Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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
-- 2 --
`` ~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;
:
1136635
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
.
1136635
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 -
.~ .
1136635
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~
1136635
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
1136635
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
-12-
,j : .
,: ,. ~ 1
.
1136635
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~
.
-13-
'
1136635
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-
-14-
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.
-15-
113663S
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.
- 17 -
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
- 18 -
~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.
19
1136635
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.
-20-
.:
~` 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.
-21-
1136635
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.
1136635
EXAMPLE 1
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.
EXAMPLE 2
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.
EXAMPLE 3
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
-23-
113663S
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.
EXAMPLE 4
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.
EXAMPLE 5
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.
EXAMPLE 6
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)
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1136635
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.
EXAMPLE 7
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.
EXAMPLE 8
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.
EXAMPLE 9
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
-25-
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.
EXAMPLE 10
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.
EXAMPLE 11
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.
EXAMPLE 12
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
-26-
1136635
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.
EXAMPLE 13
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.
EXAMPLE 14
-
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.
EXAMPLE 15
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.
1136635
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.
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1136635
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.
EXAMPLE 44
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
-29-
: '
3~
1136635
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.
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1136635
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.
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1136635
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.
EXAMPLE 84
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.
-32-
1136fi;~5
EXAMPLE 85
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.
EXAMPLE 86
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.
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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.
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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.
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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.
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EXAMPLE 154
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.
EXAMPLE 155
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.
EXAMPLE 156
.
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.
EXAMPLE 157
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.
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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.
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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.
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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.
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1136635
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.
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221. 1-(4-p-Chlorophenoxy-phenyl)-4-(2-methyl-1-imidazolyl)-
butene.
- EXAMPLE 222
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-
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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-
~ ,
113663S
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.
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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
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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.
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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.
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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
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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.
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~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.
