CA1065324A - 2-aminoalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2h-indazoles and related cyclohepta (c) pyrazoles and cyclopentapyrazoles - Google Patents
2-aminoalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2h-indazoles and related cyclohepta (c) pyrazoles and cyclopentapyrazolesInfo
- Publication number
- CA1065324A CA1065324A CA226,132A CA226132A CA1065324A CA 1065324 A CA1065324 A CA 1065324A CA 226132 A CA226132 A CA 226132A CA 1065324 A CA1065324 A CA 1065324A
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- Prior art keywords
- phenylmethylene
- compound
- phenyl
- hexahydro
- dimethyl
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
- C07C49/683—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings having unsaturation outside the aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Abstract
Abstract New compounds, useful as central nervous system depressants, have the following formula wherein X is hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R is hydrogen or lower alkyl with the proviso that only one occurrence of R may be lower alkyl;
m is an integer from 2 to 4; A is straight or branched alkylene of from 1 to 8 carbon atoms; B is -NH2, , , or
m is an integer from 2 to 4; A is straight or branched alkylene of from 1 to 8 carbon atoms; B is -NH2, , , or
Description
lO~S~ MT75 This invention relates to new compounds of the formula (I) X
~ m ~
wherein X is hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R is hydrogen or lower alkyl with the proviso that only one occurrence of R may be lower alkyl;
m is an integer from 2 to 4; A is straight or branched alkylene of from 1 to 8 carbon atoms; B is -NH2, -N \ 1 ' -N ~ 1 ~ or -N ~ 1 wherein R is lower alkyl and R is phenyl or phenyl-lower alkyl; and the acid-addition and quaternary salts and N~oxides thereofO These new com-pounds are central nervous system depressants.
The terms "lower alkyl" and "lower alkoxy" as employed herein include both straight and branched chain radicals of le88 than eight carbon atoms, preferably 1 to 3 carbon atoms, as for example, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, igopropoxy, etc. The term "phenyl-lower alkyl"
includes such lower alkyl groups attached to a phenyl with benzyl and phenethyl being preferred. The term "halogen" includes all the halogens but is preferably Cl.
The term "alkylene" as employed herein includes both straight and branched chain radicals of 1 to 8 carbon atom8, P ~ (CH2) ~ (CH2)2-, -ICH-CH2-~ -CH21CH-CH2-, etc.
The term "acid addition salts" is intended to mean salts which may be formed for the purposes of isolation, purification~ and storage, such as the oxalate salt, lO~;S3~t maleate salt, etc. and pharmaceutically acceptable salts meant for administration of the compound to a host, such as the hydrochloride, sulfate, acetate, citrate salts, etc.
The quaternary salts include those formed with alkyl halides (e.g. methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide), benzyl halides (e.g. benzyl chloride) and dilower alkyl sulfates (e.g. dimethyl sulfate) by a conventional quaternization reaction.
The N-oxide may be formed by dissolving the free base of Formula I in a solvent inert to hydrogen peroxide, e.g., ethanol or chloroform, adding excess (on a molar basis) hydrogen peroxide, and allowing the mixture to stand at room temperature for several hours. An acid-addition salt of the N-oxide may be formed by addition of the desired acid, for example, those mentioned above.
The new compounds of formula I are prepared by reacting the appropriate cycloalkylone represented by formula (II) ~1 ?
(CHR
with a substituted benzaldehyde of formula (III) ~CHO
lO~S3~ MT75 to produce the intèrmediate of formula ~CH ~CH
C~)m The compounds of formula IV are converted to a com-pound of formula I by reaction with a hydrazine of formula (V) ~ N-N-A-B
H
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, prefer-ably for about 4 hours.
The hydrazine of formula V is prepared by reacting a haloamine, B-A-halo, with an excess of hydrazine, H2NNH2 ' Alternatively, the compound of formula IV
can be reacted with a hydroxyalkyl hydrazine of formula (VI) \ N-N -A-OH
H H
to form the alcohol of formula (vII) ~ ~ X
il)~S3'~4 The alcohol of formula VII is reacted by heating with p-toluenesulfonyl chloride to form the tosylate of formula (VIII) ~ Cl ~TS
which in turn is treated with the amine of formula HB to form the compounds of formula I. This method is particularly useful in producing compounds of formula I where B is amino (i.e. the tosylate of formula VIII is reacted with ammonia).
Preferred are the compounds of formula I wherein X is hydrogen, lower alkyl of 1 to 3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms, trifluoromethyl, or halogen.
R is hydrogen or lower alkyl of 1 to 3 carbon atoms.
A is straight or branched chain alkylene of from 2 to 5 carbon atoms.
Rl is lower alkyl of 1 to 3 carbon atoms.
