Note: Descriptions are shown in the official language in which they were submitted.
This inventi~n relates to l-amino-lower-alkyl 3,4-
diphenyl-lEI-pyrazoles, u~ful aR anti~d~pressants and.
analge~ia~ O
Rosenthal, Arch. Intern. Pharma~odynamie, 96, 22G-
5 ~3~ (1953) di~cl~se~ 1-t2-aminoathyl)-3,5-diphenyl-1~-pyrazole
: having loaal anssthetic a~tivity; Grandberg et al., Zh~ Ob ch.
: Khim. 31, 370~-37Q5 ~19~1); C.A. 57, 9839 ~1957~ disclose~
l-t3-am~nopro~yl)-3,5-diphenyl-lH-pyrazoLe ~or which no
utility i~ a~serted; T~rF et al~, Biol. Aktivn. Soedin, Akad.
~}0 Nauk SSR, 1965, 171-174; C.A. 63t 16329~ ~1965) disclo~es
~ l-t~-diethylaminoethyl)-3,5-diphenyl-lH-pyrazole; ~or ~hich
:~' no utility i~ deRcribed, Jones et al., J. Org. Chem. 19
: l428-1434 (1954~ di~cl~e3 va~lou~ l-t2-aminoethyl)-3-ph2nyl~
y
:` : lH-pyrazole whioh were tested and found ~naotive a3 ga3tric
, lS s~c~etory ~timulants an~ histaminic agent~; and B~chi et al.,
, ~
Helv. Chlm. Acta., 38, 670-679 ~195$) di lo~e~ t2-dimethyl-
aminoethyl)~3~phenyl-4-methyl lH-pyrazole for which analge~ic
: activity iB as~erte~.
However, none ~f the known art suggests the ~p~cific
:
'
-2-
~k
group of 1 amino-lower-al.kyl-3,4 diphenyl-lH-pyrazoles
h~re diRclosed and claimed which owe theix desi.red anti-
depre~sant and analge~ic activities to certain precise
structur31 featuxes.
This invention relates to compounds having the
formula:
C6"s~ 6Hs
(C~2 ) n-N=B
I
and chemically de~ignated 1-~3-(N=B)-propyl]- and 1-[2-(N=B~-
ethyl]-3,4 diphenyl-lH-pyrazoles where n i~ 2 and N=B i~
~iethylamino; or where n is 3 and N=B i~ amino, methylanino,
dimethy}amino or diethylamino. The ~pecies where n iR 3 an~
N-B i~ either dimethylamino or methylamino are paxticularly
u eful as anti depre~ant aglants, whlle those whexe n i~ 3 and
N~B i~ amino or diethylamino and those whexe n is 2 and N~B
lS i~ diethylamino are u~eful as analgesic agent~.
The compounds of Formula I are prepaxed by redu~ing,
with an alkali metal aluminum hydride, an ~-[l-~3,4-diphenyl-.
lH-pyxazolyl)3-lower-alkanamide having the Formula II:
6 5 rTC6H5 C6H5 ~ ~ C H
(~H2) n ~N~ (IH2) n N B
II I
where n and ?~~B hav~ the meanings given above, and n' i~ the
next lower inte~er to n. The reaction is preferably carried
out in an organic sol~en~ inert under the conditions o~ the
reaction, for example dioxan~, diethyl ether or tetrahydrofuran
at temperatures from about -10C. to .he boiling point of the
solvent used. The method is particularly advantageous for the
preparation of compounds where n' is 2 and n is 3. The desired
starting materials of foxmula II are prepared by reactlon o~
3,4-diphenylpyrazole with a lower-alkyl acrylate in the
presence of a strong base~ saponification o~ the rP~ulting
ester, conversion of th resulting acid to the corresponding
acid chloride, and reaction of the lat~er with an appropr~ate
amine in the presence of an acid acceptor, e.g. pyriaine.
- ~no~her method for pxeparing the compounds of formula
. ~ pref~rably
I comprises reducing with hydroge~ kver a Raney nlcke7 catalyst,
in the presence of ammonia a l-(cyano-lower alkyl)-3,4-diphenyl-
l~-pyrazole of formuIa III to produce the corresponding compounds
where N-B is amino. If the compounds where N-B i~ ~.ethylamino,
,
dimethylamino or diethylamino' are desired~ then the r~act~on is
carried out in thP~presence of msthylamin~, dimeth~l2mine or
: : d~ethylamine, respe~ti~ely. The method is illustrated by the
following reaction: : ~
.
