Note: Descriptions are shown in the official language in which they were submitted.
"
1~9
The present invention relates to novel 3,4~
dihydroxy-4-phenylpiperidine derivatives, processes for the
production thereof and compositions containing same.
According to one aspect of the present invention
there are provided such no~el 4-phenylpiperidine derivatives
of the genexal formula I:
~ ~X-~2
~ -H ...... I .
~NJ -~3
R.~ .
wherein Rl represents stràight or branched chain lower alkyl
or benzyl;
R2 represents a lower straight or branched chain
alkyl which may carry a lower alkoxy; cycloalkyl; lower
alkenyl; lower alkynyl: phanyl optionally mono- or di-
substituted by halogen, lower alkyl or lower alkoxy; or
with the proviso that X represents only oxygen, a lower
acyl of formula -~O-R wherein R is a straight or branched
chain lower alkyl, cycloalkyl or phenyl,
R3 represent hydroxy or an ester derivative
thereof of formula -OCO-R5 wherein Rs is straight or
branched chain lower alkyi optionally substituted by lower
alkoxy carbonyl or chlorophenoxy; cycloalkyl; lower alkenyl;
diphenylmeth~.l; 2- or 3-furyl or phenyl, optionally substituted :~
by amino, halogen, nitro, up to two lower alkyl groups t UP
to three lower alkoxy groups, CF 3 / an ester moiety of
formula -OCOlower alkyl, lower acylamino; and.
X represents oxygen or sulphur;
as well as pharmaceutically acceptable acid addition salts
thereof with organic or inorganic acids.
Since the compounds of formula I have chiral
centres at C3 and C~, it will be o~svious to one skilled in
the art that these compounds may be present as optical
isomers. The connotation of the general formulae presented
herein is to include all such isomers either separated or
in d,l mixtures.
Also, it will be noted that substitutent groups
X-R2 and R3 are always trans to each o~her in the compounds
of formula I.
Throughout this specification the terms "lower
alkyl", "lower alkoxy", "lower acyll', "lower alXenyll' and
"lower alkynyll' refer to such groups having at most six, and
preferably at most four, carbon atoms. Examples of lower
alkyl groups include methyl,ethyl, isopropyl, propyl, butyl,
isobutyl sec. and tert. b~tyl, pentyl, isopentyl, neopentyl
and the various hexyl isomers; lower alkoxy includes methoxy,
ethoxy and isopropoxy. Lower alkynyl includes ethynyl and
2-propynyl and lower alkenyl includes vinyl and 2~propenyl. ,
Lower acyl groups include acetyl, propionyl, etc. The term
lower aralkyl refers to such groups having at most six,
preferably at most four, carbon atoms in the alXyl moiety,
examples thereof being phenyl~lower-alkyl, phenethyl, ~ut
especially benzyl, and naphthyl-lower-alkyl such as 2-
naphthylmethyl.
The term cycloalkyl as used herein means cyclo-
propyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
- 2 -
A restricted class of compounds of formula I are
those wherein Rl represents a straight or bxanched chain
lower alkyl; or lower phenylalkyl;
R2 represents straight or branched chain lower alkyl which
may carry a lower alkoxy; cyclohexyl; phenyl, optionally -
mono- or di-substituted by halogen; lower alkyl; lower
alkoxy; with the proviso that X represents only oxygen,
lower acyl of formula -COR wherein R is a lower alkyl;
cycloalkyl or phenyl;
R3 represents hydroxy, or an ester derivative thereof of
formula -OCO-R5 wherein Rs is straight or branched chain
lower alkyl optionally substituted by lower alkoxy carbonyl or
chlorophenoxy; cycloalkyl; lowex alkenyl, diphenylmethyl;
2- or 3-furyl or phenyl, optionally substituted by amino,
halogen, nitro, up to two lower alkyl groups, up to three
lower alkoxy groups, CF~, an ester moiety of formula
-OCOlower alkyl, lower acylamino; and
X represents oxygen or sulphur, especially oxygen;
a~ well as pharmaceutically acceptable acid addition salts
thereof with organic or inorganic acids.
- A preferred class of compounds according to the
present invention on account of their advantageous
pharmacological activity are those compounds of formula I
above wherein R2 and R3 are such that positions 3 and 4
carry ester moieties, especially those of formula -OCO-R
wherein R is lower alkyl, cycloalkyl or phenyl, optionally
substituted by lower alkyl, lower alkoxy or halogen. In
such cases the two ester moieties may be the same or different.
of partlcular note are compounds of formula:
O-R2 ;~
R3
.. .. , .. , . . . _ .
wherein Rl represents lower alkyl; :~
R~ represents -COCH3; -COC~Hs or -COCHCH2CH2; and
R3 represents -OCOCH3, -OCOC2Hs, -OCO-cycloalkyl or
-OCOC6H4-Z wherein Z is hydrogen, chlorine, lower alkyl or ~:
lower alkoxy
and pharmaceutically acceptable acid addition salts thereof.
with organic or inorganic acids. :
The present invention in a further aspect, -~
provides processes ~or producing compounds of formula I. In
one process, the nove} compounds of the present~invention may `
be prepared from an epoxide of formula IV:
.
~ '
. ...... IV
~ ~
wherein Rl i5 hydrogen, straight or branched chain lower
alkyl or ben~yl.
The compounds of formula IV are converted into the
compounds of formula I by a reaction involving cleavage of
the epoxide ring, the choice of cleavage agent being ` ;~
~;
- 4 - ~
~39139~8 :~
determined primarily by the -X-R2 moiety desired in the
product of formula I.
