Note: Descriptions are shown in the official language in which they were submitted.
11'~8943
RAN 4450/46
The present invention relates to heterocyclic compounds.
More particularly, the invention is concerned with hetero-
cyclic compounds,a process for the manufacture thereof,fungicidal compositions containing said compounds and a
process for the production of sald compositions. The
invention is also concerned with the use of the present
heterocyclic compounds.
The present invention provides heterocyclic compounds
of the general formula
R CH3 ~ H3
H3C ~ ~ C
H3
wherein R represents ethyl or phenyl,
as well as salts and N-oxides of these compounds.
The process provided by the present invention for
the manufacture of the compounds of formula I and of salts
and N-oxides thereof comprises
As / 1 3 . 6 . 1 9 8 0
11~89~3
- 2 -
(a) reacting a halide of the general formula
R CH3
H3C~ C H3 II II
~CH2--Y
wherein R has the significance given
earlier and Y represents chlorine,
S bromine or iodine,
with a compound of the formula
~CH3
,~,
HN
III
~CH3
or
(b) reducing a compound of the general formula
llZ&943
-- 3 --
H~ ~H3
H3
wherein R has the significance given
earlier and one of t.he two broken lines
represents an additional bond,
S or
(c) reacting a compound of the formula
H3
~C
H3
with a compound which yields a carbonium ion of the general
f ormul a ,~
ïlZ&~43
-- 4 --
> C--C~3 VI
H3C
wherein R has the significance given
earlier, ln the presence of a Friedel-
Crafts catalyst;or
(d) reacting a compound of the general formula
R ~ CHO VII
wherein R has the significance given
earlier,
under hydrogenating conditions with a compound o formula III
hereinbefore, or, for the manufacture of a N-oxide, treating
a compound of formula I with hydrogen peroxide or a peracid,
or, for the manufacture of a salt, converting a base of
formula I into a salt with an acid in a manner known per se.
In accordance with embodiment (a) of the foregoing
process, a halide of formula II is reacted with an amine of
formula III, conveniently in an inert solvent, for example,
in an ether such as diethyl ether, tetrahydrofuran or dioxan~,
J-~. O
llZ8~43
-- 5 --
in dimethyl sulphoxide, or, preferably, in a high-bolling
alcohol such as ethyleneglycol or glycerine, in the presence
of a base, for example, trlethylamine or an excess of amine
o~ formula III . The reaction is preferably carried out
in a temperature range between 50C and lS0C. Ethylene-
glycol is especially preferred as the inert solvent and a
temperature of 100-110C is also especially preferred.
In accordance with embodiment (b) of the foregoing
process, a compound of formula IV is reduced. When a
compound of formula IV in which the double-bond is situated
in the a-position to the morpholine ring is used as the
starting material, then the reduction can be carried out
catalytically or using formic acid.
Especially suitable catalysts are noble metal catalysts
such as, for example, platinum, palladium, ~ptionally pre-
cipitated on charcoal, and Raney nickel. Palladium-on-
-charcoal is the preferred catalyst. Suitable solvents
for the catalytic reduction are hydrocarbons such as benzene,
toluene or xylene, and alcohols such as methanol or ethanol.
Toluene is the preferred solvent. The catalytic reduction
is advantageously carried out at a temperature between
0C and 50C, preferably at room temperature. The reduction
of a compound of formula IV with formic acid is preferably
carried out in the absence of a solvent, the formic acid
being added dropwise to the compound of formula IV at a
temperature of from vC to 100C, preferably at 50-70C, ?~,
l~Z~943
- 6 -
if necessary whilst cooling.
When a compound of formula IV in which the double-bond
is situated in the a-position to the phenyl ring is used as
the starting material, the reduction can be carried out
-~~catalytically. ~latinum or palladium is preferably used
as the catalyst, with water or alcohol being used as the
solvent. In order to avoid a possible hydrogenolysis, at
least one equivalent of acid, preferably hydrochloric acid,
is added to the reduction mixture.
The alkylation of a compound of formula VI in
accordance with embodiment (c) of the foregoing process is
carried out in the presence of a suitable amount of a
Friedel-Crafts catalyst. Suitable catalysts are the known
Friedel-Crafts catalysts such as, for example, aluminium
chloride, iron chloride, zinc chloride, boron trifluoride,
tin chloride, hydrogen fluoride, sulphuric acid and
phosphoric acid. Sulphuric acid is especially preferred
for the purpose of the present invention.