R2 is phenyl, benzyl, or phenethyl.
- 20 The most preferred compounds are those where X is hydrogen or Cl, especially hydrogen.
R is hydrogen or methy~, especially hydrogen.
H ~R
\ Rl or N\ 1 ~ especlally~-N(cH3)2.
( 2)2 or -(CH2)3-, especially -(CH2) The new compounds of the present invention are useful as central nervous system depressants in mice, cats, rats, dogs and other mammalian species when administered in amounts ranging from about 1.0 mg. to about 100 mg. per kg. of body weight per day. A pre-10~;5;~;~4 ferred dosage regimen for optimum results would be from about 10 mg. to about 50 mg. per kg. of body weight per day, and such dosage units are employed that a total of from about 35 mg. to about 3 g. of active ingredient in single or divided doses are administered in a 24 hour period. These compounds when administered to rats in the above stated dosages produced the following central nervous system depressant symptoms; decreased motor activity, ataxia, and decreased screen grip.
Eor these purposes a compound or mixture of compounds of formula I and their pharmaceutically acceptable acid-addition salts, quaternary salts, or N-oxides may be administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like. These may be con-ventionally formulated in an oral or parenteral dosage form by compounding with a conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice.
The following examples are illustrative of the invention. All temperatures are expressed on the centigrade scale.
Example 1 3~3a~4~5~6~7-Hexahydro-N,N-dimethyl-3-phenyl-7-(phen methylene)-2--indazole-2-propanamine~ oxalate salt a) 2~6-Bis(phenylmethylene)cyclohexanone A solution of 32.0 g~ (0.33 mole) of cyclohexanone, 70.0 g. (0.66 mole) of benzaldehyde, 200 ml. of ethanol and 20 m]. of concentrated HCl is heated and then refluxed for one hour. Crystallization from the deep red solution occurs and after cooling the crystallized 2,6-bis(phenylmethylene)-cyclohexanone is filtered and washed with cold ethanol and dried it~;S;~'~4 yielding 72.0 g.; m.p. 114-116. This material is re-crystallized from 120 ml. of DMF (dimethylformamide) yielding 56.0 g. (63%) of yellow 2,6-bis(phenylmethylene)-cyclohexanone; m.p. 114-116.
b) 3,3a,4,5,6,7-Hexahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate s_ 11.0 g. (0.04 mole) of 2,6-bis(phenylmethylene)-cyclohexanone from part (a) is reacted with 4.8 g. (0.041 mole) of 3-dimethylaminopropyl hydrazine[see Nogrady et al., Can. J. Chem., 47, 2001 (1969)] in 100 ml. of methanol and refluxed for 4 hours. The residue remaining after the evaporation of the methanol is suspended in 100 ml. of methanol, layered over with 100 ml. of ether, stirred and basified with K2CO3. The layers sPparate and the aqueous phase is extracted with ether. The combined ether layers are dried (MgSO4) and the solvent is evaporated yielding 14.5 g. of oily base.
A warm solution of 14.0 g. of the oily base in 70 ml.
of MeCN is treated with a warm solution of 6.7 g. of oxalic acid in 70 ml. of MeCN. On cooling, 13.9 g (75%) of the oxalate salt gradually separates; m.p. 168-170 (dec). Crystallization from 25 ml. hot DMF-75 ml.
MeCN yields 12.5 g. (68~) of colorless 3,3a,4,5,6,7-l~exahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt; m.p. 177-179 (dec).
1()~53'~
Example 2 3a,4,5,6,7,8-Hexahydro-N,N-dimethyl-3-phenyl-8-(phenyl-methylene)-cyclohepta[c~pyrazole-2(3H)-propanamine, maleate salt a) 3a,4,5 ! 6,7 ! 8-Hexahydro-N,N-dimethyl-3-phenyl-8-(~henyl-methylene)-cyclohepta[c]pyrazole-2(3H)-propanamine, oxalate salt 8.0 g. (0.028 mole) of 2,7-bis(phenylmethylene)-cycloheptanone [See Piantadosi et al., J. Med. Chem., 16, 770 (1973)] and 3.4 g. (0.029 mole) of 3-dimethylamino-propylhydrazine are reacted in 70 ml. of methanol as des-cribed in example l(b) yielding 11.2 g. of oily base.
11.0 g. of this oily base is dissolved in 70 ml. of MeCN and treated with a warm solution of 2.8 g. of oxalic acid in 50 ml. of MeCN. On rubbing and cooling, 13 g. of the ox~late salt slowly separates; m.p. 143-145 (s. 137).