For example,
(A) When X = O, R~ - lower alky~or cycloalky~ and
R3 = hydro~en
The selected epoxide of formula IV is reacted with
the corresponding alcohol of formula~ HO-R2
in the presence of at least one molar equivalent of
a strong acid. The reaction may be conducted in a
solvent, which may be constituted by an excess of
the alcohol reactant. Preferred alcohols are
methanol, ethanol and isopropanol.
(B) When X = O, Rz = lower acyl, cycloalkylcarbon~l and
R3 = hydrogen ~ ;~
The selected epoxide of formula IV is reacted with
the corresponding carboxylic acid of formula:
HO-CO-R
wherein R is lower alkyl or cycloalkyl, in the
presence of at least one molar e~uivalent of a
strong acid. Again a solvent may be used and this
may be constituted by an excess of the carboxylic
acid reactant.
Preferred acids include acetic acid and propionic -~
acid.
In these two process embodiments, the strong acid ; -
may be p-toluenesulphonic acid, sulphuric acid and
hydrochloric acid.
Reaction is usually effected by heating, co~veniently
at the reflux temperature of the reaction medium.
_ 5 _
}~ , .
(C) When R3 = hydrogen and (i) X = S and R2 = lower alkyl,
cycloalkyl or phenyl option-
ally substituted as defined
above;
(ii) X = O and Rz = phenyl
optionally substituted as
defined above.
The selected epoxide of formula IV is treated with
the corresponding thiol of fo~muLa: ~S-R
LO or phenol of formula: HO-R~
ln a solvent, such as ethylene glycol and in the ~- .
presence of a base conveniently alkali metal ':
hydroxides such as sodium hydroxide and potassium
hydroxide. :~.
tD) An alternative process for producing those compounds ;- ~:
:~ - : .
of formula I wherein X = O and R~ - acyl involves
reactin~ a diol:of fonmula~
: - ~ OH
,.... III :
2G ~ ~
wherein Rl is as defined above with the acid halide
or anhydride of the corresponding carboxylic acid.
In some instances, depending inter alia on the
~ starting diol and the esterifying reagent, it is ;~
: possi~le to convert both hydroxy groups into ester
moieties. In such cases~ use of at least two molar
equivalents of the esteri~ying agent will result in
- 6 -
~(~9~
the diester having similar ester moieties at the
3 and 4 positions.
As will be appreciated, compounds of formula IV
wherein Rl is hydrogen are secondary amines and in certain
instances may be involved in undesirable competing reactions
involving cleavage of the epoxide ring with the selected
cleaving agent. This is only likely to occur to any
significant extent when the cleaving agent is bulky in
nature, and the possibility of said undesira~le reactions
occurring may be reduced by effecting the reaction at a
lower temperature than in the other instances, for example,
a temperature below 100C compared with a temperature of
between 100-200C, usually about 150C. However, in such
cases~ it is preferred to produce compounds of formula I
but wherein Rl is hydrogen by cleaving the epoxide ring o~
a corresponding comp~und of formula I wherein Rl is an amine
-~ protecting group~ such as acyl, with the desired cleaving
agent and subsequently convertinggroup Rl to hydrogen in
known manner, for example, by hydrolysis with acid or base.
Such N-unsubstituted compounds may be utilized as starting
materials in producing desired compounds of formula I.
Moreover, compounds of formula I may in general
2~
by used as intermediates in ~he obtainment of other compounds
of formula I. For example, those compounds of formula I
whsrein Rl is alkyl may be obtained from the compound of
formula I wherein Rl is hydrogen by simple alkylation by
known standard procedures using, for example, alkyl halides,
or by benzyl-chloride. Likewise, compounds of formula
I wherein R3 is a hydroxyl-group derivative may be obtained
-- 7 --
r ~
~ 8~
from the corresponding fee hydroxyl compound, for example,
by esterification in known manner. This method may be
used to produce compounds having different ester moieties
at positions 3 and 4.
If the mixture of isomers obtained as the product
in any specific reaction is not u~ilizable in that form due
to the undesirable presence of one or more isomers, the
isomers may be separated by standard techniques generally
utilizing differences in the physical and/or chemical
properties between the isomers, suchas relative solubilities,
differing recrystallization rates and different retention
rates in chromatographic separation processes, such as ~~
column chromatography.
The 4-phenylpiperidines of formula I form acid
addition salts with various inorganic or organic acids and
such salts are included within the scope of the present
invention. Of special interest are the pharm2ceutically
acceptable acid addition salts which are usually more
convenient to handle than the free compounds of formula I.
Acids which fo~m such salts include hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, nitric
acid, acetic acid, maleic acid, fumaric acid, tartaxic acid,
2~
succinic acid, citric acid, camphorsulfonic acid, ethane-
sulfonic acid, ascorbic acid and lactic acid.
Of the starting materials, namely, the 3,4-epoxy-
- piperidines of formula IV:
~1;3i9~
~, ~ .
...... IV
Rl ~
the compound wherein R~ is methyl is known being described :~:
in the literature along with its preparation. Other
compounds of formula IV where.in Rl is as defined ~bo~e may be ~;~
prepared in an analogous manner. For example r they may
be obtained by the epoxidation of compounds of formula
,10
J V
.
Rl ~:
: wherein R1 is as defined above.
