Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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~055937
This invention relates to compounds of the formula:
N- N'' R
R-CH ~, IH-R3
1111 4
wherein R and R3 are ~ ~ or ~
X and Xl are hydrogen, chloro, fluoro, lower alkyl, lower
alkoxy or trifluoromethyl; Rl is hydrogen, lower alkyl,
X ~ lower alkyl, hydroxy lower alkyl or lower alkanoyl;
R is B- lower alkyl wherein B is di-lower alkylamino, lower
alkyl amino, piperidino, pyrrolidino, morpholino, N-lower
alkyl piperazino and N-(2-hydroxyethyl)piperazino; and
N-oxides and the acid addition salts thereof.
1055937 MT62
In addition, this invention encompasses the methods
for preparing said compounds, pharmaceutical compositions
containing said compounds and methods for using said compo-
sitions as central nervous system depressants.
The term "lower alkyl" is intended to mean a straight
or branched hydrocarbon fragment of from one to eight carbon
atoms.
The term "lower alkoxy" is intended to mean "lower
alkyl-O-".
TOhe term "lower alkanoyl" is intended to mean "lower
alkyl -C-".
The term "acid addition salts" is intended to mean
salts which may be formed for the purpose of isolation,
purification and storage, such as the oxalate salt, etc. and
pharmaceutically acceptable salts meant for administration
of the compound to a host, such as the hydrochloride, sulfate,
acetate, citrate, etc.
The compounds of this invention are prepared in the
following manner. Compounds of the formula II .
R-CH f
II III
~ 3
IV V
105593'7
wherein Rl is as previously defined, are reacted with com-
pounds of the formula RCHO, wherein R is as previously de-
fined utilizing the reaction procedure described in The
Journal of the American Chemical Society, _, 1824 (1948),
to give compounds of the formula IV. By adjusting the
ratio of reactants so as to have an excess of the compound
of formula II present, compounds of formula III are prepared.
Compounds of the formula V are prepared by reacting
compounds of the formula III with an aldehyde of the formula
R3CHo, wherein R3 is as previously described, in the manner
described in The Journal of the American Chemical Society,
70, 1824 (1948).
The compounds of the formulae IV and V are generally
isolated in the form of their acid-addition salts.
The compounds of the formulae IV and V, preferably in the form
of their salts, such as the hydrochloride salt, sulfate salt,
phosphate salt, etc. are converted to a compound of the formula I
by reaction with a hydrazine of the formula H2NNHR2, wherein R2 is
as previously defined in an organic solvent, preferably an
alcohol of up to four carbon atoms at temperatures of from
about 40C to about 120C, preferably at about the reflux
temperature of the solvent, for from about 1/2 hour to about
12 hours, preferably 4 hours. Alternately, the compound of
this invention may be prepared by heating the appropriate
hydroxy lower alkyl compound with p-toluenesulfonyl chloride
and then reacting the resulting tosylate with the appro-
priate amine, i.e.,
:..S','~
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~ N--alkyl--OH
R--Cl~/i ~H--R3 R--C~ kyl~O--Ts
~NJ TsCl ~, ~ N J
!l 11
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1055937
The preferred compounds prepared by these procedures
are those wherein R and R3 are phenyl, X and Xl are hydrogen,
Rl is lower alkyl or hydrogen and R2 is 3-dialkylaminopropyl.
The 2-amino-lower alkyl-7-substituted-3,3a,4,5,6,7-
hexahydro-3-substituted-2H-pyrazolo[4,3-a]pyridines, their
N-oxides and their non-toxic pharmaceutically acceptable
mono- or di-acid addition salts are useful as central nervous
system depressants in mammals when administered in amounts
ranging from about 0.5 mg to about 10.0 mg per kg of body
weight per day. A preferred dosage regimen for optimum re-
sults would be from about 1 mg to about 5 mg per kg of body
weight per day, and such dosage units are employed that a
total of from about 35-mg to about 7 g of active ingredient
for a subject of about 70 kg body weight are administered in
a 24 hour period.
The compounds of the present invention in the described
dosages are intended to be administered orally; however,
other routes, such as rectally, intraperitoneally, subcutaneously,
intramuscularly or intravenously may be employe-d.
The active compounds of the present invention are
orally administered, for example, with an inert diluent or
with an assimilable edible carrier, or they may be enclosed
in hard or soft gelatin capsules, or they may be compressed
into tablets, or they may be incorporated directly with the
food of the diet. For oral therapeutic administration, the
active compounds of this invention may be incorporated with
excipients and used in the form of tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, chewing gum, and the
like. Such compositions and preparations should contain at
--5--
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1055937
least 0.1% of active compound. The percentage in the com-
positions and preparations may, of course, be varied and may
conveniently be between about 5~ to about 75~ or more of the
weight of the unit. The amount of active compound in such
therapeutically useful compositions or preparations is such
that a suitable dosage will be obtained. Preferred compo-
sitions or preparations according to the present invention
are prepared so that an oral dosage unit form contains be-
tween about 2 and 500 milligrams of acti`ve compound, pre-
ferably between 2 and 25 mg.