Crystallization from 25 ml. warm DMF-75 ml. MeCN yields 7.0 g. of cream colored 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta[c]pyrazole-2(3H)-propanamine, oxalate salt; m.p. 152-154.
b) 3a,4,5,6,7,8-Hexahydro-N,N-dimethyl-3-phenyl-8-(phenyl-methylene)-cyclohepta[c]pyrazole-2(3H)-propanamine The oxalate salt from part (a) is suspended in water and is basified with K2CO3 and extracted with ether yielding 5.5 g. of oily base. 5.0 g. of this oily base is crystallized from 25 ml. of MeCN yielding 4.4 g. of cream colored 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta-~c]pyrazole-2(3H)-propanamine; m.p. 92-94 (s. 90).
c) 3a,4,5!6!?,8-Hexahydro-N~N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta [c]pyrazole-2(3~)-propanamine~ maleate salt, lO~S3'~
The base from part (b) and 1.3 g. of maleic acid are dissolved in 25 ml. of warm MeCN and diluted to approximately 600 ml. with ether. On rubbing and standing in the cold, the crystalline maleate salt slowly separates. After four days in the cold, the maleate salt is filtered, washed with ether, and dried in vacuo yielding 4.1 g. (32%);
m.p. 109-111. Crystallization from 25 ml. methanol-250 ml.
ether yields 3.5 g. (27%) of nearly colorless 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta-[c]pyrazole-2(3H)-propanamine, maleate, m.p. 109-111.
Example 3 3a,4,5,6-Tetrahydro-N,N-dimethyl-3-phenyl-6-(phenylmethylene~-cyclopentapyrazole-2(3-)-propanamine~ hydrochloride This compound is prepared by following the procedure of example 1 but substituting cyclopentanone for the cyclo-hexanone to give the free base, m.p. 116-118. The hydro-ch;orid~ salt, made in the usual manner, was crystallized from acetonitrile, m.p. 167-169.
Examples 4-11 3,3a,4,5,6,7-Hexahydro-N,N-dimethyl-3-(substituted phenyl)-7-[(substituted-phenyl)methylene]-2H-indazole-2-propanamine, oxalate salts According to the procedure of example la, upon substituting in place of the benzaldehyde, one of the following substituted benzaldehydes:
o-chlorobenzaldehyde p-chlorobenzaldehyde p-trifluoromethylbenzaldehyde m-fluorobenzaldehyde o-methylbenzaldehyde 1()~53~ MT75 p-propylbenzaldehyde m-ethoxybenzaldehyde p-propoxybenzaldehyde one obtains the following
~ m ~
wherein X is hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; R is hydrogen or lower alkyl with the proviso that only one occurrence of R may be lower alkyl;
m is an integer from 2 to 4; A is straight or branched alkylene of from 1 to 8 carbon atoms; B is -NH2, -N \ 1 ' -N ~ 1 ~ or -N ~ 1 wherein R is lower alkyl and R is phenyl or phenyl-lower alkyl; and the acid-addition and quaternary salts and N~oxides thereofO These new com-pounds are central nervous system depressants.
The terms "lower alkyl" and "lower alkoxy" as employed herein include both straight and branched chain radicals of le88 than eight carbon atoms, preferably 1 to 3 carbon atoms, as for example, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, igopropoxy, etc. The term "phenyl-lower alkyl"
includes such lower alkyl groups attached to a phenyl with benzyl and phenethyl being preferred. The term "halogen" includes all the halogens but is preferably Cl.
The term "alkylene" as employed herein includes both straight and branched chain radicals of 1 to 8 carbon atom8, P ~ (CH2) ~ (CH2)2-, -ICH-CH2-~ -CH21CH-CH2-, etc.
The term "acid addition salts" is intended to mean salts which may be formed for the purposes of isolation, purification~ and storage, such as the oxalate salt, lO~;S3~t maleate salt, etc. and pharmaceutically acceptable salts meant for administration of the compound to a host, such as the hydrochloride, sulfate, acetate, citrate salts, etc.
The quaternary salts include those formed with alkyl halides (e.g. methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide), benzyl halides (e.g. benzyl chloride) and dilower alkyl sulfates (e.g. dimethyl sulfate) by a conventional quaternization reaction.
The N-oxide may be formed by dissolving the free base of Formula I in a solvent inert to hydrogen peroxide, e.g., ethanol or chloroform, adding excess (on a molar basis) hydrogen peroxide, and allowing the mixture to stand at room temperature for several hours. An acid-addition salt of the N-oxide may be formed by addition of the desired acid, for example, those mentioned above.
The new compounds of formula I are prepared by reacting the appropriate cycloalkylone represented by formula (II) ~1 ?
(CHR
with a substituted benzaldehyde of formula (III) ~CHO
lO~S3~ MT75 to produce the intèrmediate of formula ~CH ~CH
C~)m The compounds of formula IV are converted to a com-pound of formula I by reaction with a hydrazine of formula (V) ~ N-N-A-B
H
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, prefer-ably for about 4 hours.