The epoxidation may be effected in several ways ~or example:
1) oxidation using a percarboxylic acid according to ~:
the following scheme:
Zl~ ¢~ , ~' ~0
~ + RCOOH ~ RC~a OH
R6 R6
wherein R6 is acyl and a protecting group described
hereinbefore at page 7, or
2) ~rom a halohydrin in the presence of a base
according to the following scheme:
~Q91~9~8
Y ~ ~
N N N
V" ' :"
10
wherein the nitrogen is basic in character and
Y is halogen.
However, it will be obvious to the skilled chemist
that the actual procedure used for the epoxidation must be
. _ .. ._. . _ ................................ :
chosen to avoid the possibility of undesirable side reactions.
It will:be readily apparent that in general the
, ~
~ said epoxy compounds where the nitrogen is substituted may ~ ;
.
: be obtained from the corrPsponding epoxy compounds where
the nitrogen is unsubstituted by alkylation, etc. in known
: manner of the latter compounds.
Some of the 4-aryl-1,~,3,6-tetrahydropyridines of
formula V, namely those of formula VI: :~
":
¢~ ` ~';
T .. ~.. y~
~NJ .
. ~ - 1 0 ~ ~ '
f ~A
3~i8
wherein Rl is various hydrocarbon moieties are known com-
pounds being described along with a process for their
preparation, for example, in J.A.C.S. (1956) Vol. 78, p.
425-428. AnY novel compounds of formula V may be prepared
in a similar manner to the known compounds witht of course,
the appropriate choice of starting materials.
An alternative process for preparing these
compounds comprises reacting formaldehyde, an appropriately
substituted ~-methylstyrene and an amine according to the
following scheme:
1) RINEji CHzO;
2) E
.. , ~1 ~ R~ :
wherein Rl is asdefined above, and amine RlNH2 is in the
form of an acid addition salt.
Again, starting compounds wharein substitutent
Rl' is hydrogen may be converted into compounds wherein R
is other than hydrogen by standard known procedures as
described above.
~9~
Of the 4-phenylpiperidine-3,4-diols of formula III
some are know~,for example, l-methyl-4-phenylpiperidine-3,4-
diol (J.O.C. 30, 399 ~1965] R.E. Lyle and W.E~ Kruger). Any
novel compounds of formula III may be prepared in a similar
manner to the said known compound with, of course, the
appropriate choice of starting materials. ~`~
The novel 4-phenylpiperidines of the present inven-tion
possess useful biolo~ical properties and generally~hey have `~
activity, as determined by standard tests, indicative of
at least one of the following activities,!antidepressant,
antiaggresive, diuretic, antiparkinson, bronchodilator and
antiarthritis, antithrombotic and muscular relaxant activities.
For example, compounds of restricted formula I when adminster-
ed to mice have generally been found to have a signficant
stimulatory effect on the central nervous system indicative
of ultimate antidepressant and similar clinical use in ~`
humans. Moreover, this activity is associ~ted with an
acceptable tOXiClty index.
The following table summarizes the results
obtained when some compounds of pre~erred formula I ;~
above were evaluated for antidepressant activity using
standard test procedures (ref. R.A. Turner, P. Hebborn, ~
Screening Methods in Pharmacology, Vol. II, Acad. Pr., ~;
N.Y., London, 1971, paye 214). Reserpine was used to induce
ptosis and the test compounds were administered per os. The
results obtained in the same test for the known antidepressant
imipramine are in~luded as a comparison. Response values
>3 are considered pharmacologically significant.
,
- 12 -
¦ Compound Mg/kqRe spon se .
l-methyl 3-acetoxy-4- 25 `---- -8- - -
A propionyloxy-4- 1 8
phenylpiperidine 0.5 5
.. ...... . ..... .. _....... ........... ~........ . . . ......... ... _ .. .. _
B ~l-methyl-3-ethylcarbonyloxy- 50 1 8
4-(~-chlorophenoxy)- 10 7
14~phenylpiperidine 5 5
C l-methyl-3-hydroxy- 50 10
t4-phenylthio- 10 6
14-phenylpiperidine 5 4
~ - - -.. ~ _ . .. .. __ . ~
D l-methyl-3-cyclopropylcar-
bonyloxy-4-ethylcarbonyloxy- 0 05 1 4
4-phen~ peridine . I
_~..... . ...... ....... _.~_ _.~ .,. __
E l-methyl-3-cyclobutylcar-
bonyloxy-4-ethylcarbonyloxy-
1 4-phenylpiperidine 0.25 5
_ _ . .... .~ . ~ .. ~.~ . ~
F l-methyl-3-cyclohexylcar
bonyloxy-4-ethylcar~onyl-
oxy-4-phenylpiperidine 0.25 5
__ . . __ ~ __.... ~
Imipramine 25 4
_ ~ .~ l
It can be seen that the antidepressant activity
of the compounds of the present invention compares very
favourably with the known antidepressant Imipramine. This
is especially so for the compounds of formula I having an
ester moiety at positions 3 and 4 as exemplified by Compound
A above.
In other similar screening tests, the following
results were obtained:
Diuretic Activity (PO)
` Base (mg/kg) Response*
Compound A 5 4.3
Compound E 10 2.9
Compound F 5 3.0
Hydroflurmethiazide _ 2.6
* Respollses ~2 are considere~ pharmacologically significant.