. .
~ 6 5 ~ C6H5 ~ C6~5 ~ C6~5
'
CH2)n,C-N ~ ~C~2)n ~ B
where n and n' hav~ ~he meanings given abo~e, and N-~ ~ 3
.. . .
-~5 amino, me~hylamino, dimethylamino or diethylamino. R~duction ls
~ 4
'~I i' ~ , .
~ 27
carried out in an organic solvcnt inert under the reaction
conditicns~ for ~xarnple a lower~alkar~ol, at ambient temperature
and at hydrogen pressur~s in the range from S0 to about ~0 p.s.i,
The method is particularly advantageous for the preparation of
compol~nds w~.ere n is 3.
The starting mat~rials of formula III where n' is
2 are prepared by reactlsn of 3,4-diphenylpyrazole with acrylo-
nitrile in the presence of a strong base.
A third method for prep~ring the compounds o~ formula
I comprises reactin~ a 1-[3-(tosyloxy)propyll- or 1- [2- ..
~tosyloxy)ethyl~-3,4-diph~nyl-lH-pyrazole having th~ ormula
IV with an appropriate amine, H-N=B, as represented by th~
foliowing reaction: ~
C6xs ~j--r C6H5 C6~5 ~r C6~i5
~N
(~H2 ) n (CH2 ) n-N=B
IV
and Ts is toluenesulfonylcdc~
15 where n and N=B have the maanings given abo~. The reaction
carried out by h ating a mixture of the ~ompound o~ formul~ .
V with the amine in an orga~ic solvent inert under the con~itions
of the reaction, for exam~le acetoni~rile or a lower-alkanol,
at a temperature from abo~t 100 to about 150C.
The interm~diates of formula IV are prepared by
condensation of formyldesoxybenzoin ~Russell et al., J. Am.
.
Chem~ Soc. 76, 5714-5718 (1954)~ with an ~-hydroxyalkyl-
hydrazi~e followed by reaction of the resulting 1-(3-hydr~xy-
propyl)~3,4-diphenyl-lH-pyrazole or.l-t~-hydrox~athyl)-3,4-
2S diphenyl-lH-pyraz~le with a toluen~sulfonyl halide in ~he
presence o~ pyxidine. -- : ~
Another m~thod for preparing the compounds of formula
~ ~ "
,
''"'.~;~
I is preceded by forming a salt of a strorlg ba e of the Formula
V by reacting a 3,4-diphenyl-lH-pyrazole with a strong base,
for example sodium hydride, in an organic solv~nt inert under
the conditions of the reaction, for example tetrahydrofuran,
5 dioxane or diethyl ekher. One reacts th~ salt of the strsng
base with halo-lower-alkylamine indicated below in the same
Qolvent system at the reflux temperaturs thereof. The m~thod
is illustrated by the following reaction:
C6H5 . ~ C6 5 ~j~ C6H5 ~ C6 5
~N~' X (CH2) n N B ~N/
V (CH2) n N B
10 where n and N-~ have the meanings given above, and X
repre~ents halogen.
Another meth~d for prepaxing the compounds of Formula
I where n is 3 and N-B is dimethylamino compri~e~ reduolng
either with formic ~cid or with hyclrogen in the precence of a
15 catalyst a mixture of 1-(3-aminopropyl)-3,4-diphenyl-lH-pyraz31e
and at least two equivalents of formaldehydeJ The reaction is
preferably carried out in an organic olvenk inert under the
conditiona ~f the reaction, for example a lower-alkanol such
as ethanol. A preferred meth~d comprises reducing the reaction
20 mixture with hydro~en ~ver a catalys~ at a hydrogen pressure of
50-90 E3. ~ . i ., and a pr~ferred cataly3t i~ platinulTI oxide.