The hydrazine of formula V is prepared by reacting a haloamine, B-A-halo, with an excess of hydrazine, H2NNH2 ' Alternatively, the compound of formula IV
can be reacted with a hydroxyalkyl hydrazine of formula (VI) \ N-N -A-OH
H H
to form the alcohol of formula (vII) ~ ~ X
il)~S3'~4 The alcohol of formula VII is reacted by heating with p-toluenesulfonyl chloride to form the tosylate of formula (VIII) ~ Cl ~TS
which in turn is treated with the amine of formula HB to form the compounds of formula I. This method is particularly useful in producing compounds of formula I where B is amino (i.e. the tosylate of formula VIII is reacted with ammonia).
Preferred are the compounds of formula I wherein X is hydrogen, lower alkyl of 1 to 3 carbon atoms, lower alkoxy of 1 to 3 carbon atoms, trifluoromethyl, or halogen.
R is hydrogen or lower alkyl of 1 to 3 carbon atoms.
A is straight or branched chain alkylene of from 2 to 5 carbon atoms.
Rl is lower alkyl of 1 to 3 carbon atoms.
R2 is phenyl, benzyl, or phenethyl.
- 20 The most preferred compounds are those where X is hydrogen or Cl, especially hydrogen.
R is hydrogen or methy~, especially hydrogen.
H ~R
\ Rl or N\ 1 ~ especlally~-N(cH3)2.
( 2)2 or -(CH2)3-, especially -(CH2) The new compounds of the present invention are useful as central nervous system depressants in mice, cats, rats, dogs and other mammalian species when administered in amounts ranging from about 1.0 mg. to about 100 mg. per kg. of body weight per day. A pre-10~;5;~;~4 ferred dosage regimen for optimum results would be from about 10 mg. to about 50 mg. per kg. of body weight per day, and such dosage units are employed that a total of from about 35 mg. to about 3 g. of active ingredient in single or divided doses are administered in a 24 hour period. These compounds when administered to rats in the above stated dosages produced the following central nervous system depressant symptoms; decreased motor activity, ataxia, and decreased screen grip.
Eor these purposes a compound or mixture of compounds of formula I and their pharmaceutically acceptable acid-addition salts, quaternary salts, or N-oxides may be administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like. These may be con-ventionally formulated in an oral or parenteral dosage form by compounding with a conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice.
The following examples are illustrative of the invention. All temperatures are expressed on the centigrade scale.
Example 1 3~3a~4~5~6~7-Hexahydro-N,N-dimethyl-3-phenyl-7-(phen methylene)-2--indazole-2-propanamine~ oxalate salt a) 2~6-Bis(phenylmethylene)cyclohexanone A solution of 32.0 g~ (0.33 mole) of cyclohexanone, 70.0 g. (0.66 mole) of benzaldehyde, 200 ml. of ethanol and 20 m]. of concentrated HCl is heated and then refluxed for one hour. Crystallization from the deep red solution occurs and after cooling the crystallized 2,6-bis(phenylmethylene)-cyclohexanone is filtered and washed with cold ethanol and dried it~;S;~'~4 yielding 72.0 g.; m.p. 114-116. This material is re-crystallized from 120 ml. of DMF (dimethylformamide) yielding 56.0 g. (63%) of yellow 2,6-bis(phenylmethylene)-cyclohexanone; m.p. 114-116.
b) 3,3a,4,5,6,7-Hexahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate s_ 11.0 g. (0.04 mole) of 2,6-bis(phenylmethylene)-cyclohexanone from part (a) is reacted with 4.8 g. (0.041 mole) of 3-dimethylaminopropyl hydrazine[see Nogrady et al., Can. J. Chem., 47, 2001 (1969)] in 100 ml. of methanol and refluxed for 4 hours. The residue remaining after the evaporation of the methanol is suspended in 100 ml. of methanol, layered over with 100 ml. of ether, stirred and basified with K2CO3. The layers sPparate and the aqueous phase is extracted with ether. The combined ether layers are dried (MgSO4) and the solvent is evaporated yielding 14.5 g. of oily base.
A warm solution of 14.0 g. of the oily base in 70 ml.
of MeCN is treated with a warm solution of 6.7 g. of oxalic acid in 70 ml. of MeCN. On cooling, 13.9 g (75%) of the oxalate salt gradually separates; m.p. 168-170 (dec). Crystallization from 25 ml. hot DMF-75 ml.
MeCN yields 12.5 g. (68~) of colorless 3,3a,4,5,6,7-l~exahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt; m.p. 177-179 (dec).