Bronchodialitory Activity (in vit~o - PO)
Basë (Mg/kg)¦ Response**
~ . . . . . ~ t ------- ---
Compound B i
Aminophylline 200 ¦ +
** Responses are positive (+) or negative (~
~he present inven~ion further provides in another
of its aspects a pharmaceutical composition comprising as an ;~
essential active ingredient at least one active compound of
formula I or a pharmaceutically acceptable acid addition salt
thereof in association with a pharmaceutically acceptable
carrier therefor.
The compositions of the present invention are
preferably administered orally, rectally or parenterally~
Advantageously, the composition is in a dosage unit form -
appropriate to the desired mode of administration. For
example, the dosage unit may be a tablet, capsule, pill,
powder, packet, granule, wafer, elixir, suppository, or a
measured quantity of a suspension, solution, a syrup or
segregated multiples of the foregoing. The term "dosage
units form" as used in the specification and claims refers
to physically discrete units suitable as unitary dosages
for human subjects and animals, each unit containing a
predetermined quantity of active material calculated to
produce the desired therapeutic effect in admixture, or
otherwise in association, with a pharmaceutical carrier~
the quantity of the active ingredient being such that one
or more units are normally required for a single therapeutic
administration or that, in the case of severable units such
as scored tablets, at least one fraction such as half or a
qua~ter of a severable unit is required for a single thera-
peutic administration.
~r . 1 A
Usu~lly the compositions of this invention contain
the active ingredient in an amount of at least 0.5% by weight
based on th~ total weight of the composition and not more
than 95~ by weight. Conveniently, the compositions of the
invention when in dosage unit form contain 0.5 mg. to 100 mg.,
and more conveniently from ~ mg. to 50 mg., of the active
ingredient of Formula I.
The compositions of the present invention will
normally consist of at least one compound of formula I,
advantageously a compound of formula IIa, or a pharmaceutically
acceptable acid addition salt thereof, admixed with a carrier,
or diluted by a carrier, or enclosed or encapsulated by a
carrier in the form of a capsule, sachet, catchet, paper or
other container. A carrier which serves as a vehicle,
excipient or diluent medium for the therapeutically active
ingredient may be a solid, semi-solid or a sterile liquid.
Some examples of the carriers which may be employed
in the pharmaceutical composition of the invention are
lactose, dextrose, sorbitol~ mannitol, starches such as
wheat, corn, or potato starch, gum acacia, calcium phosphate,
liquid paraffin, cocoa butter, oil of theobroma, alginates,
tragacenth, gelatin, syrup B.P., methyl cellulose,
polyoxethylene sorbitan monolaurate, and methyl and propyl
:,
hydroxybenzoates. The choice of carrier is determined by
the preferred form of administration the solubility of the
.~.
compound and standard pharmaceutical practice, all as more
clearly set forth in "Remington's Practice of Pharmacy" by
E.W. Martin and E.F. Cook, a well-known reference work in
this field. In the case of tablets, a lubricant may be
incorporated to prevent sticking and binding of the powd~red
ingredients in the dies and on the punch of the tabletting
~ -~, . ..
machine. For such purposes, there may be employed, for
example, talc! aluminum, magnesium or calcium stearates or
polyethylene glycols "Carbowaxes" (Registered Trade Mark) of
suitable molecular weight.
The pharmaceutical compositions of this invention
may contain, in addition to the active 4-arylpiperidine
in~redient, one or more other physiologically ac-tive
ingredients which elicit desirable complementary effects.
ExamplPs of suitable pharmaceutical compositions
according to the present invention are presented below for :-~
the purposes of facilitating a better understanding of this
aspect of the inventionO
Compositions
Composition 1
: .
For oral administration, sugar coated tablets may have the
~ following composition, tne tablets being made up in the ~
-~ usual manne~. r
: Ingredient Amount tmg)
:
: l-Methyl-3-acetoxy-4-propionyloxy-4-
; phenylpiperidine 10 ~:
Lactose 60 :
Starch 50
Sugar 75
Talc . 5
Gum Arabic . 5
Composition 2
Capsules, made up in the usual manner may have the following
composition: -
Ingredient Amount (m~)
l-Methyl-3 propionyloxy-4-(~-chloro-
phenoxy)-4-phenylpiperidine S
Lactose 145
Composition 3
-
Tablets for oral administraton may also be made up according
to the known procedure descrihed below:
- ]6 -
~' f~ .
Ingredient Amount (mg)
l-Methyl-3-cyclopropylcarbonyloxy-
4-et~ylcarbonyloxy-4-phenylpiperidine 0.175
Lactose 0.502
Starch 0.122
Dextrin ~20% solution) q.s.
Stearic acid 0.004
Magnesium stearate 0.002
It will be appreciated that the above speciic compounds
may be replaced by other active compounds of the present
invention. .
As indicated hereinbefore, it has been found in
accordance with the present invention that the compounds
of Formula I possess useful biological properties in that
such compounds possess the inherent applied use characteristics
of exerting for example, antidepressants on the central
nervous system. Compounds possessing such activity may have
very valuable therapeutic utility as potential medicaments
in the form of pharmaceutical composi~ions in eliciting
advantageous central nervous system effects when administered
to humans and animals. Accordinglyl central nervous
system effects, on humans and animals, may be elic.ited
by administering a therapeuti.cally effective dose of one or
more of the active compounds of Formula I, (preferably a
compound of formula II) wherein CNS symptom being treated,
the age, health and weight of the recipient, the extent
of the symptom, kind of concurrent treatment, if any, and
the prec.ise nature of the effect desired. In practise,
based upon standard pharmacological animal studies,
particularly in mice, it has been found that the administra-
tion of doses of 1 to 100 mg of the active compounds of
this invention per kg of anima; body weight will usually
elicit the aforementioned CNS, especially antidepressant
effect(s) normally without producing any marked s.ide effects.
