CA1101426A - 4-diphenylmethylene-1-hydroxybenzyl-piperidine compounds - Google Patents
4-diphenylmethylene-1-hydroxybenzyl-piperidine compoundsInfo
- Publication number
- CA1101426A CA1101426A CA294,674A CA294674A CA1101426A CA 1101426 A CA1101426 A CA 1101426A CA 294674 A CA294674 A CA 294674A CA 1101426 A CA1101426 A CA 1101426A
- Authority
- CA
- Canada
- Prior art keywords
- diphenylmethylene
- piperidine
- process according
- hydroxybenzyl
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
ABSTRACT OF THE DISCLOSURE:
New 4-diphenylmethylene-1-hydroxybenzyl-piperidines having the formula
New 4-diphenylmethylene-1-hydroxybenzyl-piperidines having the formula
Description
The present invention relates to new piperidine deriva-tives and the pharmaceutically acceptable acid addition salts thereof, as well as to processes for the preparation of these new piperidine derivatives. The present inyention relates also to pharmaceutical compositions containing the new compounds and/or their salts and to the therapeutic use thereof.
The new piperidine derivatives according to the present invention are 4-diphenylmethylene-1-hydroxybenzyl-pipeLidines of the general formula:
A
1~ , .
~ ~ OH
A2 C ~ -CH ~ ~I) wherein Al, A2, A3 and A4, taken separately, each represents hy-drogen, halogen, trifluoromethyl, alkyl containing 1 to 4 carbon atoms or alkoxy containing l to 4 carbon atoms, and the pharma-ceutically acceptable acid addition salts thereof.
In preferred compoands according to the present invention, the symbols Al, A2, A3 and A4, which may be the same or different, are hydrogen, chlorine~or fluorine atoms or trifluoromethyl radi-cals or alkyl or alkoxy radicals containing up to 4 carbon atoms.
- The compounds according to the present invention in the form of the free bases or of salts with pharmaceutically acceptable inorganic or organic acids, have valuable pharmacological proper-ties. They have a very favourable action on the cerebral,peripheral and coronary circulations. In addition, they are active on the central nervous system in general.
The new compounds of general formula (I) according to the present invention can be prepared by several known chemical '~
11~14Z6 methods, which may be illustrated by the following three non- .
limiting examples:
1) A 4-diphenylmethylene-piperidine of the general formula:
A
~2 C=~ ~H (II) ~ ' / ~ - , ~Y
A4 ~ ~~~ ~~~ ~ ;- -~-- -_ _ ~ , , . . . , _ _ 111~14Z6 wherein ~ 2~ ~3 and ~4 have the s~me meanings as above, is condensed with a benzyl compound of the general formula:
0--~
X-CH2 ~ (III~
wherein x is halogen atom or an equivalent reactive group and A5 is a protective group for the hydroxyl group which can be easily eliminated by hydrolysis, for example a benzoyl radical, in the presence of an acid acceptor and in solution in an inert solvent, for example xylene, and the l-benzyl-4-diphenylmethylene-piperidine thus obtained of the general formula:
A13~
A2 C=~--C~32~o_A5 IIV) wherein Al, A2, A3, A4 and A5 have the same meanings as above, is subsequently subjected to hydrolysis.
The new piperidine derivatives according to the present invention are 4-diphenylmethylene-1-hydroxybenzyl-pipeLidines of the general formula:
A
1~ , .
~ ~ OH
A2 C ~ -CH ~ ~I) wherein Al, A2, A3 and A4, taken separately, each represents hy-drogen, halogen, trifluoromethyl, alkyl containing 1 to 4 carbon atoms or alkoxy containing l to 4 carbon atoms, and the pharma-ceutically acceptable acid addition salts thereof.
In preferred compoands according to the present invention, the symbols Al, A2, A3 and A4, which may be the same or different, are hydrogen, chlorine~or fluorine atoms or trifluoromethyl radi-cals or alkyl or alkoxy radicals containing up to 4 carbon atoms.
- The compounds according to the present invention in the form of the free bases or of salts with pharmaceutically acceptable inorganic or organic acids, have valuable pharmacological proper-ties. They have a very favourable action on the cerebral,peripheral and coronary circulations. In addition, they are active on the central nervous system in general.