1()~53'~
Example 2 3a,4,5,6,7,8-Hexahydro-N,N-dimethyl-3-phenyl-8-(phenyl-methylene)-cyclohepta[c~pyrazole-2(3H)-propanamine, maleate salt a) 3a,4,5 ! 6,7 ! 8-Hexahydro-N,N-dimethyl-3-phenyl-8-(~henyl-methylene)-cyclohepta[c]pyrazole-2(3H)-propanamine, oxalate salt 8.0 g. (0.028 mole) of 2,7-bis(phenylmethylene)-cycloheptanone [See Piantadosi et al., J. Med. Chem., 16, 770 (1973)] and 3.4 g. (0.029 mole) of 3-dimethylamino-propylhydrazine are reacted in 70 ml. of methanol as des-cribed in example l(b) yielding 11.2 g. of oily base.
11.0 g. of this oily base is dissolved in 70 ml. of MeCN and treated with a warm solution of 2.8 g. of oxalic acid in 50 ml. of MeCN. On rubbing and cooling, 13 g. of the ox~late salt slowly separates; m.p. 143-145 (s. 137).
Crystallization from 25 ml. warm DMF-75 ml. MeCN yields 7.0 g. of cream colored 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta[c]pyrazole-2(3H)-propanamine, oxalate salt; m.p. 152-154.
b) 3a,4,5,6,7,8-Hexahydro-N,N-dimethyl-3-phenyl-8-(phenyl-methylene)-cyclohepta[c]pyrazole-2(3H)-propanamine The oxalate salt from part (a) is suspended in water and is basified with K2CO3 and extracted with ether yielding 5.5 g. of oily base. 5.0 g. of this oily base is crystallized from 25 ml. of MeCN yielding 4.4 g. of cream colored 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta-~c]pyrazole-2(3H)-propanamine; m.p. 92-94 (s. 90).
c) 3a,4,5!6!?,8-Hexahydro-N~N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta [c]pyrazole-2(3~)-propanamine~ maleate salt, lO~S3'~
The base from part (b) and 1.3 g. of maleic acid are dissolved in 25 ml. of warm MeCN and diluted to approximately 600 ml. with ether. On rubbing and standing in the cold, the crystalline maleate salt slowly separates. After four days in the cold, the maleate salt is filtered, washed with ether, and dried in vacuo yielding 4.1 g. (32%);
m.p. 109-111. Crystallization from 25 ml. methanol-250 ml.
ether yields 3.5 g. (27%) of nearly colorless 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta-[c]pyrazole-2(3H)-propanamine, maleate, m.p. 109-111.
Example 3 3a,4,5,6-Tetrahydro-N,N-dimethyl-3-phenyl-6-(phenylmethylene~-cyclopentapyrazole-2(3-)-propanamine~ hydrochloride This compound is prepared by following the procedure of example 1 but substituting cyclopentanone for the cyclo-hexanone to give the free base, m.p. 116-118. The hydro-ch;orid~ salt, made in the usual manner, was crystallized from acetonitrile, m.p. 167-169.
Examples 4-11 3,3a,4,5,6,7-Hexahydro-N,N-dimethyl-3-(substituted phenyl)-7-[(substituted-phenyl)methylene]-2H-indazole-2-propanamine, oxalate salts According to the procedure of example la, upon substituting in place of the benzaldehyde, one of the following substituted benzaldehydes:
o-chlorobenzaldehyde p-chlorobenzaldehyde p-trifluoromethylbenzaldehyde m-fluorobenzaldehyde o-methylbenzaldehyde 1()~53~ MT75 p-propylbenzaldehyde m-ethoxybenzaldehyde p-propoxybenzaldehyde one obtains the following
2,6-bis[(2-chlorophenyl)methylene]cyclohexanone 2,6-bis[(4-chlorophenyl)methylene]cyclohexanone 2,6-bis[(4-trifluoromethylphenyl)methylene]cyclohexanone 2,6-bis[(3-fluorophenyl)methylen`e]cyclohexanone 2,6-bis[(2-methylphenyl)methylene]cyclohexanone 2,6-bis[(4-propylphenyl)methylene]cyclohexanone 2,6-bis[(3-ethoxyphenyl)methylene]cyclohexanone 2,6-bis[(4-propoxyphenyl)methylene]cyclohexanone Upon substituting the above compounds in example lb one obtains the following:
3,3a,4,5,6~7-hexahydro-N,N-dimethyl-3-(2-chlorophenyl)-7-[(2-chlorophenyl)methylene]-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-(4-chlorophenyl)-7-[(4-chlorophenyl)methylene]-2_-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-(4-trifluoromethyl-phenyl)-7-[(4-trifluoromethylphenyl)methylene]-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-(3-fluorophenyl)-7-[(3-fluorophenyl)methylene]-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-(2-methylphenyl)-7-[(2-methylphenyl)methylene]-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-(4-propylphenyl)-7-[(4-propylphenyl)methylene]-2H-indazole-2-propanamine, _g_ 10~iS3'~4 oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-t3-ethoxyphenyl)-7-[(3-ethoxyphenyl)methylene]-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-(4-propoxyphenyl)-7-[(4-propoxyphenyl)methylene]-2H-indazole-2-propanamine, oxalate salt Similarly, the substituted benzaldehydes are employed to produce the various 2,7-bis[(substituted phenyl)methylene]-cycloheptanones and 2,5-bis[(substituted phenyl)methylene]-cyclopentanones which are reacted to produce the appropriate 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-(substituted-phenyl)-8-[(substituted-phenyl)methylene]-cyclohepta[c]pyrazole-2(3H)-propanamines and 3a,4,5,6-tetrahydro-N,N-dimethyl-3-(substituted-phenyl)-6-[(substituted-phenyl)methylene]-cyclopentapyrazole-2(3H)-propanamines.