- 17 -
'8
The present invention will be further described
with reference to, but not limited by, the following
specific examples.
_XAMPLE 1
4-~p-Chlorophenoxy)-3~hydroxy-1-methyl-4-phenylpiperidine
-
and its ~drochloride
20 Ml of 10% sodium hydroxide solution was added
to a solution of 6.45 g ~0.05 mole) of p-chlorophenol in 40 ml of
ethylene glycol and the resulting solution stirred at room
temperature for five minu~es. 3.8 G (0.02 mole) of 3,4-
epoxy-l-methyl-4-phenylpiperidine was added with stirriny
to the above solution and the resulting solution was heated
at 120C on an oil bath for 18 hours.
The solid which resulted was filtered, washed
with water and dissolved in methylene chloride, rrhe result-
ing solu~ion was dried over sodium sulEate and concentrated
in vacuo to give 3.6 g of a white solid. Recrystallization
of this solid from ethyl acetate gave 4-(p-chlorophenoxy)-
3-hydroxy-1-methyl-4-phenylpiperidine as colourless crystals
having a melting point of 164-5C.
The corresponding hydrochloride ~las prepared in
the usual manner and had a melting point of 221C.
Elementary Analysis: C1 8H2 Q'N2C1
Calc. C: 68.02 H: 6.34 N: 4.41
Found C: 68.10 El: 6.62 N: 4.34
EXAMPLE 2
3-Acetoxy-l-methyl-4-(m~methylphenoxy)-4~phenylpiperidine
and its hydrochloride
2.12 Ml (.015 mole) of triethylamine was added to
- 18 -
~7:
~9~8
a solution of 3.0 g (.010 mole) of 3-hydroxy-1-methyl-4-
(m-methylphenoxy)~4-phenylpiperidine in 30 ml of dry methyl-
ene chloride and the solution cooled in an ice-bath. This
solution was stirred and 1.08 ml (.015 mole) of acetyl
chloride was added dropwise. The reaction mixture was
stirred at room temperature for 20 minutes and a precipitate
(triethylamine hydrochloride) appeared after one minute and
this was filtered off. The solvent was evaporated and the
residue diluted with water. The aqueous mixture was basified
with 10~ sodium carbonate solution and extracted with ethyl
acetate. The organic phase was washed with brine, dried over
Na2SO4 and concentrated in vacuo to give 3.50 g of the
desired base as a yellow-coloured oil. This was converted to
.~ .
the hydrochloride which was recrystallized from hot ethyl
iacetate/acetone to give 1.9 g of 3-acetoxy-1-methyl-4-
(m-methylphenoxy)-4-phenylpiperidine hydrochloride as a
.
white solid having a melting point of 197-9C.
EXAMPLE 3
3-Hydroxy-l-methyl-4-phenyl-4-propionyloxypiperidine
and lts hydrochloride
`A solution of 4.0 g of 3,4-epoxy-1-methyl-4-
phenylpiperidine and 4.5 g of p-toluenesulfonic acid
monohydrate in 50 ml of propionic acid was stirred at
room temperature for 10 minutes then the mixture evaporated
to dryness. Water was added to the residue and the mixture
made alkaline with sodium carbonate. The residual solid
was filtered off and washed with water. Recrystallization
of this solid from hot ethyl acetate gave 2.4 g of 3-
hydroxy-l-methyl-4-phenyl-4-propionyloxypiperidine with
a melting point of 142-3C. The corresponding hydrochloride
salt had a melting point of 186-8C.
, `
~9~
EXAMPLE 4
4-Ethoxy-3-hydroxy-1-methyl-4-phenylpiperidine and
its hydrochloride
A solution of 12 g (0.063 mole) of 3,4-epoxy-
l-methyl-4-phenylpiperidine and 14.4 g (0.075 mole) of ;-
p-toluenesulfonic acid monohydrate in 100 ml ethanol was
refluxed for eight minutes. The solution was concentrated
to 20 ml and then diluted with water. The aqueous solution
was basified with 10% sodium hydroxide solution and extracted
with ethyl acetate. The organic phase was washed with
brine, dried over sodium sulfate and concentrated in vacuo
to give 13.25 g of a beige solid. Recrystallization of the
solid from hot ethanol gave 7.6 g of 4-ethoxy-3 hydroxy-l-
methyl-4-phenylpiperidine having a melting point of 145-6C.
Elementary Analysis:
Calc: C: 71.45 H: 9.00 N: 5.95
Found: C: 71.25 H: 9.16 N: 5.86
~ .
The corresponding hydrochloride salt, prepared in
the usual manner, and recrystallized from acetone/isopropanol
had a melting point of 205C.
_ AMPLE 5
4-(t-Butylthio)-3-hydroxy-l~methyl-4-phenylpiperidine
':
and its hydrochloride
20 Ml of 10~ sodium hydroxide solution was added
to a solution of 5.4 ml (0.050 ~ole) of t-butylthiol in
40 ml of ethylene glycol and the resulting solution stirred
at room temperature for 10 minutes. 3.8 G (0.02 mole) of
3,4-epoxy-1-methyl-4 phenylpiperidine was added with
stirring to the above solution and the resulting solution
was heated at 100C (oil bath temperature) for three hours.