The tablets, troches, pills, capsules and the like
may also contain the following: a binder such as gum tra-
gacanth, acacia, corn starch or gelatin; an excipient such
as dicalcium phosphate; a disintegrating agent such as corn
starch, potato starch, alginic acid and the like; a lubri-
cant such as magnesium stearate; and a sweetening agent such
as sucrose, lactose or saccharin may be added or a flavoring
agent such as peppermint, oil of wintergreen, or cherry
flavoring. When the dosage unit form is a capsule, it may
contain in addition to materials of the above type a liquid
carrier such as a fatty oil. Various other materials may
be present as coatings or to otherwise modify the physical
form of the dosage unit, for instance, tablets, pills or
capsules may be coated with shellac, sugar or both. A
syrup or elixir may contain the active compounds, sucrose
as a sweetening agent, methyl and propyl parabens as pre-
servatives, a dye and a flavoring such as cherry or orange
flavor. Of course, any material used in preparing any
dosage unit form should be pharmaceutically pure and sub-
stantially non-toxic in the amounts employed.
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1055937
The following examples are provided for illustrative
purposes and may include particular features of the in-
vention; however, the examples should not be construed as
limiting the invention, many variations of which are possible
without departing from the spirit or scope thereof.
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1055937
Example 1
- 7-Benzylidene-2-[3-(dimethylamino)propyl]-3,3a,4,5,-
6,7-hexahydro-5-methyl-3-phenyl-2H-pyrazolo[4,3-d]-
pyridine, hydrochloride
.
A. 3,5-Dibenzylidene-l-methyl-4-piperidone, hydro-
chloride
A solution of 57.0 g (0.5 mole) of 1-methyl-4-piperi-
done and 106.0 g (1.0 mole) of benzaldehyde in 400 ml of
ethanol is cooled in an ice bath and treated with HCl gas
until 250 g is absorbed. The red-colored solution is
allowed to stand at room temperature overnight. The re-
sulting deep red-brown solution is seeded, allowed to stand
overnight at room temperature, and the crystalline solid is
filtered on a sintered-glass funnel and washed with cold
ethanol, followed by ether. After drying in a desiccator,
the solid (146 g) is digested in 400 ml of hot ethanol (75),
cooled and filtered to give 120 g (74~) of pale yellow pro-
duct, m.p. 242-244(dec).
Recrystallization of 11 g of this material from 35 ml
of dimethylformamide (DMF) gives 9.2 g of product, m.p.
242-244(dec).
- B. 7-Benzylidene-2-[3-(dimethylamino)propyl]-3,3a,-
- 4,5,6,7-hexahydro-5-methyl-3-phenyl-2H-pyrazolo-
[4,3-c]pyridine, hydrochloride
Ten grams (0.031 mole) of 3,5-dibenzylidene-1-methyl-4-
piperidone HCl was reacted with 3.8 g (0.032 mole) of 3-di-
methylaminopropylhydrazine [See Nogrady & Morris, Can. J.
Chem., 47, 2001 (1969); bp 80-85/10 mm] in 100 ml of MeOH
and refluxed for 4 hours. Evaporation of the MeOH left 14 g
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of a yellow foamy residue. This was suspended in 100 ml of
MeOH, layered over with 100 ml of ether, stirred, basified
with K2CO3, the layers separated, the aqueous phase extracted
with ether, the combined ether layers dried (MgSO4), and the
solvent evaporated to give 11.5 g of viscous base.
A solution of the base in 60 ml of warm MeCN was
treated with a warm solution of 7.8 g of oxalic acid in 60 ml
- of MeCN. The oxalate separated as an oil which slowly became
crystalline on rubbing, standing at room temperature, and
finally cooling; wt., 16.5 g; m.p. 170-172 (foaming).
Crystallization from 50 ml hot DMF-150 ml MeCN gave 13.6 g of
a pale yellow solid; m.p. 148-151(foaming); s. 115.
The dioxalate was converted to the base as above and
the latter (8.4 g) was dissolved in 80 ml of MeCN, cooled,
treated with 7 ml of 6.2 N alcholic HCl, and poured into
500 ml of stirred ether to precipitate the solid 2 HCl salt.
The latter was filtered under N2, washed with ether, and
dried in vacuo; wt., 9.2 g; m.p. 159-161(foaming); s. 135.
Following crystallization from a boiling mixture of 50 ml of
MeCN and 50 ml of EtOAc gave 7.7 g of pale yellow solid;
m.p. 174-176(dec).
Example 2
7-Benzylidene-2-[3-(dimethylamino)propyl]-3,3a,4,5,-
6,7-hexahydro-3-phenyl-2_-pyrazolo[4,3-c]pyridine,
hydrochloride
A. 3,5-Dibenzylidene-4-piperidone, hydrochloride
14 Grams (0.1 mole) of N-acetyl-4.piperidone and 32 g
(0.3 mole) of benzaldehyde are reacted in 150 ml of EtOH con-
taining 33 ml of concentrated HCl. A solid separates after
_g_
~055937 MT62
approximately 45 minutes of refluxing. Refluxing is con-
tinued for a total of 6 hours, and the mixture is kept
overnight at room temperature.
The light yellow solid is filtered, washed with EtOH,
then with ether, and air-dried; weight 26 g; m.p. 273-275
(dec).