The new compounds of general formula (I) according to the present invention can be prepared by several known chemical '~
11~14Z6 methods, which may be illustrated by the following three non- .
limiting examples:
1) A 4-diphenylmethylene-piperidine of the general formula:
A
~2 C=~ ~H (II) ~ ' / ~ - , ~Y
A4 ~ ~~~ ~~~ ~ ;- -~-- -_ _ ~ , , . . . , _ _ 111~14Z6 wherein ~ 2~ ~3 and ~4 have the s~me meanings as above, is condensed with a benzyl compound of the general formula:
0--~
X-CH2 ~ (III~
wherein x is halogen atom or an equivalent reactive group and A5 is a protective group for the hydroxyl group which can be easily eliminated by hydrolysis, for example a benzoyl radical, in the presence of an acid acceptor and in solution in an inert solvent, for example xylene, and the l-benzyl-4-diphenylmethylene-piperidine thus obtained of the general formula:
A13~
A2 C=~--C~32~o_A5 IIV) wherein Al, A2, A3, A4 and A5 have the same meanings as above, is subsequently subjected to hydrolysis.
2) An alpha,alpha-diphenyl-4-pyridinemethanol of the general formula A ~ 0 C ~ N (V) A
wherein Al, A2, A3 and A4 have the same meanings as above, is concensed with a benzyl compound of the general formula X-CH2 ~ O-A5 (III) `X~
.
1~14Z6 wherein X and A5 have the same meanings as above, the l-benzyl-4-(alpha-hydroxy-diphenylmethyl)-pyridinium compound thus obtained of the general formula A2 \ OH O-A
C ~ ~ -CH2 ~ X (VI) 10 wherein Al, A2, A3, A4, A5 and X have the same meanings as above, is reduced catalytically, the corresponding l-benzyl-alpha,alpha-diphenyl-4-piperidinemethanol thus obtained of the general formula:
A
\ ' ~ N-CH2 ~ O-A5 (VII~
wherein Xl, A2, A3, A4 and A5 have the same meanings as above, is dehydrated with a dehydrating agent, for example anhydrous hydrogen chloride in alcoholic solution, and the resulting l-benzyl-4-diphenylmethylene-piperidine of the general formula A ~
C ~ N-CH ~ O-A5 (IV) wherein Al, A2, A3, A4 and A5 have the same meanings as above, is finally subjected to hydrolysis.
~ -4-~Q14~6
wherein Al, A2, A3 and A4 have the same meanings as above, is concensed with a benzyl compound of the general formula X-CH2 ~ O-A5 (III) `X~
.
1~14Z6 wherein X and A5 have the same meanings as above, the l-benzyl-4-(alpha-hydroxy-diphenylmethyl)-pyridinium compound thus obtained of the general formula A2 \ OH O-A
C ~ ~ -CH2 ~ X (VI) 10 wherein Al, A2, A3, A4, A5 and X have the same meanings as above, is reduced catalytically, the corresponding l-benzyl-alpha,alpha-diphenyl-4-piperidinemethanol thus obtained of the general formula:
A
\ ' ~ N-CH2 ~ O-A5 (VII~
wherein Xl, A2, A3, A4 and A5 have the same meanings as above, is dehydrated with a dehydrating agent, for example anhydrous hydrogen chloride in alcoholic solution, and the resulting l-benzyl-4-diphenylmethylene-piperidine of the general formula A ~
C ~ N-CH ~ O-A5 (IV) wherein Al, A2, A3, A4 and A5 have the same meanings as above, is finally subjected to hydrolysis.
~ -4-~Q14~6
3) A 4-diphenylmethylene-piperidine of the general formula A
C~ NII (II~
A3`~
wherein Al, A2, A3 and A4 have the same meaning as above, is condensed with a hydroxybenzaldehyde in a inert solvent, for example ethanol, in the presence of catalytically activated hydrogen.
The starting material~ of formula II can be prepared according to the method already described i.n British Patent Specification No. 1,242,169 by the reduction of an alpha,alpha-diphenyl-4-pyridinemethanol of the formula:
1~
A2 \ OH
C ~ N (V) A~
wherein Al, A3, A3 and A4 have the same meanings as above, to give an alpha,alpha-diphenyl-4-piperidine-methanol of the formula:
A2><===/\0H
~C_~H (VI I I ) A3~/
A4~X
wherein Al, A2, A3 and A4 have the same meanings as above, j.,, ~ 1426 followed by dehydration to give the desired compound of formula II.
The benzoyloxybenzyl bromides of formuIa III (X=
bromine; A5=benzoyl) can be prepared by the method described by J.H. B~RNES et al. (J. Chem. Soc. 1953, 773).
It is to be understood that each of the new compounds according to the present invention can be prepared by any of the above-described methods or by equivalents thereof.
The present invention also provides pharmaceutical compositions comprising at least one of the new compounds in admixture with a solid or liquid pharmaceutical diluent or carrier.
The following Examples are given for the purpose of illustrating the present invention:
Preparation of the starting 4-diphenylmethylene-piperidines of the formula II.
