether. The acid aqueous solution is rendered alkaline with sodium hydroxide solution and worked up in the customary manner, to give l-methylamino-2-methyl-3-p-phenoxyphenyl-propane.
Example 266 A mixture of 2.39 g of 1-p-phenoxyphenyl-2-methyl-3-amino-propene, 5 ml of formic acid, 0.7 g of sodium formate and 4 ml of 40~ formaldehyde solution is heated at 60 for 3 hours and then at 100 for 12 hours. After the customary working up, there is obtained l-p-phenoxyphenyl-2-methyl-3-dimethylamino-propene. - -Example 267 A mixture of 2.97 g of 1-p-phenoxyphenyl-2-methyl-3-isobutylamino-propane, 12 ml of formic acid and 2 g of 40 formaldehyde solution is heated at 60 for 3 hours and 1~36635 then at 100 for 12 hour6, and is then evaporated. After the customary working up, l-p-phenoxyphenyl-2-methyl-3-(N-methyl-N-isobutylamino)-propane is obtained.
F~LE 268 A mixture of 2.19 g of 1-p-isopentoxyphenyl-3-amino-propene, 1.38 g oE potassium carbonate, 4 g of ethyl iodide and 15 ml of n-butanol is boiled for 24 hours, while stirring. The mixture is Eiltered, the filtrate is evaporated and the residue is worked up in the customary manner to give l-p-isopentoxyphenyl-3-diethylamino-propene hydro-chloride, m.p. 135 - 136.
EXAMPLES 269 to 272 In analogy to Example 44, there are obtained from 1-(4-o-chloro-phenoxy-phenyl)-3-chloro-propan-1-one or from 1-(4-o-chlorophenoxy-phenyl)-2-methyl-3-chloro-propan-1-one with imidazole or 2-methyl-imidazole, respectively:
269. 1-(4-o-Chlorophenoxy-phenyl)-3-(1-imidazolyl)-propan-1-one.
270. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-one.
271. 1-(4-o-Chlorophenoxy-phenyl)-3-(2-methyl-1-imidazo]yl)-propan-l-one.
272. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)-propan-l-one.
EXAMPLES 273 to 276 In analogy to Example 86, there are obtained from the corresponding ketones with NaBH4:
273. 1-(4-o-Chlorophenoxy-phenyl)-3-(1-imidazolyl)-propan-1-ol.
274. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-l-ol.

11~6~i35 275. 1-(4-o-Chlorophenoxy-phenyl)-3-(2-methyl-1-imidazolyl)-propan-l-ol.
276. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(2-methvl-1-imidazolyl)-propan-l-ol.
Examples 277 to 280 In analogy to Example 154, there are obtained by dehydration of the corresponding alcohols:
277. 1-(4-o-Chlorophenoxy-phenyl)-3-(1-imidazolyl)-propene.
278. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propene.
279. 1-(4-o-Chlorophenoxy-phenyl)-3-(2-methyl-1-imidazolyl)-propene.
280. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)-propene.
Examples 281 and 282 In analogy to Example 222, there are obtained by reductlon of the corresponding alcohols:
281. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane.
282. 1-(4-o-Chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-lmidazolyl)-propane.

1~36635 The examples which follow relate -to pharmaceutical formulations which contain ethers of the formula I or their acid addition salts:
Example A: Tablets h ~ixture of 1 kg of 1-(4-p-chlorophenoxy-phenyl)-3-(1-imidazo:!yl)-pl!onene hydrochloride, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of mag-nesium stearate is comp~essed ~,G tablets in the customary manner, in such a way that each tar,let contains 50 ~g of the active ingredient.
Example B: Sugar-coated tablets:
Tablets are compress.ed analogously to Example A and are subsequently coated in the customary manner with a coating of sucrose, potato starch, talc, ~ragacanth and a dyestuff Example C: Capsules 10 kg of 1-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propene hydrochloride is filled into hard gelatin capsules in the customary mallner, so that each capsule contains 50 mg of the active ingredient.
EaA~LE D: Ampoules A solution of 1 kg of 1-p-phenoxyphenyl-2-methyl-3-(1-imidazolyl)-propane hydrochloride in 30 1 of twice distilled water is sterile-filtered, filled into ampoules and lyophilised under sterile conditions and the ampoules are sealed under sterile conditions. Each ampoule contains 20 mg of the active ingredient.
EXAMPLE E: Ointment 2 kg of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propàne hydrochloride is dissolved in a warm, liqueEied mixture of 40 kg-of polyethylene glycol 400`and 58 kg of polyethylene glycol 1500.
The solution is stirred as it cools and it is used as an ointment for the treatment of mycoses and bacterial infections.
EXAMPLE F: Cream A mixture of 20 kg of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(l-imidazolyl)-propene hydrochloride, 200 kg of polyethylene glycol 1000 monocetyl ether, 50 kg of polyethylene glycol 1500 monocetyl ether, 150 kg of petroleum jelly, 50 kg of paraffin oil and 2 kg of sorbic acid is warmed in the customary manner and allowed to cool and 528 kg of water is stirred in.
EXAMPLE G: Cream A mixture of 2 kg of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(l-imidazolyl)-propene hydrochloride, 5.kg of 1,2-propane-diol, 5 kg of glycerol stearate, 5 kg of spermaceti, 10 kg of isopropyl myristate and 4 kg of polysorbate 60 is warmed and allowed to cool and 69 kg of water is stirred in.