B. 7-Benzylidene-2-[3-(dimethylamino)propyl]-3,3a,4,5,6,7-
hexahydro-3-phenyl-2H-pyrazolo[4~3-c]pyridine~
hydrochloride
A mixture of 9.6 g (0.031 mole) of the material from Part A,
3.8 g (0.032 mole) of 3-dimethylaminopropyl hydrazine and 100 ml
of methanol was reacted in the same manner as in Example I to
give 16.7 g of the oxalic acid salt, mp 149-152. After
crystallization from some of dimethylformamide-50 ml of
acetonitrile, the light yellow solid weighed 13.5 g., mp
165-167 (s. 15~ . This oxalic acid salt was connected to the
dihydrochloride salt according to the procedure described in
Example I to give 6.1g of materia~mp 181-183(dec.). After
recrystallization from 30 ml. of methane 35 ml. of ether, the
pale yellow product weighed 4.6 g., mp 201-203(dec.).
--10--
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Example 3
7-Benzylidene-2-[2-(dimethylamino)ethyl]-3,3a,4,5,6,7-
hexahydro-5-methyl-3-phenyl-2_-pyrazolo[4,3-c]pyridine,
hydrochloride
A. 7-Benzylidene-3,3a,4,5,6,7-hexahydro-5-methyl-3-
phenyl-2_-pyrazolo[4,3-c]pyridine-2-ethanol,
hydrochloride (1:2)
A suspension of 10 g (0.0306 mole) of 3,5-dibenzylidene-
l-methyl-4-piperidone, hydrochloride in 100 ml of MeOH is
treated with 2.35 g (0.031 mole) of (2-hydroxyethyl)hydra-
zine; a solid rapidly separates. The mixture is heated and
the resulting solution is refluxed for 4 hours, cooled, and
the bulk of MeOH evaporated to give 12.5 g of a golden yellow
foamy residue. The latter is triturated with ether, cooled
overnight, filtered, and dried in vacuo; weight 11.6 g; m.p.
100-102. A cooled solution of this material in l00 ml of
CH3CN is treated with 4.8 ml of 6.4 N ethanolic HCl. On
rubbing, the crystalline 2 HCl salt separates. After cool-
ing overnight, the yellow solid is filtered, wa~hed with
CH3CN and ether, and dried in vacuo; weight 8.2 g m.p.
135-137(foaming). Following crystallization from 70 ml
MeOH-150 ml ether, the light yellow material weighs 6.2 g;
m.p. 142-144(foaming).
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B. 7-Benzylidene-3~3a~4~5~6~7-hexahydro-5-methyl-3-phen
2H-p~_zolo-[4,3-c]pyridine-2-ethanol, tosylate ester,
hydrochloride.
A stirred solution of 16.8 g (0.048 mole) of the free base
of the material from Part A in 80 ml of pyridine was cooled to
5 and treated dropwise with a solution of 10 g (0.052 mole) of
tosylchloride in 30 ml of pyridine; the temperature remained at
4 5. After standing overnight at room temperature, the reddish
solution was poured into 1.2 liters of stirred ether to pre-
cipitate the product.as a gum which became granular on rubbingand cooling overnight. The ether liquor was decanted and the
material was crystallized from 150 ml of MeCN. The yield of
nearly colorless product was 14.7 g (57%); mp 131-133 (foaming).
C. 7-Benzylidene-2-[2-(dimethylamino)ethyl]-3,3a,4 ! 5!6_'7-
hexahydro-5-methyl-3-phenyl-2H-pyrazolo[4~3-c]pyridine~
hydrochloride (1:2):
A stirred suspension of the material from Part B (14.6 g;
0.027 mole) in 350 ml benzene was treated with a cold solution
of 50 g of dimethylamine in 200 ml of benzene and kept at room
temperature for 4 days~ After refluxing for 6 hr., the bulk of
benzene was evaporated, the residue was shaken with 250 ml of ether
and 125 ml of H2O, basified with excess K2CO3, the layers
separated, the aqueous phase extracted with ether (2 X 125 ml),
the combined ether layers dried (MgSO4), and the solvent
evaporated to give 9~2 g of viscous base~ The latter was dis-
solved in 50 ml of warm MeCN, stirred, and treated with a warm
solution of 6~7 g of oxalic acid in 5.0 ml of MeCN~ The oxalate
separated as an oil which readily crystallized on rubbing and
cooling overnight~ wt~, 14~5 g; mp 166-168 (foaming at 180)~
-12-
~055937 MT62
Following crystallization from 40 ml of hot DMF- 120 ml MeCN,
the cream-colored solid weighed 11.7 g; mp 201-203.
The dioxalate salt was stirred with 250 ml of H2O and 125
ml of ether, basified with K2CO3, the layers separated, the
aqueous phase extracted with ether (3 X 50 ml~, the combined
ether layers dried (MgSO4), and the solvent evaporated to give
7.4 g of viscous base. TLC: 1 spot (EtOAc on alumina; Rf 0.60).
A cooled and stirred solution of the base in 75 ml of MeCN
was treated with 6.4 ml of 6.2 N alcoholic HCL and diluted to
400 ml with ether. The 2 HCL salt separated as a gum which
became granular on rubbing. After cooling overnight, the material
was filtered under N2, washed with ether, and dried 1n vacuo;
wt., 8.6 g (68%); mp 124-127 (s.96). Since attempts to
crystallize the product were unsuccessful, it was dissolved in
75 ml of MeCN, filtered, and added portionwise to 700 ml of
stirred ether to reprecipitate the light yellow solid. The final
yield of slightly hygroscopic material was 8.1 g (64%); mp
132-135(s.96).