Examples 12 to 17 3,3a,4,5,6,7-Hexahydro-N,N-dimethyl-3-(phenyl)-(5 or 4 and/or 6-lower alkyl)-7-(phenylmethylene)-2~-indazole-2-propanamine, oxalate salts According to the procedure of example la, upon substituting in place of the cyclohexanone, one of the following:
p-methylcyclohexanone p-ethylcyclohexanone p-propylcyclohexanone p-t-butylcyclohexanone m-methylcyclohexanone m-ethylcyclohexanone one obtains the following:
~0~
2,6-bis(phenylmethylene)(4-methylcyclohexanone) 2,6-bis(phenylmethylene)(4-ethylcyclohexanone) 2,6-bis(phenylmethylene)(4-propylcyclohexanone) 2,6-bis(phenylmethylene)(4-t-butylcyclohexanone) 2,6-bis(phenylmethylene)(3-methylcyclohexanone) 2,6-bis(phenylmethylene)(3-ethylcyclohexanone) Upon substituting the above compounds in example lb one obtains the following:
3,3a,4,5,6,7-hexahydro-N,N-dimethyl-5-methyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6 r 7-hexahydro-N,N-dimethyl-5-ethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-phenyl-5-propyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-5-(t-butyl)-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt m.p. 140-143 (crystallized from isopropyl alcohol) 3,3a,4,5,6,7-hexahydro-N,~-dimethyl-(4 and/or 6-methyl)-3-phenyl 7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-(4 and/or 6-ethyl)-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt Similarly, lower alkyl substituted cycloheptanones and cyclopentanones are employed to produce the various 2,7-bis(phenylmethylene)(lower alkyl-cycloheptanones)and 2,5-bis-(phenylmethylene)(lower alkyl-cyclopentanones)which are reacted to produce the appropriate lower alkyl substituted 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta-[c]pyrazole-2(3H)-propanamines and 3a,4,5,6-tetrahydro-N,N-dimethyl-3-phenyl-6-(phenylmethylene)-cyclopentapyrazole-2-(3H)-propanamines.
10~
Example 18 3,3a,4,5,6,7-Hexahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-.
2H-indazole-2-ethanamine, oxalate salt According to the procedure of example 1 but substituting 2-dimethylaminoethyl hydrazine for the 3-dimethylaminopropyl hydrazine in example lb, the title compound is obtained; m.p.
157-159 (crystallized from ethanol-methanol). In the usual manner, this oxalate is converted to the free base and then to the maleic acid salt; m.p. 137-139 (crystallized from methanol-ether).
Example 19 3,3a,4,5,6,7-Hexahydro-N,N-diethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt According to the procedure of example 1 but substituting 3-diethylaminopropyl hydrazine for the 3-dimethylaminopropyl hydrazine in example lb, the title compound is obtained.
Crystallization from DMF (dimethylformamine)-acetonitrile gives a colorless crystalline product; m.p. 145-147. After conversion of the oxalate to the free base and then to the maleic acid salt in the usual manner, crystallization from methanol-ether gives a crystalline product which is nearly colorless; m.p. 104-106.