' ~ ~

~13663S

EXAMPLE H: Solution 2 kg of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane hydrochloride is dissolved in 98 kg of 1,2-propanediol. The solution is used for the treatment of mycoses and bacterial infections.
EXAMPLE I: Spray The spray consists of a so].ution of 1 part by weight of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propene hydrochloride, 10 parts by weight of isopropyl myristate, 15 parts by weight of paraffin oil, 30 parts by weight of ethanol and 44 parts by weight of isopropanol.
Tablets, sugar-coated tablets, capsules, ampoules ointments, creams, solutions and sprays which contain one or more of the other active compounds of the formula (I) and/or of their physiologically acceptable salts are obtainable analogously.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

Claims (14)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for the production of an ether of the formula wherein G is an unsubstituted phenyl or benzyl group, a phenyl or benzyl group which is monosubstituted or disub-stituted by halogen, or alkyl of 1-6 carbon atoms; Z is 1-imidazolyl or 2-methyl-1-imidazolyl; A is -CH=CR1, -CO-CHR1-, -CHOH-CHR1- or -CH2-CHR2-; n is 1, 2 or 3; R1 is H
or alkyl of 1-4 carbon atoms; and R2 is alkyl of 1-4 carbon atoms, and the physiologically acceptable acid addition salts thereof, which process comprises any of the steps of a) reducing a compound of the formula wherein G, Z, A and n are as above;

b) solvolyzing a compound of the formula wherein L is OLi, OMgBr, OMgCl or OAc, Ac is alkanoyl, aroyl, alkylsulfonyl or arylsulfonyl of up to 10 carbon atoms each and G, Z, n and R1 are as above;

c) reacting a compound of the formula wherein X is Cl, Br, I or OH and G, A and n are as above with an imidazole of the formula H - Z

wherein Z is as above;

d) dehydrating a compound obtained by any of (a) to (c) of the formula wherein G, Z, n and R1 are as above;

e) reducing a compound obtained by any of (a) to (d) of the formula wherein A' is -CH=CR1-, -CO-CHR1- or -CHOH-CHR1 - and G, Z, n and R1 are as above;

f) converting a base obtained by any of (a) to (e) to one of its physiologically acceptable acid addition salts by treatment with an acid.
2. A process according to Claim 1 wherein G is phenyl or p-chloro-phenyl, R1 and R2 are each methyl ænd n is 1.
3. A process according to Claim 1 wherein E is p-chlorophenyl, A is -CH=C(CH3)- or -CH2-CH(CH3)- and n is 1.
4. A process for.the production of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane which comprises reducing 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-1-ol with hydroiodic acid.
5. A process for the production of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propene which comprises dehydrating 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propan-1-ol with benzene/sulfonic acid in benzene.
6. A process for the production of 1 (4-p-chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)_propane which comprises reducing 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)-propan-1-ol with hydroiodic acid.
7. A process for the production of 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)-propene which comprises dehydrating 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imidazolyl)-propan-1-ol with benzenesulfonic acid in benzene.
8. An ether of the formula wherein G is an unsubstituted phenyl or benzyl group, a phenyl or benzyl group which is monosubstituted or disubstituted by halogen, or alkyl of 1-6 carbon atoms; Z is 1-imidazolyl or 2-methyl-1-imidazolyl; A is 'CH=CR1, -CO-CHR1-, -CHOH-CHR1 -or -CH2-CHR2-; n is 1, 2 or 3; R1 is H or alkyl of 1-4 carbon atoms; and R2 is alkyl of 1-4 carbon atoms, and the physiologi-cally acceptable acid addition salts thereof, whenever produced by the process of Claim 1 or an obvious chemi-cal equivalent thereof.
9. An ether according to Claim 8 wherein G is phenyl or p-chloro-phenyl, R1 and R2 are each methyl and n is 1, whenever produced by the process of Claim 2 or an obvious chemical equivalent thereof.
10. An ether according to Claim 8 wherein G is p-chlorophenyl, A is -CH=C(CH3)- or -CH2-CH(CH3)- and n is 1, whenever produced by the process of Claim 3 or an obvious chemical equivalent thereof.
11. 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-propane, whenever produced by the process of Claim 4 or an obvious chemical equivalent thereof.
12. 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidszolyl)-propene, whenever produced by the process of Claim 5 or an obvious chemical equivalent thereof.
13. 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(2-methyl-1-imida-zolyl)-propane, whenever produced by the process of Claim 6 or an obvious chemical equivalent thereof.
14. 1-(4-p-chlorophenoxy-phenyl)-2-methyl-3-(1-imidazolyl)-pro-pene, whenever produced by the process of Claim 7 or an ob-vious chemical equivalent thereof.
CA000336319A 1978-09-30 1979-09-25 Basic ethers, pharmaceutical preparation thereof and processes for preparing them Expired CA1136635A (en)

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