-13-
M~6Z
1055937
ExamEles 4-6
2-[3-(Dimethylamino)propyl]-7-heterocyclyidene-
3,3a,4,5,6,7-hexahydro-5-methyl-3-heterocyclic-2H-
.
pyrazolo[4,3-c]pyridine, hydrochlorides
A. 3,5-Disubstltuted-l-methyl-4-piperidones
According to the procedure of Example 1, upon sub-
stituting in place of benzaldehyde, one of the following
compounds:
thiophene-2-carboxaldehyde,
pyridine-4-carboxaldehyde, and
thiophene-3-carboxaldehyde;
one obtains:
3,5-bis-(2-thienylidene)-1-methyl-4-piperidone, hydrochloride;
3,5-bis-(4-pyridylidene)-1-methyl-4-piperidone, hydrochlorlde;
- and
3,5-bis-(3-thienylidene)-1-methyl-4-piperidone, hydrochloride,
respectively.
B. 2-[3-(Dimethylamino)propyl]-7-heterocyclyidene-
3,3a,4,5,6,7-hexahydro-5-methyl-3-heterocyclic-2H-
- ~
pyrazolo[4,3-c]pyridine, hydrochlorides
According to the procedure of Example i, upon
substituting the above compounds, one obtains:
2-[3-(Dimethylamino)propyl]-7-(2-thienylidene)-3-(2-thienyl)-
3,3a,4,5,6,7-hexahydro-5-methyl-3-2H-pyrazolo[4,3-c]pyridine,
hydrochloride;
2-[3-(Dimethylamino)propyl]-7-(4-pyridylidene)-3,3a,4,5,6,7-
hexahydro-5-methyl-3-(4-pyridyl)-2H-pyrazolo[4,3-c]pyridine,
hydrochloride; and
2-[3-(Dimethylamino)propyl]-7-(3-thienylidene)-3,3a,4,5,6,7-
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1~55937
hexahydro-5-methyl-3-(3-thienyl)-2H-pyrazolo[4,3-c]pyridine,
hydrochloride,
respectively.
Example 7
7-(o-Chlorobenzylidene)-3-(o-chlorophenYl)-2-r3-(dimethylamino)-
propyll-3,3a,4,5,6,7-hexahydro-5-methyl-2H-pyrazolo~4,3-c]-
p~yridine, hydrochloride
A. 3,5-Bis(o-chlorobenzylidene)-l-methyl-4-piperidone,
hydrochloride
A mixture of l-methyl-4--piperidone (22.6 g; 0.2 mole),
85 g (0.6 mole) of o-chlorobenzaldehyde, concentrated HCl
(66 ml) and EtOH (300 ml) are refluxed together for 5 hours.
After removal of solvent, the crude product weighs 9.3 g
(12~), m.p. 218-220(dec). Crystallization from 20 ml of
hot DMF and 40 ml of MeCN gives 7.9 g (10~) of yellow solid;
m.p. 221-223(dec). Lit. m.p. 227-229(dec) [JACS, 70,
1825 (1948); different procedure].
B. 7-(o-Chlorobenzylidene)-3-(o-chlorophenyl)-
2-[3-(dimethylamino)propyll-3~3a~4~5~6~7-hexahydro-5
methyl-2H-pyrazolor4,3-clpyridine, hYdrochloride
The above compound (7.7 g; 0.0195 mole) and 2.4 g
(0.02 mole) of 3-dimethylaminopropyl hydrazine are reacted
in 100 ml of MeOH as described in Example 1. Evaporation
of the MeOH yields the product.
-15-
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Examples 8-11
2-[3-(Dimethylamino)Propyl]-7-(substituted benzylidene)-
3-(substituted phenyl)-3,3a,4,5,6,7-hexahydro-5-methyl-
2H-pyrazolo[4,3-c]pyridine, hydrochlorides
A. 3,5-Di(substituted benzylidene~-l-methyl-4-
piperidone, hydrochloride
According to the procedure of Example 7, upon sub-
stituting in place of o-chlorobenzaldehyde, one of the
following compounds:
p-methoxybenzaldehyde,
m-ethylbenzaldehyde,
o-trifluoromethylbenzaldehyde, and
p-fluorobenzaldehyde,
one obtains:
- 3,5-bis(p-methoxybenzylidene)-1-methyl-4-piperidone,
hydrochloride,
3,5-bis(m-ethylbenzylidene)-1-methyl-4-piperidone, hydro-
chloride,
3,5-bis(o-trifluoromethylbenzylidene)-1-methyl-4-piperidone,
hydrochloride, and
3,5-bis(p-fluorobenzylidene)-1-methyl-4-piperidone,
respectively.
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s. 2-[3-(Dimethylamino?propyl]-7-(substituted benzyli-
dene)-3-(substitute_ phenyl ? -3,3a,4,~,6 ! 7-hexa-
hydro-5-methyl-2H-pyrazolo[4,3-c]pyridine, hydro-
.. . . . . _ _
chlorides
. . .