As indi~ated above, preparation of the inal product~
; of Formula I requlre~ either the alkylation of 3,4-diphenyl-
pyrazc)le by Michael addikion 0f a lower-alkyl acrylate or
25 acrylonitrile [here de~ignated Mekhod ~a) ]; ~che ~lkylakion
of 3,4-diphenylpyrazole with a h~lo-lower-alkylamine in the
pre3ence of an acid-accept~r ~here designated Method (b~;
--6--
i~
~-.J;
35;~7
or the lntr~duction of an hydroxy~lower-alkyl group at the
l-position of 3,4-diphenylpyrazole by condensation of formyl-
desoxybenzoin with an ~-hydroxy-lower-alkylhydrazine [here
designated Method (c)]. These various transformations are shown
schematically in the following flow diagram:
C6H5 1~ C6Hs < - - ~ C6H5 1 1 C6H5
N / ~ N-H
H (b ~ X-~cH2)n-N=B (a)\ CN~
~-~ ~ COOR
6 5 ~ ~ C6H5 C~H5 ~ C6H5 N
(CH ) -N=B ~(C~2)2 ~
C6H5 >-~ C6H5 --C6H5 C6H5
CHO O + H2NNH(CH2)nO~ ~ ~ CH~)nOH
where n, N=B and X have the meanings given abo~e. Fxom the
above flow diagram, it will be seen that all three methods
result in the formation o a mixture of the 3,4~dlphenyl
and 4,5-diphenyl products. In Methods la~ and (b), thes~
. mixtures result from alkylation of one of the two possible
tautomeric forms of the diphenylpyrazole starting material.
In Method (c), the mixtures result from the lack o~ rea~tlon
selectivity of the ketone and aldehyde caxbonyl groups of the
formyldesoxybenzoin staxting material. Generally ~peaking,
alkylation with a lower~alkyl acrylate or with acrylonitrile
lM~thod (a)] produces about 85% of ~he desired 3,4-diphenyl
isomer; alkylation with a halo-lower-alkylamlne lMethod ~b)~
produces about a 50:50 mixture of isomers; and Method (c)
appears to favor formation of the 3,4-isomer. In any event,
-- 7 --
__,
:~ ,
5Z7
it i5 necessary ~o separate khe 3,4- and 4,5-isomers from one
another at some point in the overall syn~hesis irrespective
of which method is used.
The structural assignments for the 3,4- and 4,5-
diphenyl isomers are made on the basis of their ultraviolet
and NMR spectra and their behavior on gas chromatography.
Thus a consistent and unambiguous relationship can be seen
between the isomers in the ultraviole~ spectra. One member
of each pair of isomers shows absorption maxima at 223 nm and
at 249+2 nm, while the other shows absorption maxima at 227~2
and 252~1 nm in 95% ethanol. Moreover the extinction coeEicients
are generally higher for the 227/252 mamber of the pair. Thus
the ultraviolet spectra can be used to identify an isomer once
any particular isomer of the en~ire series has been assigned a
~15 particular structure
Such an assignment can be made using NMR data. Elguer~
and Jacquier [J. Chim. Phys. 63, 1242 ~1966)~ have shown that
in highly polar solvents, such as hexamethyl phosphorotriamide,
the proton at the 3-position of a series of 1,4-d~substituted
pyrazoles~always fell upfield of the 5-position protGn. Applying
this tG the instant series leads to the assignment of the 3,4~
diphe~yl-substitution to members of the series with the 227/252
uv maxima and of the 4,5-diphenyl-substitution to the
233/249 series, since in the NMR spectra, the same downield
absorption from the 5-position proton is obtained for the 3,4
diphenyl isomer, the upfield absorption from the 3-position
being absent. Conversely the same upfield absorption from the
3-po~ition proton is obtained fox the 4,5-diphenyl i~omer, while
the downfield absorption from the 5-position proton is absent.
2~
In the NMR spectra, a completely regular and predict-
able relationship between members o~ a pair al~o obtains for the
- chemical shifts of the methylene protons adjacent to th~ nitrogen
atom at the l-position of the pyrazole xingD The 3,4~diphenyl
5 isomer is always found down-fi~ld of the 4,5-diphenyl isomer~
Finally the retention times of the isomers on gas
chromatography mirror the abo~e-noted dichotomy found in the
spectral data, the 3,4-is~mer having the lsnger retention
time in all cases,
1~ Due t~ the pre~ence of a basic amino grouplng, the
free base f~rm represented by Formula I above reacts with
organic and inor~anic acids to form acid~addition saltq. The
acid-addition salt forms ~re prepared from any organic or in-
organic acid~ They are obtained in conventional fashion, for
15 instance either by ~irect mixing of the base with the acid or,
when this i~ not appropriate, by di~solving either or ~oth of
; the base and the acid separately in water or an organic solvent
and mixing the two ~olutionq, or by dissolving both the ba~e
and the acid together in a solventO The resulting acid addition
20 sal~ i~ isola~ed by filtration, if it is insoluble in the re-
aation medium, or by Pvap~r~tion of the reaction medium to
leave the acid~a~dltion salt as a residueO The acid moieties
r anions in these salt forms are in themselves n~ither novel
nor oritical and there~re can be any acîd anion ~r acid like
25 substance capable of salt formation with the ~ase.