Examples 12 to 17 3,3a,4,5,6,7-Hexahydro-N,N-dimethyl-3-(phenyl)-(5 or 4 and/or 6-lower alkyl)-7-(phenylmethylene)-2~-indazole-2-propanamine, oxalate salts According to the procedure of example la, upon substituting in place of the cyclohexanone, one of the following:
p-methylcyclohexanone p-ethylcyclohexanone p-propylcyclohexanone p-t-butylcyclohexanone m-methylcyclohexanone m-ethylcyclohexanone one obtains the following:
~0~
2,6-bis(phenylmethylene)(4-methylcyclohexanone) 2,6-bis(phenylmethylene)(4-ethylcyclohexanone) 2,6-bis(phenylmethylene)(4-propylcyclohexanone) 2,6-bis(phenylmethylene)(4-t-butylcyclohexanone) 2,6-bis(phenylmethylene)(3-methylcyclohexanone) 2,6-bis(phenylmethylene)(3-ethylcyclohexanone) Upon substituting the above compounds in example lb one obtains the following:
3,3a,4,5,6,7-hexahydro-N,N-dimethyl-5-methyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6 r 7-hexahydro-N,N-dimethyl-5-ethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-phenyl-5-propyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-5-(t-butyl)-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt m.p. 140-143 (crystallized from isopropyl alcohol) 3,3a,4,5,6,7-hexahydro-N,~-dimethyl-(4 and/or 6-methyl)-3-phenyl 7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-(4 and/or 6-ethyl)-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt Similarly, lower alkyl substituted cycloheptanones and cyclopentanones are employed to produce the various 2,7-bis(phenylmethylene)(lower alkyl-cycloheptanones)and 2,5-bis-(phenylmethylene)(lower alkyl-cyclopentanones)which are reacted to produce the appropriate lower alkyl substituted 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta-[c]pyrazole-2(3H)-propanamines and 3a,4,5,6-tetrahydro-N,N-dimethyl-3-phenyl-6-(phenylmethylene)-cyclopentapyrazole-2-(3H)-propanamines.
10~
Example 18 3,3a,4,5,6,7-Hexahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-.
2H-indazole-2-ethanamine, oxalate salt According to the procedure of example 1 but substituting 2-dimethylaminoethyl hydrazine for the 3-dimethylaminopropyl hydrazine in example lb, the title compound is obtained; m.p.
157-159 (crystallized from ethanol-methanol). In the usual manner, this oxalate is converted to the free base and then to the maleic acid salt; m.p. 137-139 (crystallized from methanol-ether).
Example 19 3,3a,4,5,6,7-Hexahydro-N,N-diethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt According to the procedure of example 1 but substituting 3-diethylaminopropyl hydrazine for the 3-dimethylaminopropyl hydrazine in example lb, the title compound is obtained.
Crystallization from DMF (dimethylformamine)-acetonitrile gives a colorless crystalline product; m.p. 145-147. After conversion of the oxalate to the free base and then to the maleic acid salt in the usual manner, crystallization from methanol-ether gives a crystalline product which is nearly colorless; m.p. 104-106.
Claims (28)
1. A process for preparing a compound of the formula wherein R is hydrogen or lower alkyl with the proviso that only one occurrence of R may be lower alkyl; m is an integer from 2 to 4; A is straight or branched alkylene of from 2 to 5 carbon atoms; B is -NH2, or , wherein R1 is lower alkyl;
or an acid-addition salt thereof, which comprises reacting a compound of the formula with a hydrazine compound of the formula to produce the final compound, and optionally converting to an acid-addition salt thereof.
or an acid-addition salt thereof, which comprises reacting a compound of the formula with a hydrazine compound of the formula to produce the final compound, and optionally converting to an acid-addition salt thereof.
2. The process according to claim 1 wherein R is hydrogen.
3. The process according to claim 1 wherein R1 is lower alkyl of 1 to 3 carbon atoms.
4. The process according to claim 1 wherein A is (CH2)2 or (CH2)3.
5. The process according to claim 1 wherein B is .
6. The process according to claim 1 wherein A is (CH2)3; and B is N(CH3)2.
7. The process according to claim 1 wherein m is 2.
8. The process according to claim 1 wherein m is 3.
9. The process according to claim 1 wherein m is 4.
10. The process according to claim 1 wherein 2,6-bis(phenylmethylene)cyclohexanone is reacted with 3-dimethylamino-propylhydrazine and the reaction product is treated with oxalic acid to produce 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt.
11. The process according to claim 1 wherein 2,7-bis(phenylmethylene)cycloheptanone is reacted with 3-dimethyl-aminopropylhydrazine and the reaction product is treated with maleic acid to produce 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta-[c]pyrazole-2(3H)-propanamine, maleate salt.
12. The process according to claim 1 wherein 2,5-bis(phenylmethylene)cyclopentanone is reacted with 3-diemthylamino-propylhydrazine and the reaction produce is treated with hydrochloric acid to produce 3a,4,5,6-tetrahydro-N,N-dimethyl-3-phenyl-6-(phenylmethylene)cyclopentapyrazole-2(3H)-propanamine, hydro-chloride.
13. The process according to claim 1 wherein 2,6-bis(phenylmethylene)cyclohexanone is reacted with 2-dimethylamino-ethylhydrazine and the reaction product is treated with oxalic acid to produce 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-(2H)-indazole-2-ethanamine, oxalate salt.