According to the procedure of Example 1, upon sub-
stituting the above compounds, one obtains:
2-[3-(dimethylamino)propyl]-7-(_-methoxybenzylidene)-3-
(p-methoxypehnyl)-3,3a,4,5,6,7-hexahydro-5-methyl-2_-
pyrazolo[4,3-c]pyridine, hydrochloride;
2-[3-(dimethylamino)propyl]-7-~m-ethylbenzylidene)-3-(m-
ethylphenyl)-3,3a,4,5,6,7-hexahydro-5-methyl-2H-pyrazolo
[4,3-c]pyridine, hydrochloride;
2-~3-(dimethylamino)propyl]-7-(o-trifluoromethylbenzylidene)-
3-(_-trifluoromethylphenyl)-3,3a,4,5,6,7-hexahydro-5-methyl-
2H-pyrazolo[4,3-c]pyridine, hydrochloride; and
2-[3-(dimethylamino)propyl]-7-(_-fluoromethylbenzylidene)-
3-(p-fluorophenyl)-3,3a,4,5,6,7-hexahydro-5-methyl-2_-
pyrazolo[4,3-c]pyridine, hydrochloride, respectively.
Example 12
7-(p-Chlorobenzylidene)-3-(p-chlorophenyl)-2-[3-(di-
methylamino)propyl]-3,3a,4,5,6,7-hexahydro-5-methyl-
2H-pyrazolo[4,3-c]pyridine, hydrochloride (1:2)
A. 3,5-Bis(p-chlorobenzylidene)-l-methyl-4-piperidone,
hydrochl_ride
l-Methyl-4-piperidone (22.6 g; 0.2 mole) and 85 q
(0.6 mole) of _-chlorobenzaldehyde are reacted in 300 ml of
EtOH in the presence of 66 ml of concentrated HCl according
to Example 7 to give 19 g (24%) of crude product; m.p.
253-255(dec). Following crystallization from 120 ml of hot
.
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DMF and 2~0 ml of MeCN, the yellow solid weighs 13.7 g
(17%); m.p. 256-258(dec).
B. 7-(p-Chlorobenzylidene)-3-(p-chlorophenyl~2-
.
[3-(dimethylamino)propyl]-3,3a,4,5,6,7-hexahydro-5-
methyl-2H-pyrazolo[4,3-c]pyridine, hydrochloride (1:2)
The above material (9 g; 0.023 mole) and 3.0 g (0.025
mole) of 3-dimethylaminopropylhydrazine are reacted in 100 ml
of MeOH as described in Example 1 to give the product.
Example 13
2-[3-(Dimethylamino)propyl]-3,3a,4,5,6,7-hexahydro-5-
methyl-3-(2-pyridyl)-7-(2-pyridylidene)-2H-pyrazolo
[4,3-c]pyridine, hydrochloride (1:2)
A. l-Methyl-3,5-bis-(2-pyridyliden~-4-piperidone
l-Methyl-4-piperidone (11.3 g; 0.1 mole) and pyridine-
2-carboxaldehyde (32 g; 0.3 mole) are reacted in 150 ml of
EtOH containing 33 ml of concentrated HCl as described in
Example 5. The bulk of EtOH is evaporated and the residue
is diluted with 100 ml of H2O, washed with ether (2 x 100 ml;
washes discarded), cooled, basified with a cold solution of
20 g of NaOH in 60 ml of H2O, extracted with 3:1 ether-CHC13
(4 x 25 ml), dried (MgSO4), and the solvents evaporated to
give 34.7 g of a dark viscous oil.
The material s chromatographed on basic alumina (Woelm
Act. IV 25 g/l g). The desired product is eluted with
benzene and 90:10 benzene-EtOAc; crude yield 4.0 g (14%);
m.p. 134-137. Crystallization from 20 ml of MeCN gives 2.4 g
-18-
lO5S937 MT62
(8.3~) of yellow solid; m.p. 146-148. Lit. m.p. 147
[Buu-Hoi, et al. r Bull. Soc. Chim., 1964, 3096 (different
procedure)].
B. 2-[3-(Dimethylamino?propyl]-3,3a ! 4,5,6,7-hexahydro-
5- methyl-3-(2-pyridyl)-7-(2-pyridylidene)-2H-pyrazolo
,
[4,3-c]pyridine, hydrochloride (1:2)
A stirred suspension of the above material (2.4 g;
0.0083 mole) in 30 ml of MeOH is treated with 0.9 ml of 9.5 N
alcoholic HCl (1 equiv.) and then reacted with 1.05 g (0.0089
mole) of 3-dimethylaminopropylhydrazine as described in
Example 1 to give the product.
Examples 14-17
2-[3-(Dimethylamino)propyl]-7-(substituted benzylidene)-
3-phenyl-3,3a,4,5,6,7-hexahydro-5-methyl-2H-pyrazolo
[4,3-c]pyridine, hydrochlorides
A. 3-Benzylidene-l-methyl-4-piperidone-, hydrochloride(l:l)
A stirred solution of 22.6 g (0.2 mole) of 1-methyl-4-
piperidone and 16 g (0.15 mole) of benzaldehyde in 500 ml of
EtOH is cooled to 15 and treated portionwise with 66 ml of
concentrated HCl; the temperature is not allowed to exceed
25. After refluxing for 4.5 hours, the bulk of EtOH is
evaporated at 1 mm. The residue is diluted to 150 ml with
H2O, cooled, basified with a cold solution or 40 g of NaOH
in 120 ml of H2O, extracted with ether (4 x 200 ml), dried
(MgSO4), and the solvent is evaporated to give 24 g of oil.
The latter is redissolved in 300 ml of ether, washed with H2O
(4 x 50 ml), dried and the ether is evaporated. The residue
--19--
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1055937
(19 g) is distilled to give 3.9 g of the product as a
yellow oil; bp 137-143/0.1-0.2 mm.