Representative acids for the :Eormation of the acid-
addition salts includ~ formlc acid, acekic acid, isobutyrio
acid, alpha-mercaptopropionic acid, trifluoroacetic aeid~
malic acid, fumaric acid, succinic acid, ~uacinamlc acid,
30 tannic acid, glutamia aci~, tartarlc acid, oxalic acid,
_g_
5;d"~;9
pyromucic acid~ citric acid, lactic acid, glycolic acid,
gluconic acid, saccharic acid, ascorbic acid, penicillin,
benzoic acid, phthalic acid, salicylic acid, 3,5~dinitro-
benzoic acid, anthranilic acid, cholic acid, 2~pyridinecar-
boxylic acid, pamoic acid, 3-hydroxy~2-naphthoic acid, picric
acid, quinic acid, tropic acid, 3-indoleacetic acid, bar-
bituric acid, sulamic acid, me~hanesulfonic acid, ethane-
sulfonic acid, isethionic acid, benzenesulfonic acid, ~-
toluenesulfonic acid, butylarsonic acid, methanephosphonic
: 10 acid, acidic resins, hydrofluoric acid, hyd.rochloric acid,
hydrobromic acid, hydriodic acid, perchloric acid, nitric
acid, sulfuric acid, phosphoric acid, arsenic acid, and the
like.
All of ~he acid-addition salts are useful a~
sources of the free base foxms, by reaction with an inorganic
base. It will thus be appreciated that if one or more of the
characteristics, such as solubility, molecular weight r
physical appearance, toxicity, or the like o~ a given base
or acid-addition salt thereof render that form unsuitable
~20 ~or ~he purpose at hand, it can be readily conver~ed to
. another, more suitable form. For pharmaceutical purposes,
acid-addition salts o~ relatively non-toxic; pharmaceutically-
acceptable acids, for example hydrochloric acid, lac ic
acid, tartaric acid, and the like~ are of course employed.
As indicated above, in standard pharmacological
test procedures, the compounds of formula I above where n
is 3 and N=B is methylamino or dimethylamino and the acld-
addition salts thereof have been found useful~as antl-
depressant agents, while the compounds of formula I above
where n is ~ and N-B is amino or diethylamino and those
-- 10 --
35'~
where n is 2 and N=B i5 diethylamino have been found useful
as analgesics.
The compounds of formula I can be administered in
the same manner as known anti-depressants and analge~ics,
i.e. either parenterally or orally in any of t~e conventional
pharmaceutical forms, as for instance solutions, suspensions,
tablets, capsules and the like.
The useful properties of the compounds of ~his
lnvention were demonstrated by standard pharmacological
procedures readily carried out by technicians having ordlnary
skill in pharmacological test procedures, so that the actual
determination of the numerical biological data definitive fo~
a particular te~t compound can be ascertained without the need
for any extensive experimentation.
lS The test procedure used to determi~e the anti-
depressant activity o~ the comp~unds of the in~entlon 1~
described as follows: Male Swi!;s~Webster mice (Taconic Farms)
weighing from 19~24 gO were divided into four groups o~ nine
~; ~ to ten mice per group~ The fîrst three groups were administered
~ the test compound at respective doses of 64, 16 and 4 mg./kgO
dissolved either in water as a water soluble acid-addition
~ salt ox as a suspension in 1~ gum tragacanth. The fourth
- group received the ~ehicle only. Four hours following medica-
tion, all the contxol and the test animals were medicated with
50 mg./kg. (i.p.) of tetrahenazine and were placed in a pho~o~
cell activity cage ~described by Harxis et al.~ Psychon. Sci.,
4, ~67 (1965)] equipped with a digital counter to record ~he
- number o~ times that a light beam impinging on a photocell ls
interrupted during the test period. Beginning thirty minutes
3b after tetrabenazlne medication~ the photocell units were
activated and the photocell counts recorded over a if~y minute
period. The compounds were then recorded as being either
active or inactiv~, activity being defined as a significant
difference (.05 level or less, two-tailed~ between the drug
and control group ph~tocell counts according to the ~ruskal
Wallis statistical probability test.
The test procedures used to determine the analgesic
activities of the compounds of the invention h~ve been
described in detail in the prior art and are as ~ollows:
The acetylcholine-induced abdominal constriction test, which
ls a primary analgesic screening test to measure the ability
of a test agent to suppress acetylcholine-induced abdominal
con~triction in mice described by Collier et al., Brit. ~.