The use of an inert organic solvent in embodiment (c)
is not essential, but is preferred. Especially suitable
inert organic solvents are alkanes such as hexane and cyclo-
hexane as well as chlorinated hydrocarbons such as chloroform,
ethylene dichloride and methylene chloride, with methylene
chloride being especially preferred. The temperature at
which the alkylation is carried out is not critical,
1128943
-- 7 --
but generally lies between 0C and 50C, preferably between
18C and 20C.
Preferably, and especially when sulphuric acid is
used as the catalyst in embodiment (c), after completion of
the al~ylation the product obtained in the salt form is
- extracted with an ~nert organic solvent such as, for example,
methylene chloride. If desired, the free amine can be
obtained with a suitable base such as sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate
or calcium hydroxide.
Preferred compounds which yield the carbonium ions
of general formula VI are the corresponding tertiary alcohols
such as 2-methyl-2-butanol or tertiary chlorides such as
2-chloro-2-methyl-butane.
The reaction of a substituted cinnamaldehyde of
formula VII with the cis-2,6-dimethyl-morpholine of formula III
in accordance with embodiment (d) of the foregoing process
is carried out under hydrogenating conditions, for example
using a palladium catalyst (e.g. in methanol).
In order to manufacture a N-oxide of a compound of
formula I, a compound of formula I is treated with hydrogen
peroxide or a peracid. When hydrogen peroxide is used as
the oxidising agent, an alcohol such as methanol, ethanol or,
preferably, isopropanol is used as the sol~ent. This
~128943
-- 8 --
oxidation is preferably carried out at a temperature between
0C and 50C, especially at 40C. Examples of peracids
which can be used are peracetic acid, perbenzoic acid,
metachloroper~enzoic acid and peradipic acid. Preferred
solvents for the peracids are halogenated hydrocarbons such
as methylene chloride, chloroform or ethylene chloride.
The oxidation with a peracid is suitably carried out at the
same temperature as that previously mentioned in
connection with the oxidation using hydrogen peroxide.
Compounds of formula I form salts with organic and
inorganic acids. Preferred salts of the compounds of
formula I are salts formed with physiologically compatible
acids. These include, in particular, the salts for~.ed
with hydrohalic acids (e.g. hydrochloric acid and hydrobromic
acid), phosphoric acid, nitric acid, monofunctional and
bifunctional carboxylic acids and hydroxycarboxylic acids
(e.g. acetic acid, maleic acid, succinic acid, fumaric acid,
tartaric acid, citric acid, salicylic acid, sorbic acid
and lactic acid), and sulphonic acids (e.g. 1,5-naphthalene-
-disulphonic acid). The preparation of such salts is
carried out in a manner known per se.
The starting materials of formulae II and VI are known
compounds. The starting materials of formulae III and IV
are known as the cis/trans mixture. The cis starting
materials of formulae III and IV can be prepared in analogy
1128943
g
to the process for the manufacture of the cis/trans mixture.
The starting materials of formula IV in which ~che
double-bond is situated in the a-position to the morpholine
ring can be prepared, for example, by reacting a corresponding-
3 ly substituted phenyl-2-methyl-propionaldehyde with cis-2,6-
-dimethyl-morpholine. The hydrogenation of a thus-obtalned
compound of formula IV is conveniently carried out in situ.
The starting materials of formula IV in which the
double-bond is situated in the a-position to the phenyl ring
can be prepared, for example, by reacting a halide which
corresponds to formula II, but which carries a double-bond
in the a-position to the phenyl ring, with cis-2,6-dimethyl-
-morpholine.
The starting materials of formula V can be prepared
by mixing a compound of the formula
~ CHO VIII
llZ8943
-- 10 --
with a conspound of formula III hereinbefore and catalytically
hydrogenating the mixture.
An organic solvent (e.g. an alcohol such as methanol)
is preferably used as the solvent. The temperature is not
critical, but generally lies between 0C and 5~C.
S The catalytic hydrogenation can be carried out using
a customary hydrogenation catalyst such as, for example,
platinum, Raney nickel or palladium, with 5~ palladium/charcoal
being especially preferred.