The base is dissolved in 20 ml of MeCN, cooled, treated
with 3.1 ml of 6.3N alcoholic HCl, and diluted to 40 ml with
ether. On rubbing and cooling, the crystalline HCl salt
gradually separates crude yield 4.1 g (11%) m.p. 148-151"
(s. 135). Following crystallization from 20 ml of MeCN,
the cream-colored material weighs 2.7 g (7.3~); m.p. 150-152
(s. 138).
B. 3-Benzylidene-5-substituted-1-methyl-4-piperidone
According to the above procedure of this Example, upon
substituting in place of l-methyl-4-piperidone, the free
base of the product of part A above (3-benzylidene-1-methyl-4-
piperidone) and upon substituting in place of the benz-
aldehyde, one of the following compounds:
o-chlorobenzaldehyde,
o-(isopropyl)benzaldehyde,
m-trifluoromethylbenzaldehyde, and
o-methoxybenzaldehyde
one obtains:
3-benzylidene-5-(_-chlorobenzylidene)-1-methyl-4-piperidone
hydrochloride,
3-benzylidene-5-(o-isopropyl)benzylidene-1-methyl-4-
piper~idone hydrochloride,
3-benzylidene-5-m-trifluoromethylbenzylidene-1-methyl-4-
piperidone hydrochloride, and
3-benzylidene-5-o-methoxybenzylidene-1-methyl-4-piperidone
hydrochloride,
respectively.
-2~-
lOS 59 37 ~T62
C. 2-[3-(Dimethylamino)propyl]~7-(substituted
benzylidene)-3-phenyl-3,3a,4,5,6,7-hexahydro-
5-methyl-2_-pyrazolo[4,3-c]pyridine, hydro-
-
chlorides
The above material (0.021 mole) and 3-dimethylamino-
propylhydrazine (0.022 mole) are reacted in 100 ml of MeOH
as described in Example 1 to give:
7-(o-chlorobenzylidene)-2-[3-(dimethylamino)propyl]-3-
phenyl-3,3a,4,5,6,7-hexahydro-5-methyl-2H-pyrazolo[4,3-c]
pyridine hydrochloride;
2-[-3-(dimethylamino)propyl]-7-(o-isopropylbenzylidene)-3-
phenyl-3,3a,4,5,6,7-hexahydro-5-methyl-2_-pyrazolo[4,3-c]
pyridine hydrochloride;
2-[3-(dimethylamino)propyl]-7-(m-trifluoromethylbenzylidene)-
3-phenyl-3,3a,4,5,6,7-hexahydro-5-methyl-2H-pyrazolo
[4,3-c]pyridine hydrochloride; and
2-[3-(dimethylamino)propyl]-7-(o-methoxybenzylidene)-3-
phenyl-3,3a,4r5,6,7-hexahydro-5-methyl-2H-pyrazolo[4,3-c]
pyridine hydrochloride, respectively.
Example 18
.
7-Benzylidene-5-butyl-3,3a,4,5,6,7-hexahydro-2-[3-
(dimethylamino)propyl]-3-phenyl-2_-pyrazolo[4,3-c]
pyridine, hydrochloride (1:2), hydrate
A. 3,5-Dibenzylidene-l-butyl-4-piperidone, hydrochloride
A stirred solution of 31 g (0.2 mole) of 1-butyl-4-
piperidone and 64 g (0.6 mole) of benzaldehyde in 300 ml of
EtOH is cooled to 15, treated dropwise with 66 ml of con-
centrated HCl (the temperature rises to 25), refluxed for
-21-
1055937 MT62
5 hours, and kept overnight at room temperature.
The bulk of EtOH is evaporated and the syrupy residue
is cooled, diluted to 600 ml with H2O, treated with 300 ml
of ether, stirred, and rubbed; a solid gradually separates.
After cooling for several hours, the yellow solid is fil-
tered, washed with ether, and air-dried; weight, 36.7 g
(50%); m.p. 203-205. Following crystallization from 100 ml
of DMF, the material weighs 24.2 g (33%); m.p. 212-214.
B. 7-Benzylidene-5-butyl-3,3a,4,5,6,7-hexahydro-2-
[3-(dimethylamino)propyl]-3-phenyl-2H-pyrazolo[4,3-c]
pyridine, hydrochloride (1:2?, hydrate
The above prepared material (7.7 g; 0.021 mole) and
2.6 g (0.022 mole) of 3-dimethylaminopropylhydrazine are re-
acted in 100 ml of MeOH as described in Example 1 to give
the product.
Example 19
5-Benzyl-7-benzylidene-2-[3-(dimethylami~no)propyl]-
-
3,3a,4,5,6,7-hexahydro-3-phenyl-2H-pyrazolo[4,3-c]
.
pyridine, hydrochloride (1:2)
A. l-Benzyl-3,5-dibenzylidene-4-piperidone, hydro-
chloride
19 Grams (0.1 mole) of 1-benzyl-4-piperidone and 32 g
(0.3 mole) of benzaldehyde is reacted in 150 ml of EtOH in
the presence of 33 ml of concentrated HCl by the method
described in Example7 ; crude yield, 23 g (58%); m.p.
210-212(dec). Crystallization from 60 ml of hot DMF and
~055937 MT62
120 ml of MeCN gives 14.2 g (36%) of yellow solid; m.p.