Pharmacol. Chemotherap. 32 r 295 (1968) and the phenyl p-~uinona-
induced writhing test, also a primary analge~ic screen$ng
test, designed to measure the ability of a te~t agen~ ~o prevent
phenyl p-quinone-induced writhing in mice, ~escribed by
Pearl and Harxis, J. Pharmacol. Exptl. Thsrap. 154, 319-323
(1966),
The structures of the compounds of this invention
~0 were astablished by the modes of synthesis, by elementary
analyses and by ultraviolet, infrared and nuclear magnetlc
reasonance spectra. The course of reactions and homogeneity
of the products were ascertained by thin layer chromatoyraphy.
The manner and process o~ maklng and using the
~5 lnvention, and the best mode contemplated by the inventor of
carrying out ~he invention will now be dascribed so as to
enable any person skilled in the art to which it pertains to
make and u~e the same. The meltlng poin~s are uncorrec~ed
unless noted otherwise.
- 12
Preparation of Intermediate~
___
~ ion 1
To a solution of 22 g. (0.1 mole) o~ 3,4-diphenyl-
- pyrazole in 150 ml. of dioxane was added 10 ml. of Trlton B
(~enzyl ~rimethylammonium hydroxide), and the ~olution then
treated dropwise with 26~3 ml. (0.4 mole~ of acrylon~trlle
while maintaining the temperature at 40 45C. The mixture
was stirred for an additional twenty minutes at ambient
temperature, acidi~ied by the addition of 3 ml. of ac~tic
acid and poured into 700 ml. of ice/water. The mixture was
then treated with 200 ml. of ethyl acetate and about one
tablespoon o sodium chloride, shaken and filtered to remove
: an insoluble precipitate~ The organic layer was separated
: from the filtrate, and the aqueous layer extracted twice
I5 with ethyl acetate. The combined organic extra~t~ were
washed with saturated sodium bicarbonate, then with brine,
dried over magnesium sulfate, aharcoaled, filtered and
e~aporated to dryness to give a red oil which w~s crystal-
lized from 60 ml. of methanol. There was thus obtained 13.82 g.
of material, m.p. 90 103C. which, on gas chromatographic
analysis, showed the presence of two isomers in a ratio ~f
13/87 comprislng 13% of the 4,5-diphenyl isomer and ~7% of
the 3,4-diphenyl isomer o~
yrazole.
: In another run, a thin suspension of 7.7 g.
(0~14 mole) potassium hydroxide and 805 g. (3- 65 moles)
3~4 diphenylpyrazole in 3.4 liters o~ ethanol was st1rred
rapidly while treating with 292 ml. (4.4 mole~) o~ acrylo-
nitrile added dropwi~e over a two hour pariod. When addition
was complete~ stirring was continued for two hours while
~ 13 -
S~
cooling in an external ice bath, and the mixture was
then allo~ed to stand for two days at ambient temperature.
The mixture wa~ then cooled once again to 0C. and the
~olid product collected and dried to give 723 g. of material,
m.p. 103-108C. Recry~tallization of the latter fxom ethanol
afforded 681 g. of material, m.p. 108-111C. (~oft~ 106C.)
which was shown by vapor phase chromatography to be 92-93%
o the 3,4-isomer and 6-7~ of the 4,5-diphenyl isomer of
~.
Preparation 2
Tv a solution of 28 g. (0.127 mole) of 3,4-diphenyl-
pyrazole in 130 ml. o~ dioxane was added 11 ml. of Triton B.
The solution was then treated dropwise at ambient temperature
with ~5 ml. of methyl acrylate over a period of about fifteen
minutes. The mixture was stirred for an additional hour and.
forty-~ive minutes, acidified to p~ $.5 wit~ acetic acid
..and then poured onto ice. The mixture was worked up in the
; manner describea above in Preparat~on 1 to give 4.0 ~. o~
: a mixture of methyl ~-[1-(3j:4-diPhenYI~ Yrazolyl)]~ro~
: 2~ ~ and methyl~ -[1~(4,5-diphenyl-lH-pyrazolyl)]~ro=
.
~ as an oil.