- 20 -
A solid separated during the reaction period. The reactionmixture was cooled in an ice-bath, the solid filtered/
washed with acetone and finally supended in acetone and
filtered. Recrystallization of this product Erom isopropanol/
ether gave 3.2 g of the desired 4-(t-butylthio)-3-hydroxy-1-
methyl-4 phenylpiperidine as a white solid having a melting
point of 202.5-203C.
The corresponding hydrochloride salt was prepared
in the usual manner, crystallized from acetone/ethylacetate ~'-
and was found to have a melting point of 222-3OC.
EXAMPLE 6
~ 3-Hydroxy-l-methyl-4-phenyl-4-(phenylthio)piperidine
:' :
, and its hydrochloride
,~ 9.6 Ml of 10~ codium hydroxide solution was added
to a solution of 2.46 ml (0.024 mole) of thiophenol in lS ml ~
~, of e~hylene glycol and the resulting solution stirred at ''
room temperature for five minutes. 1.9 G (0.01 mole) of
3,4-epoxy-1-methyl-4~phenylpiperidine was added with
stirring to the above solution and the resulting solution
stirred at room temperature for a further one hour. A
solid began to separate after five minutes. The solid was
filtered and suspended in acetone. Filtration of the solid
gave 2.6 g of 3-hydroxy-1-methyl-4-p,henyl-4-(phenylthio)-
piperidine as a white solid having a melting point of 217-9C.
Elementary Analysis:
Calc. C: 64.36 H: 6.60 N: 4.17
Found C: 64.33 H: 6.86 N:~ 4.02
The corresponding hydrochloride was prepared in
the usual manner and recrystallization from ethanol/ether
gave colourless crystals of the hydrochloride salt having a
melting point of 208.5-210.5C.
- 21 -
, ,i, ."
8 ::
EXAMPLE 7
_ Acetoxy-l-methyl-4-(1-methyl-1-propylthio)-4-phenyl
piperldine and its hydrochloride
0.6 Ml (.0077 mole) of acetyl chloride was added ;~
dropwise to a stirred solution of 1.8 g (.0065 mole) of
3-hydroxy-1-methyl-4-(1-methyl-1-propylthio)-4-phenyl-
piperidine in 25 ml of dry methylene chloride cooled in an
ice-bath. The reaction mixture was stirred at room tempera-
ture for 20 minutes. The solvent was then removed ln vacuo
to give 2.0 g of a white solid. Recrystallization of the
solid from acetone/isopropanol gave 1.3 g of 3-acetoxy-
l-methyl-4-(1-methyl-1-propylthio)-4-phenylpiperidine
hydrochloride having a melting point of 214-6C.
. :
. ~'
Purther compounds of Formula 1 according to
the present invention are laid out in the following table,
these compounds being prepared by the procedures detailed
in the preceding Examples but with the appropriate changes
in ~tarting materials etc. These compounds all ~all within
the formula I wherein
~ ' ~
R2
I
J R3 .......
N
Rl
- 2~ -
- ` :
M.P. (C~
Exa~le Rl R2 R3 X Base HCl Salt
: 8 -CX 3 ~ Oc~ 3-OCOC~3 O 2l2-4
: CH3
: 9 -CH3 ~ -OH O 221-2
'''` ' ' ;'
-C~3 ~ -o~ o 214-5
CX3 ~ -OCOCH3 O 240-l
c~
:~ 12 -CH3 -CX3 -OCOC-CH3 O 230
; CH3
:j
'! l3 . .-CH3 -CH2C~3-OCOCH3 O 234-6
i .,
14 -CH3 -CH3 -OCO ~ O 205 ;
: . '.
lS -CH3 ~ -OH , O 163-S 209-12 :`
- '
16 -CH3 ~ ~OCOCH3 O sublimes
17 -CII3 ~ Cl -OCOC2Hs sublimes
'''~
18-CH 3 -COCH 3 -OCOCH3 O 25~1-5
19~C~ 3 ~COc 2H a - CCOCH 3 0 1 g 9-200 . ;
.
C~I 3
-CH 3 -CH~ -OH O 2q4-5
C~3
- 23 ~
~ ~ .
Exam~leR I R2 R3 ~ Base HCl Salt
21 -CH 3 C ,CH 3 -OCOCH 3 0 250
:~
C1
22 -CH3 ~-Cl -OH O 243-5
23 -CH3 -(:OCX3 -OH O 228-9
24 -CH 3 -CX 3 -OX 0 135-7
C1
-CH 3 _~ -OH O 23 0-1
C1
26 ~CE3 ~ C1 -OCOCH3 0 237-g
Cl ,
-CH3 ~ OCOC~I3 0 238-40
28 -CH3 ~30CH3 OH O 223-4.5
29 -CH3 -CX3 -OCO~IH~ O 225
-CH 3 ~ -CH3 -OCO~Cl O 230-33
31 -CH 3 -C~ 3 -OCO~TO 2 0 2 5 5 - 8
3 2 -C~ 3 -CIt 3 -OCO ~'~3 0 2 2 5 - 8
33 -CX 3 -50Et -oco~3 23 3~
34 -CH3 -CX3 -OCOEt O 237-9
_ 24
~; .'f `',
'. `.- A :
~g~
~ p- ~c)
Example Rl R2 R3 X Base HCl Salt
-CH3 -CH3 -OCOCH~Ph 249-50
3 6 -CH 3 -CX 3 -O~CCH 3 0 2 4 6 - 8 ~ :
3 7 -C~I 3 ~ H 3 -OCOC 2 H s 2 ~ 4 - 5
. ~
38 -CE 3 -C2Hs -OCOCH=CH~ 0 215-7
39 -C~3 -Ca3 -OCO-~ O 263 ; :~:
-CX3 ~OCH3 -OCOEt O 217-8
41 -CH3 C~ ~OCOEt O 231-2
42 -C~ -C2:~s -OCO~ ~ 0 215-7
4 3-CH 3 -C 2 H s -aco43 0 18 3 -
44 -CH3 Cl -OCOC2Hs Q 215~7
4 5-CH 3 -COC ~ H 5 -OCCCl O 19 5 - 7
CE~ 3
46 -CH3COC\CH3 -OH O 214-5 ~ ~ ~
C~ 3 ~ ~
47 -CX3 -co~3 -OH , 160-2
4 8 -C~i 3-co~3 -OCOC'~-1 3 O 1 4 ~ - 5 0
_ 25-
M P . ( C)
ExampleR~ R2 R3 X Base ~!Cl Salt
CH3 -Cr~z-C CH -OH O 240-2
.