216-218(dec).
B. 5-Benzyl-7-benzylidene-2-[3-(dimethylamino)-
propyl]-3,3a,4,5,6,7-hexahydro-3-phenyl-2H-pyrazolo
[4,3-c]pyridine, hydrochloride (1:2)
The above prepared material (12 g; 0.030 mole) and 3.8 g
(0.032 mole) of 3-dimethylaminopropylhydrazine are reacted
in 100 ml of MeOH as describe~ in Example 1 to give the product.
Example 20
7-Benzylidene-2-[3-(dimethylamino)propyl]-3,3a,4,5,6,7-
.
hexahydro-5- ~enzyl -3-phenyl-2H-pyrazolo[4,3-c]
pyridine, hydrochloride (1:2)
A. 3~5-Dibenzylidene-l-_benzyl -4-piperidone, hydro-
chloride
.
19 Grams (0.1 mole) of 1-benzyl-4-piperidone and 32 g
(0.3 mole) of benzaldehyde are reacted in 150.ml of EtOH in
the presence of 33 ml of concentrated HCl by the method
described in Example 7; crude yield, 23 g (58%); m.p. 210-212
(dec). Crystallization from 60 ml of hot DMF and 120 ml of
MeCN gives 14.2 g (36%) of yellow solid; m.p. 216-218(dec).
B. 7-Benzylidene-2-[3-(dimethylamino)propyl]-3,3a,-
4,5,6,7-hexahydro-5- benzyl -3-phenyl-2H-pyrazolo
[4,3-c]pyridine, hydrochloride (1:2)
- The above prepared material (12 g; 0.029 mole) and
3.7 g (0.031 mole) of 3-dimethylaminoProPylhydrazine are
reacted in 200 ml of MeOH as ~eccribed in Example 1 to give
the product.
105593~ MT62
Example 21
5-Acetyl-7-benzylidene-2-[3-(dimethylamino)propyl]-
3,3a,4,5,6,7-hexahydro-3-phenyl-2_-pyrazolo[4,3-c]
pyridine, hydrochloride (1:1)
.
A. l-Acetyl-3,5-dibenzylidene-4-piperidone
A stirred solution of 14 g (0.1 mole) of N-acetyl-4-
piperidone and 23 g (0.22 mole) of benzaldehyde in 60 ml of
Ac2O is treated with 30 ml of NEt3, refluxed for 6 hours,
and kept overnight at room temperature.
The red-amber solution is poured into 400 ml of ice
water, stirred 2 hours and the heavy oil extracted with ether
(3 x 200 ml). The combined extracts are washed with H2O
(3 x 100 ml)j dried (MgSO4), and the solvent evaporated to
give 24.9 g of oil. This material is triturated with 200 ml
of isopropyl ether and cooled overnight to give 12.5 g of a
yellow gummy product. Following crystallization from 60 ml
of i-PrOH, 2.7 g (8.5~) of yellow solid is obtained; m.p.
136-138.
B. 5-Acetyl-7-benzylidene-2-[3-(dimethylamino)propyl]-
3,3a,4,5,6,7-hexahydro-3-phenyl-2H-pyrazolo[4,3-c]-
.
pyridine/ hydrochloride (1:1)
A stirred suspension of the above mentioned material
(2.7 g; 0.0085 mole) in 30 ml of MeOH is treated with 1.02 g
(0.0087 mole) of 3-dimethylaminopropylhydrazine according to
the procedure described in Example 1 to give the product.
-24-
: MT62
10~5~37
Examples 22-27
2-Aminoalkyl-?-substituted-3,3a,4,5,6,7-hexahydro-3-
substituted 2H-pyrazolo[4,3-c]pyridine, hydrochlorides
:
According to the procedure of Example 1, upon sub-
stituting in place of 3-dimethylaminopropylhydrazine, one of
the following compounds:
2-diethylaminopropylhydrazine,
2-pyrrolidinoethylhydrazine,
3-piperidinopropylhydrazine,
4-morpholinobutylhydrazine,
2-(4-methylpiperazino3ethylhydrazine, and
3-(4-hydroxyethylpiperazino)propylhydrazine,
one obtains:
7-benzylidene-2-[3-(diethylamino)propyl]-3,3a,4,5,6,7-hexa-
hydro-5-methyl-3-phenyl-2H-pyrazolo[4,3-c]pyridine hydro-
chloride (1:2),
7-benzylidene-3,3a,4,5,6,7-hexahydro-5-methyl-3-phenyl-2-
[2-(pyrrolidino)ethyl]-2H-pyrazolo[4,3-c]pyridine hydro-
chloride (1:2);
7-benzylidene-3,3a,4,5,6,7-hexahydro-5-methyl-3-phenyl-2-
[3-(piperidino)propyl]-2H-pyrazolo[4,3-c]pyridine, hydro-
chloride (1:2);
7-benzylidene-3,3a,4,5,6,7-hexahydro-5-methyl-2-[4-(morpholino)-
butyl]-3-phenyl-2H-pyrazolo[4,3c]pyridine, hydrochloride(l:2);
7-benzylidene-3,3a,4,5,6,7-hexahydro-5-methyl-2-[2-(4-
methyl-piperazino)ethyl]-3-phenyl-2H-pyrazolo[4,3-c]pyridine,
hydrochloride (1:2);
7-benzylidene-3,3a,4,5,6,7-hexahydro-2-[3-(4-hydroxyethyl-
piperazino)propyl]-5-methyl-3-phenyl-2H-pyrazolo[4,3-c]-
pyridine, hydrochloride (1:2), respectively.