: . The ~rude mixture obtai~ed above wa dissolved in
about 80 ml. of methanol, the soIution ~reated with 130 ml.
of a ~N solut:ion of potassium hydroxide in.methanol and then
refluxed for two hours.. The bulk of the solvent was then
: removed ln vacuo and ~he residue treated with dilute hydro-
ch~oria acid and ethyl acetate. On cooling, the mix~ure
3e~ up into a white mas~, which was triturate~ with water
and adjusted to pH 2 with hydrochloric acid. The solid
material w~s collected by filtra~ion to give 40.1 g. of a
- 14 -
` ~
mixture consisting e~-en~ially o~ abouL 85~ ~-[1~(3,4-
diphe~yl-lH-~razolyl?]propionic acid and 15% of ~ -(4,5-
di~henyl-lH-pyrazolyl)]pro~onic acid~ The crude material
was slurried with acetonitrile and filtered to give 30.1 g.
of the pure 3,4-diphenyl isomer, m.p. 184.5-187C.
The latter (7.0 g~, 0.024 mole) was slurried in
50 ml. o chloroform and the slurry added to 3.22 g.
(0 027 mole) of thionyl chloride. The mixture was refluxed
for about an hour with stirring, ~hen charcoaled, filtexed
and the solvent removed ln vacuo from the filtrate. The
residue was dissolved in 5~ ml. of tetrahydrofuran and the
solution added dropwise with stirring to a solution o~
25 ml. of 6N dimethylamine in tetrahydrofuran while main- -
taining the temperature at about 0-10C. When addition
was complete the mixture was allowed to warm to ambient
temperature, then refluxed for one hour and.poured intb
150 ml. of ice water and extrac-ted i~to three S0 ml.
portions of ethyl acetate~ The combLned e~hyl acetate
extracts were washed with water, then with 10% po~assium
carbonake, then with brine, dried over sodium ~ulfate,
filtered and taken to dryness to give 6 g. of a pale yellow
oil. The latter was chromatographed on 500 g. o~ silica
gel in ethyl acetate wi~h ethyl acetate elution. After
removal of about 750 mg. o ma~erial, elution was ~witched
to 5~ methanol in ethanol to give 3.50 g. of mater~al with
R30.31 which consisted of ~-[1 ~3,4-diphenyl-lH-~yrazolyl)]-
N,N-dimeth~propionamide as a yellow gum.
Pr~aration 3
A solution of 105 g. (0.47 mole) of ~ormyldesoxy-
benzoin and a molar equi~alent amou~t of 2-hydroxyethylhydra-
- 15 -
zine in 450 ml. of absolut2 ethanol was heated under xeflux
for two and a hal to three hours, then cooled, and the
solid which precipated was coll~cted by filtration. The
filtrate was taken to dryne~s to give a brown oil which
was dissolved in chloroorm, washed with water and then
evaporated to dryness to give 53 g. of off white materlal
having m.p. 99-105Co The latter wa~ recrystalli~ed ~rom
a solution of about 40 ml, of ethylene dichloride and
100 ml. of pentane to give 46 5 g. of 1- ~ ~ hy
~ , m,p. 102-103C., shown ~y gas
i
chromatography to be approximately 9i-98% pure 3,4-diphenyl
isomer. ~.
A solution of 32.6 g. (0~12 mole) of the latter i,
ln 130 ml. of pyridine was mixed with a solution of 24.5 g.
~0.13 mole) of p~toluenesulfonyl chloride in 75 ml. o~
pyridine and the solution stored in a refrigerator for
about eighteen hour~. The solid which had separated was
collected by filtration, and the ~iltrate poured lnto
about five volumes of ice/water. ~he mix~ure was allowed
to stand at about 0C. for two hours, then the liquid
decanted from the gummy solid whlch was slurried with
ether to leave a solid material which was slurried with
cold methanol to give 15 g. of ~
ethy~]-3,4-di~henyl-lH-pyrazole, m.p. 109-llO~C. as a white
solid.
.
Example 1
A. To a slurxy o~ 13.8 g. (0.05 mole~ o~ 1-(2-
cyanoethyl)~3,4-diphenyl-lH-pyrazole described in Prepara-
tion 1 above in a solution of 100 ml. o~ methanol containing
S2~
anhydrous ammonia wa~ added a small amount of Raney nickel
catalyst and the mixture reduced in a Parr shakar at
50 p.s.i. hydrogen pressure. After three days the mixture
was filtered, and the filtrate taken to dryness leaving a
residue which was dissolved in 40 ml. of isopropanol and
30 ml. of isopropyl acetate. The solution was treated with
20 ml. of 5.7N hydrogen chloride in ethanol, and the solid
which separated was collected, rinsed with additional solvent
and dried to give 15.2 g. of
~ , m.p. 177-188C. which was shown
by gas chromatography to be 94% pure isomer.