The compounds provided by the present invention
contain an asymmetric carbon atom in the propylene chain
linking the morpholine ring with the p-substituted phenyl
ring and can therefore occur in the form of racemates and in
the form of optical antipodes. The latter can be obtained
from the racemates by resolution with optically active acids,
for example with (+)-camphoric acid, (+)-camphor-10-sulphonic
acid, O,O'-dibenzoyltartaric acid (L- or D-form),L(+)-tartaric
acid, D(-)-tartaric acid, L(+)-glutamic acid 4-sulphonate,
L(-)-malic acid or D(+)-malic acid. This resolution can
be carried out according to conventional resolution methods.
1128943
The compounds provided by the present lnvention
possess fungicidal activity and can accordingly be used for
combating fungi in agriculture and in horticulture. The
compounds are especially suitable for combating powdery
mildew fungi such as, for example, Erysiphe graminis
(powdery mildew of cereals), Erysiphe cichoracearum (powdery
mildew of cucumbers), Podosphaera leucotricha (powdery
mildew of apples), Sphaerotheca pannosa (powdery mildew of
roses), Oidium tuckeri (powdery mildew of vines), rust
diseases such as, for example, those of the genera Puccinia,
Uromyces and Hemileia, especially Puccinia graminis tstem
rust of cereals), Puccinia coronata (crown rust of oats),
Puccinia sorghi (corn rust), Puccinia striiformia (stripe
rust of wheat), Puccinia recondita (leaf rust of cereals),
Uromyces fabae and appendiculatus (bean rusts), as well as
against ~emileia vastatrix (coffee rust) and Phragmidium
mucronatum (leaf rust of roses).
Furthermore, the present compounds are also active
against the following phytopathogenic fungi:
Ustilago avenae (loose smut of oats), Venturia
inaequalis (apple scab), Cercospora arachidicola (peanut
early leaf spot), Ophiobolus graminis (cereal take-all),
Septoria nodorum (cereal leaf spot) or Marssonina rosae
(rose blackspot). Certain of the present compounds possess
pronounced subsidiary activities against various species
of the following genera: Rhizoctonia, Tilletia, Helminthospo-
112&943
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rium as well as to some extent also against Perono-
spGra, Coniophora, Lenzites, Corticlum, Thielaviopsis and
Fusarium.
Furthermore, compounds of formula I are also active
against phytopathogenic bacteria such as, for example,
Xanthomonas vesicatoria, Xanthomonas oryzae and other
Xanthomonades as well as against various species of Erwinia
such as Erwinia tracheiphila.
Primarily, however, on the basis of their fungistatic
and fungicidal activity the compounds provided by the present
invention are suitable for combating infections which are
caused by fungi and yeasts; for example, those of the genera
Candida, Trichophytes or Histoplasma. They are especially
active against Candida species such as Candida albicans and
are particularly suitable for the local therapy of superficial
infections of the skin and of the mucous membranes, particu-
larly of the genital tract (e.g. vaginitis, especially that
caused by Candida~. The chosen route of a~ministration is
local, the compounds then being used as therapeutically
active preparations in the form of salves, cones, suppositories,
ovules or other suitable dosage forms.
The pharmaceutical preparations can be produced in a
manner known per se by mixing the compounds provided by this
invention with customary organic or inorganic inert carrier
materials and/or adjuvant substances such as water, gelatine,
il2~9~,3
13 -
lactose, starch, magnesium stearate, talc, vegetable oils,
polyalkyleneglycols, petroleum jelly, preserving, stabilising,
wetting or emulsifying agents, salts for the variation of
the osmotic pressure or buffers.
The dosage admin-istered will vary according to indivi-
dual requirements, but a daily administration of 1-2 tablets
which contain 50-100 mg of active ingredient (i.e. a compound
of this invention) for a few days can be a preferred dosase.
The salves conveniently contain 0.3-5%, preferably 0.5-2% and
especially preferably 0.5-1~, of active ingredient. The
following experimental report and the results given in the
Table hereinafter also provide an expert with appropriate
information appertaining to the dosage of the active in-
gredient.
The compounds provided by the invention were tested
for their activity against Candida albicans in the vaginal
c2ndidiasis test on rats described in Path. Microbiol.
23: 62-68 (1960), the following results being obtained:
~12&943
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Concentration in % at
Compound which an "ED 50" activity
occurred
_ , .