.
-25-
~055937
MT62
Example 28
3,3a,4,5,6,7-Hexahydro-5-methyl-2-[2-(4-morpholinyl)-
ethyl]-3-phenyl-7-(phen_lmethylene)-2H-pyrazolo[4,3-c]-
pyridine, hydrochloride (1:2).
7-Benzylidene-3,3a,4,5,6,7-hexahydro-5-methyl-3-phenyl-2_-
pyrazolo[4,3-c]-pyridine-2-ethanol, tosylate ester, HCl (9.5 g;
0.018 mole) was reacted with 15 g (0.17 mole) of morpholine in
350 ml of benzene (stood at room temperature overnight, then
refluxed 6 hrs.) to give 6.8 g of light yellow, almost glass-
like base. The latter was dissolved in 45 ml of warm MeCN,
cooled, and treated with- 5.4 ml of 6.0 N alcoholic HC1. On
rubbing, the crystalline dihydrochlorid-e salt separated. After
cooling overnight, the material was filtered under N2, washed
with cold MeCN and ether, and dried in vacuo; wt., 6.8 g (78%);
mp 195-197(dec.). Following crystallization from 50 ml MeOH-
100 ml ether, the colorless, slightly hygroscopic, product
weighed 6.3 g (73%) mp 204-206(dec.).
MT62
105S937
Example 29
7-Benzylidene-2-[3-(dimethylamino)propyl]-3,3a,4,5,-
.
6,7-hexahydro-5-methyl-3-phenyl-2H-pyrazolo[4,3-c]-
pyridine, N-oxide, hydrochloride (1:2)
A solution of the free base from Example 1 in acetic
acid is treated with an equivalent quantity of 30% hydrogen
peroxide and the solution then heated at 80-90 for 1 hour
and cooled. The solvent is removed on a rotary evaporator
at reduced pressure. The residue is dissolved in chloroform
and treated with two equivalents of hydrogen chloride.
Evaporation of the soivent yields the product.
Example 30
Preparation of capsule formulation
Ingredient Milligrams per Capsule
7-Benzylidene-2-[3(dimethylamino)-
propyl]-3,3a,4,5,6,7-hexahydro-5-
methyl-3-phenyl-2H-pyrazolo[4,3-c]-
pyridine, dihydrochloride (1:2) . . . ... . . . 200
Starch . . . . . . . . . . . . . . . . . . . . 80
Magnesium stearate . . . . . . . . . . . . . . 5
The active ingredient, starch and magnesium stearate are
blended together. The mixture is used to fill hard shell
capsules of a suitable size at a fill weight of 485-milli-
grams per capsule.
-27-
MT62
lOSS937
Example 31
Preparation of tablet formulation
Ingredient Mi~ligrams per Tablet
7-Benzylidene-2-[2-(dimethylamino)-
ethyl]-3,3a,4,5,6,7-hexahydro-5-methyl-
3-phenyl-2H-pyrazolo[4,3-c]pyridine,
hydrochloride . . . . . . . . . . . . . . . . 50
Lactose . . . . . . . . . . . . . . . . . . . 250
Corn starch (for mix) . . . . . . . . . . . . 75
Corn starch (for paste) . . . . . . . . . . . 75
Magnesium stearate . . . . . . . . . . . . . 8
The active ingredient, lactose and corn starch (for mix) are
blended together. The corn starch (for paste) is suspended
in water at a ratio of 10 grams of corn starch per 80 milli-
liters of water and heated with stirring to form a paste.
This paste is then used to granulate the mixed powders. The
wet granules are passed through a No. 8 screen and dried at
120F. The dry granules are passed through a.No. 16 screen.
The mixtue is lubricated with magnesium stearate and com-
pressed into tablets in a suitable tableting machine. Each
tablet contains 300 milligrams of active ingredient.
-28-
MT62
1055!~37
Example 32
Preparation of oral syrup formulation
Ingredient Amount
7-Benzylidene-2-[3-(dimethylamino)-
propyl]-3,3a,4,5,6,7-hexahydro-3-
phenyl-2H-pyrazolo[4,3-c]pyridine,
dihydrochloride (1:2) . . . . . . . . . . . 500 mg
Sorbitol solution (70% NoF~) . . . . . . . 40 ml
Sodium benzoate . . . . . . . . . . . . . . 150 mg
Saccharin . . . . . . . . . . . . . . . . . 10 mg
Red Dye (F.D. & C. No. 2) . . . . . . . . . 10 mg
Cherry flavor . . . . . . . . . . . . . . . 50 mg
Distilled water . . . qs to . . . . . . . . 100 ml
The sorbitol solution is added to 40 milliliters of distilled
water and the active ingredient is suspended therein. The
saccharin, sodium benzoate, flavor and dye are added and
dissolved in the above solution. The volume is adjusted to
100 milliliters with distilled water.
Other ingredients may replace those listed in the above
formulation. For example, a suspending agent such as bentonite
magma, tragacanth, carboxymethylcellulose or methylcellulose
may be used. Phosphates, citrates or tartrates may be added
as bu~fers. Preservatives may include the parabens, sorbic
acid and the like and other flavors and dyes may be used in
place of those listed above.
-29-