-CH3 -CH2-CH-CH2 -OH O 175-6
51 C~ 3 -C~< 3 o~o~l o 23 0- 1
CH3
C~I 3
5 2 -CH 3 -CH 3 -OCO~C-O~C 1 2 2 2 - 5
C~I 3 ~ ~
5 3 -CH 3 -CH z -CH 2 -OCH 3 -OH O 13 ~-7
54 -CH 3 CH< -oco~3 O . 23 5-7
CEI
CE~ 3 :
-CEI3 -CH/ -OCOEt O 171-3
C~3
56 -CH3 -CH3 -OCO Ç9 0 210-11
ûCOCE~ 3
:.
57 -CH~ 3 -CH z -C- CH -OCOEt O 16 5 7
5 8--CH 3 -Crd 2--C- CH --oco~ 3 O 2 23--
OCOCH
5 9 -CH 3 -5~ C - CFI -OCO~ O 19 5- 6
.
-CH3 -CH2~CH2 GCH 3 -OCO~] O 200 2
-- 26 --
M.P. ~C)
~xam~le Rl R2 R3 X ~ase HCl Sait
OC~I3
61 -CH 3-COCH 3 dOCO~OCH 3 181-2 . 5
OCH3
OC}~ 3
62 -CH3-(::OC2Hs -oco4~oC~3 O 8~-6
OCH 3
,,; ,
63 -CH1 -COCH3 -OCO~ O 225-8
64 C~3-COC~I3 -oco~3 206-8
'~
-CH 3-CCCH 3 -OCO~3Cl O 226-8
~ .
66 ~CH3 CH3 -oCo4~NH-COCH3 O 229-31
67 -CH3 -CH3 -OCO (CEI2) 3 -COOCH3 105-7
68 -CX3 -CH3 -oco4~ 211-3
~3
69 ~CH3 ~CH2-CH~-OCH3 -oco~3 O 208-i0
7 o-CH 3-COCEI 3 -OCO~ 2 3 5 -7
71 -CH 3-COCH 3 -OCO -~ O 2 3 8- 9
9~ .
.~1. P . ( ~C)
.
Rl R2 R3 X 3as~HCl Salt :
7 2-CH 2~3 -COCH 3 -OH O 2 3 4 - 5
73 -C~3 -CH~-CH 2 -OCH3 OCO~ O 184-S
jPh
74 -CH3 COCH3 -OCOC~\ O 101-3
Ph `~
7 5-CH 1 -COCH 3 -aco~ O 2 0 2 - ~ :
OCOC~ 3
76-C~ 3 -C-C2Hs -CCO~ O 245-7
77-CH 3 -COc2~s -~co~3 0 202-4
OCOC~I 3
7 8CH 3 -CH 2 CH 2-OCH 3 -OCOCEi 3 0 ;2 0 2 - 4
7 9-CH 3 -C~ 2 -C~ OC~ 3 -OCOC 2 H 5 0 18 8 - 9
8 0-CH 3 -CH 2 -ca 2 -OCH } -oco~3 0 ~ 3 4 - Q ;~`
OCOC~I3
81-C~3 COC2Hs -OC-O O 231-8
8 2-C.l } -CH 2 ~CH=C'.i 2 -OcO~) 18 ' -7
OCOC'~ 3
83-C~13 -C~C ~ , -Cf`0~3Cl O 215-7
84-.H 3 -CH2 -CH=C'i2 -CC~ ~3 0 197 -9
M . P . ( C ) :
ExampleR~ R2 R3 X Base HCl Salt ~:
~CH3 -CH3 ~OCO{~ O 117-9
OCX3
86 -CH3 -CH3 OCO~OCH3 O 22L-3 ~ ~;
OCH 3
C~I 3 O
8 7 -C~I 3 CH 1 2 0 8 -10
38 -CH3 -CH2-C--C'd -OCO~ O 238 dec.
89 -CH3 -CH2-CH=CH2 -OCO~ O 217-8
CH ~ :
-CH3 -COC2Hs -OCO-C-~Cl O 199-201
C~ 3
91 -CH 3 -COC 2H s -OCOC 2H S 171-3
~:
9 2 -CH 3 -CH 2 -C-- CH -OCO~) 2 41
93 -CH3 -CH2-CH--CH2 ~ -oco~l O 207-9
9 4 -CH 3 -CH 2 -C- CH -OCCCH 3 O 2 0 ~ -
9 5 -CH 3 -Cd 2 -CH~C~ 2 -OCO-CH--CH 2 2 0 5~7
96 -CH2-CH3 -CCC2H; -OH O 173-180
97 -~ ~3 -CH 2-C-CH -OCO-CH--C'~l 2 213-5
9 8 -C~ 3 -CH 2 ~ CH=cH 2 OCCC~d 3 O 2 3 7 ~ 9 ~;
~
:` :
911~ MOP. (C)
xampLe Rl R2 . R3 ~ Base HCl Salt
_ .:
OCH 3
9 9 -CH -COCH 3 -OC~ O ( 3 7 d~c .