Cis-4-~3-(p-tert.amyl-phenyl)-
S -2-methylphenyl]-2,6-dimethyl- 0.01
-morpholine
Cis-4-/ 3-~p-(a,a-dimethyl-
-benzyl)-phenyl]-2-methyl- 0.01
-propyl 7-2,6-dimethyl-
-morpholine
1128943
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The following E~amples lllustrate the pro~ess provided
by the present invention:
Example 1
230 g of 3-(p-tert.amyl-phenyl)-2-methyl-propionalde-
5 hyde and 137 g of cis-2,6-dimethyl-morpholine are heated at
reflux in 1000 ml of toluene using a water separator and
while gassing with nitrogen for 16 hours until the cleavage
of water has been completed. 17.5 g of 5~ palladium-on-
-charcoal are added at room temperature while gassing with
nitrogen and subsequently the mixture is hydrogenated until
the hydrogen uptake is complete. The catalyst is filtered off
and the toluene is evaporated in vacuo. By distillation of
the residue there is obtained pure cis-4-[3-(p-tert.amyl-
-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine of boiling
point 120C/0.1 Torr.
E~ample 2
In a manner analogous to that described in Example 1,
by reaction of 3-[p-(a,a-dimethyl-benzyl)-phenyl~-2-methyl-
-propionaldehyde with cis-2,6~dimethyl-morpholine and
subsequent hydrogenation there is obtained cis-4-/ 3-(p-
-(a,~-dimethyl-benzyl)-phenyl]-2-methyl-propyl /-2,6-
-dimethyl-morpholine of boiling point 162C/0.04 Torr.
llZ8g43
- 16 -
Example 3
To 1223 g of cis-4-(2-methyl-3-phenyl-propyl)-2,6-
-dimethyl-morpholine in 4 litres of methylene chloride are
added dropwise at -5C within 45 minutes 4941 g of concentrated
sulphuric acid and subsequently within 60 minutes 520 g
of 2-methyl-2-butanol. The solution is treated with water
while cooling with ice and the aqueous phase is extracted
several times with methylene chloride. The organic extracts
are washed with sodium hydroxide and subsequently with water,
dried, evaporated and the oily cis-4-[3-(p-tert.amyl-phenyl)-
-2-methyl-propyl]-2,6-dimethyl-morpholine is distilled in
vacuo; boiling point 120C/0.1 Torr.
The cis-4-(2-methyl-3-phenyl-propyl)-2,6-dimethyl-
-morpholine used as the starting material can be prepared as
follows:
1000 g of ~-methyl-cinnamaldehyde, 10 litres of metha-
nol and 789 g of cis-2,6-dimethyl-morpholine are treated
under a nitrogen atmosphere with 50 g of 5% palladium-on-
-charcoal. Subsequently, the mixture is hydrogenated while
cooling with water at 30C until the hydrogen uptake is
complete. The catalyst is filtered off, the methanol is
distilled off under reduced pressure and then the crude
cis-4-(2-methyl-3-phenyl-propyl)-2,6-dimethyl-morpholine
is distilled. The product, which is 99~ pure, boils at
109C/0.055 Torr.
1128943
Example 4
20.0 g of p-(a,a-dimethyl-benzyl)-a'-methyl-
-cinnamaldehyde and 9.6 g of cis-2,6-dimethyl-morpholine
are treated in 60 ml of methanol while gassing with argon
S with 1 g of 5~ palladium-on-charcoal and subsequently the
mixture is hydrogenated until the hydrogen uptake is complete.
The solution, freed from catalyst, is evaporated under reduced
pressure, chromatographed on aluminium oxide (activity grade II)
with chloroform and subsequently distilled in a high vacuum.
There is obtained cis-4- ~ 3-tp-(a~a-dimethyl-benzyl)-phen
-2-methyl-propyl /-2,6-dimethyl-morpholine of boiling point
162C/0.04 Torr.
Example 5
,
In a manner analogous to that described in Example 4,
from p-(tert.amyl-phenyl)-a'-methyl-cinnamaldehyde and
cis-2,6-dimethyl-morpholine there is obtained cis-4-
-t3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-
-morpholine.
