CA1055937A - 2-aminoalkyl-7-substituted-3,3a,4,5,6,7-hexahydro-3-substituted-2h-pyrazolo (4,3-a) pyridines - Google Patents

Abstract

ABSTRACT

2- Aminoalkyl-7-substituted-3,3a,4,5,6,7-hexahydro-3-substituted-2H-pyrazolo[4,3-a]pyridines and their N-oxides and the acid addition salts thereof are reported. In addition, methods for preparing said compounds, pharma-ceutical compositions containing said compounds and methods for using said compositions as central nervous system depressants are disclosed.

Description

~055937 This invention relates to compounds of the formula:

N- N'' R
R-CH ~, IH-R3 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.

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','~

~ N--alkyl--OH

R--Cl~/i ~H--R3 R--C~ kyl~O--Ts ~NJ TsCl ~, ~ N J
!l 11 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 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.

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.

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 1055~37 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.).

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).

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)~

~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).

M~6Z

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,4,5,6,7-1~55937 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.

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.

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 .

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 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 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 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.

: 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.
.

~055937 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.).

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.

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.

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.

Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula wherein R and R3 are each ; X and X1 are selected from the group consisting of hydrogen, chloro, fluoro, lower alkyl, lower alkoxy and trifluoromethyl; R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkyl, hydroxy lower alkyl and lower alkanoyl; R2 is B-lower alkyl wherein B is di-lower alkylamino, lower alkyl amino, morpholino and N-oxides and pharmaceutically acceptable acid-addition salts thereof, characterized by reacting an acid-addition salt of a compound of the formula with a compound of the formula in an organic solvent.

2. A process according to claim 1 wherein R and R3 are phenyl, X and X1 are hydrogen, R1 is hydrogen and lower alkyl and R2 is dimethylaminopropyl.

3. The process of claim 1 wherein 3,5-dibenzylidine-l-methyl-4-piperidone HCl is reacted with 3-dimethylamino-propylhydrazine to form 7-benzylidene-2-(3-(dimethylamino)-propyl]-3,3a,4,5,6,7-hexahydro-5-methyl-3-phenyl-2H-pyrazolo-[4,3-c]pyridine, dihydrochloride.

4. The process of claim 1 wherein 3,5-dibenzylidene-4-piperidone-HCl is reacted with 3-dimethylaminopropylhydrazine to form 7-benzylidene-2-[3-(dimethylamino)propyl]-3,3a,4,5-6,7-hexahydro-3-phenyl-2H-pyrazolo[4,3-c]pyridine, dihydro-chloride.

5. A compound of the formula wherein R and R3 are each ; X and X1 are selected from the group consisting of hydrogen, chloro, fluoro, lower alkyl, lower alkoxy and trifluoromethyl; R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkyl, hydroxy lower alkyl and lower alkanoyl; R2 is B-lower alkyl wherein B is di-lower alkylamino, lower alkyl, amino, morpholino and N-oxides and pharmaceutically acceptable acid-addition salts thereof, whenever prepared by the process of claim 1.

6. The compounds of claim 5 wherein R and R3 are phenyl, X and X1 are hydrogen, R1 is hydrogen and lower alkyl and R2 is dimethylaminopropyl, whenever prepared by the process of claim 2.

7. The compound of claim 5 having the name 7-benzyl-idene-2-[3-(dimethylamino)propyl]-3,3a,4,5,6,7-hexahydro-5-methyl-3-phenyl-2H-pyrazolo[4,3-c]pyridine, dihydrochloride, whenever prepared by the process of claim 3.

8. The compound of claim 5 having the name 7-benzyl-idene-2[3-(dimethylamino)propyl]-3,3a,4,5,6,7-hexahydro-3-phenyl-2H-pyrazolo[4,3-c]pyridine, dihydrochloride, whenever prepared by the process of claim 4.