OCH3 sulfate salt)
130 -CH3 ~OC2Hs -OCO-O O 241-2
101 -C~ 3 ~OC ~ H s -0(:~0~ 0 2 4 5-7
102 -C~I3 -COC2~s -OCO~) O 220-1
103 ~X3 -CO--~ -OCOC2E~s O 194 5
104 -CH3 ~OC~3 ~OCO~CH3 222-4
CH3
o
10 5-C~I 3 -COC 2 EI s -C)C ::) ~ û 231- 3
106 C~3 -COC2Hs -OCO ~ 182-5 dec.
107 -C~3 -CO(:~3 ~OCO~ 0 235-6
10~ -C~I3 -CO ~ -OCO ~ ~ 218-20
109 -C~3 ~OC2EI=~ G 221-2
.
levo rotatory
(specific rotation -48 . 4 ~
llo ~-CH3 ~ ~COC2Hs ~OCO ~ 0 223-5
dextro rotatory
(specific rotatic~ +56 .1 )
3 ~3 ~0( 0C2~5 ~; 138~201 .
112 -C~ 3 CI -OH S 2 2 3 - 8
113 ~3 Cl ~)COC~3 ~ ~02-5
9~8
M P. (Cj
Example Rl R2 R3 X E~ase HC1 Salt
C~E 3
114 ~~ 3-C~-CH 2 -CX 3 -OH S 18 3 - 5
CH 3
115 -CX 3-f -C~ 3 -OCOC~I 3 S 23 ~-4
CX3
116 -CH 3 ~3 -OCOC~I 3 ~;
"~
,
.~ = ,.
~ ; .~
~g~9B9q~8
~3asic elemental ~nalysis of some compounds of the : ~ .
above examples is contained in the following ta~le:
TABL.
C H N
Calculated: 67.10 6.97 3.73
Found: 66.. 86 7~3~ ~.98
Calculated: 64.36 6.69 3.58
Found: 64.41 6.78 3.66
~, ~ .
Calculated: 68.35 7.25 4.20
Found: 68.57 7.09 4.16
:.
Calculated: 68 .02 6. 34 4 .41
. Found 68.10 6.62 4.34
ExamDIe 4
Calculated: 71.45 9.00 5.95
Found: 71.25 9.16 5.87 :~
Calculated: 55.61 5.19 3.60
Found: ` 55.55 5.40 3.53
~ ,
Calculated: 61.02 5.98 3.95
Found: 61;12 6.14 4.10
Example 28
Calculated: 65 . 42 6 . 65 4 . 02
Found: 65.82 6.83 4.23
Exa:;nple 38
Calculated:~ 62.66 7.42 4.30
Found: 62.72 7.63 4.18
ExamDle ~0
Calculated: 72.84 8. 56 5 ~ 66
Found: 72.63 8.51 5.73
E~am~le 52
Calculated: 60.86 6.~4 3.09
Found: 60.66 6.61 `3.23
~,~
Exam ~ l ~ ;
Calculated: 61.27 6.57 3.97
Found: 61~34 6.70 4.14
Exam~le 76
Calculated: 60.99 6.14 3.56
Found: 61.02 6.28 3.74
Example 81
Calculated: 64.45 7.~7 3.42
Found: 64.12 ~.09 3.62
The detailed preparation of representative 3,4-epoxy-
piperidines which ara usPd as star~in~ materlals i~ many of ~he
specific examples co~tain~d in this speci~ication are as follows:
(a) 3 ! 4-E~o y-4-phenylpiperidlne
~ solution of 33.~ g of bromine and 60 g o~
sodium bromide in.450 ml of water ~as added ~ropwise
with stirrinq to solution comprisin~ 50 ~ of 4-phenyl-
l,2tS,6-te~rahydrQpyridine hydrobromide in 600 ml of water
and the reaction mi~tura was then stirred at room tem~erature
.
for 30 ~inutes. The solution was stirred on an ice bath
while 252 ml of 10% sodium hydroxide was added dropwise
2~ thereto. The resulting mixture then being stirred at room
temperature for a urther 30 minutes. The aqueous solution
was extracte~ wi~h methyle~e chloride and the organic phase
- solution dried over sodium sulfate and ~hen concentrated
in vacuo to give 25.2 g o~ the desired 3,4-epoxy--4-phenyl-
piperidine as an oil.
(b) ~ ~rl~-r~
2~ . 5 Ml of b~nzyl ~romide was acded dropwise to
a stirred solution OL 32 . 3 g of 3,4-e~oxy-4-phenyl-
piperidine and 38;1 ml of triethyiamine in 254 ml of benzene.
33 ~
~ .
..-. ,,
~39~9~i~
A precipitate appeared during the addition. The whole
reaction mixture was then stirred at room temperature
for three hours. The residual solid was removed by
filtration and the solvent evaporated to give 53.4 g of
l-benzyl-3,4-epoxy-4-phenylpiperidine.
- 34 -