B. Following a procedure similar to that described
in part A above, 27.3 g. (0.1 mole) o~ the 87~ pure 1-(2-
cyan~ethyl)-3,4-diphenyl-lH~pyrazole described in Preparation
1 above in a solution of methylamine in ethanol was reduced
with hydrogen over a Raney nickel catalyst at S0 p.~.i. and
.... ..the product, after isolati~n in the manner described in part
. A, converted to the hydrochloride salt which was recrystal-
lized fr~m ethanol. There was thus obtained 5~9 g. of 1-~3-
~0
m.p. 124-132C.
C. Following a procedure similar to that describ~d in
part A above, in three separate xuns, 100 y. ~0.36 mole)
poxtions of the 92-93~ pure 1-(2-cyanoethyl)-3~4-diphenyl~lH-
pyrazole described in Preparation 1 above in a solution con-
~aining 110-120 g. of mé~hylamine in 960 ml. o~ ethanol were
reduced over 5 g. of 10~ palladium-on-charcoal and the product
converted first to the oxalate salt (m.p. 140`143C) which was
reconver~ed to the ree base and the latter converted to
the dihydrochloride salt which was recrystallized from isopro-
- 17 -
35~7
panol to give a total yield from all three runs of 262 g.
of l-[3-(N,N-dlme th~lamino?~ yl~-3,4~d~henyl-lH~yra~ole
~t:,~r de, m.p. 183~185C,(so~t. 175C.). The latter
- was estimated by thin laye~ chromatography to contaln from
1~2% total impuritie~. (See Example 2).
Exam~le ?
To a stirred slurry of 0.42 g. (0.011 mole) o~
lithium aluminum hydride in 50 ml. of tetrahydrofuran was
added 3.5 g. (O.Oll mole) o~ ~-[1-(3,4-diphenyl-lH-
pyxazolyl)]-N,N-dimethylpropionamide and the mixture stir~ed
and refluxed fox about eighteen hours. The reaction mixture
was then decomposed by the careful addition of 0.4 ml. of
water followed by 0.6 ml. of ten percent sodium hydroxide,
~ollowed by an additional 1 ml. of water. The mi~ture was
stirred or an hour, then filteredf and the filtrate taken
to dryness in vacuo. The residue, consisting o~ 3.0 g. of
a yellow oil, was dissol~ed in isopropyl acetate and the
.qolution treated with 4 ml. of a 6N solution ~f hydrogen
: chloride in ethanol. The solid which saparated was collected
:~20 and recrystallized from isopropanol containing an additlonal
. ::
amount of hydrogen chloride in ethanolr ~here was thus
obtained 1.2 g. of 1-[3-~N,N-dimethy ~ ]-3,4-
diphenyl-lH-~yrazole d ~ drochloride, m.p. 170-174C.
A mixture of 29.5 g. (0.073 mole~ of 1-[2-~4-
toluenesulfonyloxy)ethyi]-3,4-diphenyl-lH-pyrazole and
103 ml. of dimethylamine in ~00 ml. of acetonitrlle wa~
heated in an autoclave for nine h~urs at 120-~130C. ~he
reaction mixture was:~ashed out o~ the autoclave with
acetonitrile, and the mixture was taken to dryness in
- 18 ~
vacuo. The residue was suspended in 800 ml. of ethyl
acetate and the suspansion washed with water con~aining a
small amount of sodium hydroxide, The organic layer was
then washed with brine, dried and taken to dryness to give
28 g. of a brown oil whlch was distilled ln vacuo. The
fraction collected at 81-100C./0.01 mm. ~15.3 g.) was
dissolved in diethyl ether and treated with a solution o~
hydro~en chloride in methanol. The solid which separated
was recrystallized from acetone to give 10.5 g. of 1-[2-(N,N-
diethylamino)ethyl]-3,4-di~henyl-lH-pyrazole h~drochloride,
m.p. 147-148C.
A mixture of 4.2 g. (0.1 mole) of sodium hydride
in 100 ml. of tetrahydrofuran and 22.0 g. (0.1 mole) of 3,4-
diphen~lpyrazole in 150 ml. of tetrahydrofuran was heated
wikh stirriny until a clear solution was obtained. The
mixture ~as then treated with 14.9 g. of N-(3-chloropropyl)-
N,N-diethyamine. The solution ~was refluxed for thirty hours,
then iltered and stripped to dryness in vacuo. The re~idue
was taken into ethyl aceta~e, extracted i~to dilute
hydrochloric acid and th~ acid solution washed once with
ethyl acetate and neutralized with potassium carbonate. The
aqueous mixture was then extracted with ethyl acetate and khe
organic extracts washed twice with brine, dried and taken to
dryness to gi~e 20.4 g. of a yellow oil. The latter was
dissolved in diethyl ether, treated with a molar equi~alent
amount of methanolic hydrogen chloride, and the solid which
~eparated after cooling was collected and dried to give 20.2 g.
of crude hydrochloride. The latter was reconverted to the free
base which was dissolved in chloroform and the chloroform
-- 19 --
5~
solution washed four time~ with 125 ml. portions of watex.