Example 6
44.3 g of 3-(p-tert.amyl-phenyl)-2-methyl-propyl
bromide are slowly added dropwise at 125C to a solution
of 22.7 g of cis-2,6-dimethyl-morpholine in 70 ml of
1128943
- 18 -
ethyleneglycol and the mixture is stirred at this temperature
for 48 hours. After cooling, the mixture is treated with
2N hydrochloric acid and the neutral constituents are ex-
tracted with ether. Subsequently, the hydrochloric acid
solution is made alkaline with 5N sodium hydroxide solution
and extracted with ether. The ether extract is washed with
water, dried over sodium sulphate and evaporated. By
distillation there is obtained pure cis-4-[3-(p-tert.amyl-
-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine of boiling
point 120C/0.1 Torr.
ExamPle ?
51.8 g of 3-[p-ta,-dimethyl-benzyl)-phenyl]-2-methyl-
-propyl bromide a-e slowly added dropwise at 125C to a
solution of 22.7 g of 2,6-cis-dimethyl-morpholine in 80 ml of
ethyleneglycol and the mixture is stirred at this temperature
for 48 hours. The working-up is carried out in a manner
analogous to that described in Example 6. By distillation
there is obtained pure cis-4- ~ 3-[p-( a, -dimethyl-benzyl)-
-phenyl]-2-methyl-propyl /-2,6-dimethyl-morpholine o~
boiling point 162C/0.04 Torr.
Example 8
266 g of cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-
-2,6-dimethyl-morpholine are dissolved in 500 ml of absolute
ethanol and at room temperature there are added dropwise 500 ml
ilZ8943
-- 19 --
of a 28~ hydrogen chloride/ethanol solutlon. The homo-
geneous solution is concentrated to dryness on a rotary
evaporator and the residue is recrystallised from 100 ml
of water. The crystallisate is washed with water and dried
at 55C in a vacuum drying oven. There is obtained
cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-
-morpholine hydrochloride in the form of white, slightly
hygroscopic crystals of melting point 204-206C.
Example 3
A solution of 60 ml of 30~ hydrogen peroxide in 60 ml
of acetic acid anhydride is added dropwise to 21 g of
cis-4-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-
-morpholine while cooling with acetone/dry-ice in such a
manner that the temperature does not exceed 50C and the
mixture is subsequently left to react at room temperature for
16 hours. The course of the oxidation is checked by thin-
-layer chromatography (hexane/ether 1:1). In order to
destroy the excess peroxide, the solution is cooled to
-10C and treated with 200 ml of 40% potassium hydroxide.
After stirring ror 20 hours, the mixture is diluted with
500 ml of water and exhaustively extracted with chloroform.
The combined chloroform extracts are washed neutral, dried
and evaporated. By recrystallisation of the residue from
100 ml of pentane there is obtained pure cis-4-[3-(p-tert.
amyl-phenyl)-2-methyl-propyl]-2,6-dimethyl-morpholine 4-oxide.
llZ~943
- 20 -
The following Examples describe pharmaceutical
preparations provided by the present invention:
Example 10
Vaginal tablets containing the following ingredients
are p~oduced in the usual manner:
Cis-4-[3-(p-tert.amyl-phenyl)-2-
-methyl-propyl]-2,6-dimethyl-
-morpholine 50 mg
Secondary calcium phosphate dihydrate400 mg
Directly pressa~le starch (STA-RX 1500~261 mg
Lactose (spray-dried) lOG mg
Polyvinylpyrrolidone 25 mg
Citric acid 5 mg
Magnesium stearate 6 mg
847 mg
Example 11
A salve containing the following ingredients is
produced:
* trade mark
1128943
- 21 -
Cls-4-/ 3-~p-(a,a-dimethyl-benzyl)-
-phenyl]-2-methyl-propyl /-2,6-
-dimethyl-morpholine 0.7 g
Cetyl alcohol 3.6 g '
Lanolin ~ g.o g
Vaseline (white) 79.3 g
Paraffin oil 7.4 g
100.0 g
ExamPle 12
A cream containing the following ingredients is
produced:
Cis-4-[3-(p-tert.amyl-phenyl)-
-2-methyl-propyl]-2,6-dimethyl-
-morpholine 0.7 g
Polyoxyethylene stearate 3.3 g
Stearyl alcohol 8.0 g
Viscous paraffin oil 10.0 g
Vaseline (white) ~ lO.O g
Carboxyvinylpolymer CARBOPOL 934 Ph 0.3 g
Sodium hydroxide (pure) 0.07g
Water (deionised) ad loO.o g
* trade mark