14. The process according to claim 1 wherein 2,6-bis(phenylmethylene)cyclohexanone is reacted with 3-diethyl-aminopropylhydrazine and the reaction product is treated with oxalic acid to produce 3,3a,4,5,6,7-hexahydro-N,N-diethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt.
15. A compound of the formula wherein R is hydrogen or lower alkyl with the proviso that only one occurrence of R may be lower alkyl; m is an integer from 2 to 4; A is straight or branched alkylene of from 2 to 5 carbon atoms;
B is -NH2, , wherein R1 is lower alkyl ; or an acid-addition salt thereof, whenever prepared according to the process of claim 1.
B is -NH2, , wherein R1 is lower alkyl ; or an acid-addition salt thereof, whenever prepared according to the process of claim 1.
16. A compound as defined in claim 15 wherein R is hydrogen, whenever prepared according to the process of claim 2.
17. A compound as defined in claim 15 wherein R1 is lower alkyl of 1 to 3 carbon atoms, whenever prepared according to the process of claim 3.
18. A compound as defined in claim 15 wherein A is (CH2)2 or (CH2)3, whenever prepared according to the process of claim 4.
19. A compound as defined in claim 15 wherein B is , whenever prepared according to the process of claim 5.
20. A compound as defined in claim 15 wherein A is (CH2)3; and B is N(CH3)2, whenever prepared according to the process of claim 6.
21. A compound as defined in claim 15 wherein m is 2, whenever prepared according to the process of claim 7.
22. A compound as defined in claim 15 wherein m is 3, whenever prepared according to the process of claim 8.
23. A compound as defined in claim 15 wherein m is 4, whenever prepared according to the process of claim 9.
24. The compound having the name 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt, whenever prepared according to the process of claim 10.
25. The compound having the name 3a,4,5,6,7,8-hexahydro-N,N-dimethyl-3-phenyl-8-(phenylmethylene)-cyclohepta-[c]pyrazole-2(3H)-propanamine, maleate salt, whenever prepared according to the process of claim 11.
26. The compound having the name 3a,4,5,6-tetrahydro-N,N-dimethyl-3-phenyl6-(phenylmethylene)cyclopentapyrazole-2(3H)-propanamine, hydrochloride, whenever prepared according to the process of claim 12.
27. The compound having the name 3,3a,4,5,6,7-hexahydro-N,N-dimethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-ethanamine, oxalate salt, whenever prepared according to the process of claim 13.
28. The compound having the name 3,3a,4,5,6,7-hexahydro-N,N-diethyl-3-phenyl-7-(phenylmethylene)-2H-indazole-2-propanamine, oxalate salt, whenever prepared according to the process of claim 14.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46917174A | 1974-05-13 | 1974-05-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1065324A true CA1065324A (en) | 1979-10-30 |
Family
ID=23862720
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA226,132A Expired CA1065324A (en) | 1974-05-13 | 1975-05-02 | 2-aminoalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2h-indazoles and related cyclohepta (c) pyrazoles and cyclopentapyrazoles |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS50160271A (en) |
| CA (1) | CA1065324A (en) |
| DE (1) | DE2521299A1 (en) |
| FR (1) | FR2270871B1 (en) |
| GB (1) | GB1512653A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4004007A (en) * | 1975-08-08 | 1977-01-18 | E. R. Squibb & Sons, Inc. | 2-Heterocyclicalkyl-3,3a,4,5,6,7-hexahydro-3-phenyl-7-(phenylmethylene)-2H-indazoles |
| ID17907A (en) * | 1997-02-20 | 1998-02-05 | Fakultas Farmasi Uni Gajah Mad | BENZILIDIN CYCYLOHEXANON BENZILIDINE CYCOPOPANANONE BINZYLIDINE ACETONE AND ITS PRODUCTION |
| KR20100037053A (en) | 2007-06-01 | 2010-04-08 | 쉐링 코포레이션 | Gamma secretase modulators |
| US8809318B2 (en) * | 2008-11-13 | 2014-08-19 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
-
1975
- 1975-05-02 CA CA226,132A patent/CA1065324A/en not_active Expired
- 1975-05-09 GB GB1968275A patent/GB1512653A/en not_active Expired
- 1975-05-13 FR FR7514896A patent/FR2270871B1/fr not_active Expired
- 1975-05-13 JP JP5788275A patent/JPS50160271A/ja active Pending
- 1975-05-13 DE DE19752521299 patent/DE2521299A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| JPS50160271A (en) | 1975-12-25 |
| FR2270871B1 (en) | 1978-08-04 |
| FR2270871A1 (en) | 1975-12-12 |
| DE2521299A1 (en) | 1975-11-27 |
| GB1512653A (en) | 1978-06-01 |
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