The organic layer wa~ then dried, taken to dryness and
the residue redis~olved in diethyl ether and treated again
with excess methanolic hydrogen chloride. There was thu~
obtained 16.5 g. of a 1,1 mixture of ~ -
~ and the cor-
responding isomeric 4,5-diphenyl compound, m.p. 143-146C.
The latter t800 mg.) was dissolved in methanol and
applied to four 20x40 cm. silica gel thin layer chromato-
graphy plates. The plates were eluted with a l9ol solution
of 95% ethanol/concentrated ammonium hydroxide, and the
upper one thixd of the plate, containing material wi h the
higher Rf value, was cut away from the lower two thirds
~ection, and both sections were separately extracted with
lS a 1:1 solution of chlorofoxm/methanol. The higher R~ frac-
tion was shown by gas chromatography to be 97~99% pure
4,5~diphenyl isomer, and the 1~3war R~ ~rac~ion wa~ shown to be
82/18 3,4-/4,5-isomer mixture. The higher R~ frac~ion origina~ly
obtained as an oil, was crystallized ~rom acetone/hexane to
give 75 mg. of 1 3 ~ ~ ~L
, m.p. 148-149C., shown by gas
~hromatography to be 99O8% pure 4,5-isomer.
The lower Rf fraction, on repeated recxy~talliz~-
tion from acetone/hexans, gaYe 103 mg. of ` ~ -
amlno)pro~yl]-3,4-diphenyl- H-~xrazole_hydrochlorlde, m.p.
165~166C., shown by gas chromatography ~o be 98% pure 3,4-
isomer. ~Noke the hydrochloride salts o~ both isomers were
carried through the chromatography and separakion despi~a
the use of concentrat0d ammonium hydroxide in the elution.)
~0
5'~7
A solution o~ 11.5 g. (0,04 mole) o~ 1-(3-
aminopropyl)-3,4-diphenyl~lH-pyrazole and 60 ml. of 35
Aqueous formaldehyde in 12S ml. of ethanol was reduced
in a Parr shak~r over 500 mg. of platinum oxide at 50 p.s.i.
hydrogen pressure. Reduction was interrup~ed after the
uptake of 29 p.s.i., another 500 mg. of catalyst was added,
and reduction was continued until an additional 39 p.s. io had
been taken up. Reduction was once again interrupted,
lG addi~ional formaldehyde and catalyst were again added and
reduction continued until a final 31 p~s.i. had been tak~n
up. The mixture was worked up in the manner described in
Example lA above and the product converted to the hydro-
chlorlde salt to give two crops totalling 6.6 g. of 1-[3-
IS (N!N-dimethylamino)propyl]-3,4-di~henyl-l~p~razole dih~dro-
chloride, 4.0 g., m9p. 178-191C. and ~.6 g., m.p. 185-19l.C
BIOLOGICAL TEST RESULTS
, _ . . .
Results obtained in the anti-tetrabenazine (TB3,
the acetylcholine (Ach) and the phenylquinone induced
: ~0 w~i~hing tests (PPQ~ on the 3,4~diphenyl compounds o~
the invention are set forth in the table below. All 3,4-
diphenyl compounds are iden~ified by the ~xample number~
above where their preparations are described, and all
doses are expressed in milligrams per kilogram (mg O /
~ TB Ach PPQ
lA Inac.(a) - ~D50=11 (s.c,) -
18 Act./16,64 - -
Inac./4
2 ~ct./4,~,16 - -
Inac~/2 .
~ 21 -
Exam~ TB ch PPQ
3B Inac. (a) 60%/100 1Q.C.) ED50~90 (P,O,)
67%/50 (~ . c~
S3%/10 (s . c. )
- ED50=29 (p.o. )
4 Inac. (a) EI:50-2.2 (s.c.)
(a) Tested at 4, 16 ar~d 64 mg . /kg c (p~ o . )
. .,
- 2~ -
.
.