These compounds are prepared by the method described in British Patent Specification No. 1,242,169. Apart from the compounds already specifically mentioned in this British Patent, the following compounds have also been synthetized (for each compound prepared, there are given by order, the starting product of formula V, the intermediate product of formula VIII and the final product of formula II):
- alpha-4-fluoro~henyl-alpha-4'-methoxyphenyl-4-pyridinemethanol (m.p. 147-150C.); alpha-4-fluorophenyl-alpha-
C~ NII (II~
A3`~
wherein Al, A2, A3 and A4 have the same meaning as above, is condensed with a hydroxybenzaldehyde in a inert solvent, for example ethanol, in the presence of catalytically activated hydrogen.
The starting material~ of formula II can be prepared according to the method already described i.n British Patent Specification No. 1,242,169 by the reduction of an alpha,alpha-diphenyl-4-pyridinemethanol of the formula:
1~
A2 \ OH
C ~ N (V) A~
wherein Al, A3, A3 and A4 have the same meanings as above, to give an alpha,alpha-diphenyl-4-piperidine-methanol of the formula:
A2><===/\0H
~C_~H (VI I I ) A3~/
A4~X
wherein Al, A2, A3 and A4 have the same meanings as above, j.,, ~ 1426 followed by dehydration to give the desired compound of formula II.
The benzoyloxybenzyl bromides of formuIa III (X=
bromine; A5=benzoyl) can be prepared by the method described by J.H. B~RNES et al. (J. Chem. Soc. 1953, 773).
It is to be understood that each of the new compounds according to the present invention can be prepared by any of the above-described methods or by equivalents thereof.
The present invention also provides pharmaceutical compositions comprising at least one of the new compounds in admixture with a solid or liquid pharmaceutical diluent or carrier.
The following Examples are given for the purpose of illustrating the present invention:
Preparation of the starting 4-diphenylmethylene-piperidines of the formula II.
These compounds are prepared by the method described in British Patent Specification No. 1,242,169. Apart from the compounds already specifically mentioned in this British Patent, the following compounds have also been synthetized (for each compound prepared, there are given by order, the starting product of formula V, the intermediate product of formula VIII and the final product of formula II):
- alpha-4-fluoro~henyl-alpha-4'-methoxyphenyl-4-pyridinemethanol (m.p. 147-150C.); alpha-4-fluorophenyl-alpha-
4'-methoxyphenyl-4-piperidinemethanol (m.p. 174-175C.); 4-(4-fluoro-4'-methoxy-diphenylmethylene)-piperidine (m.p. 76-77C.);
- alpha-phenyl-alpha-2-trifluoromethylphenyl-4-pyridinemethanol (m.p. 224-225C.); alpha-phenyl-alpha-2-trifluoromethylphenyl-4-piperidinemethanol (m.p. 173-174C.);
4-(2-trifluoromethyl-diphenylmethylene)-piperidine (b.p. 128-130C./0.001 mm.Hg.);
.
- alpha-3-fluorophenyl-alpha-phenyl-4-pyridinemethanol (m.p. 194-195C.); alpha-3-fluorophenyl-alpha-phenyl-4-piperi-dinemethanol (m.p. 149-150C.); 4-~3-fluoro-diphenylmethylene)-piperidine (b.p. 142-144C./0.001 mm.Hg.; m.p. 45-46C.);
- alpha-4-fluorophenyl-alpha-4'-trifluoromethylphenyl-4-pyridinemethanol m.p. 157-158C.); alpha-4-fluorophenyl-alpha-4'-trifluoromethylphenyl-4-piperidinemethanol (m.p. of HCl salt: 262-263C.); 4-(4-fluoro-4'-trifluoromethyl-diphenyl-methylene)-piperidine (b.p. 130-134C./0.001 mm.Hg.);
- alpha,alpha-bis-(4-chlorophenyl)-4-pyridinemethanol (m.p. 202-205C.); alpha,alpha-bis-(4-chlorophenyl)-4-piperi-dinemethanol (m.p. 175-177C.); 4-(4,4'-dichlorodiphenyl-methylene)-piperidine (m.p. 115-117C.);
- alpha-4-isopropylphenyl-alpha-phenyl-4-pyridinemethanol (m.p.-151-153C); alpha-4-isopropylphenyl-alpha-phenyl-4-piperi-dinemethanol (m.p. 216-218C.); 4-(4-isopropyl-diphenylmethylene)-piperidine (m.p. 55-56C.);
- alpha-2-fluorophenyl-alpha-phenyl-4-pyridinemethanol (m.p. 200-201C.); alpha-2-fluorophenyl-alpha-phenyl-4-piperi-dinemethanol; dehydrated without isolation to 4-(2-fluorodi-phenylmethylene)-piperidine (b.p. 122-124C./0.001 mm.Hg.;
m.p. 65-66C.);
- alpha-phenyl-alpha-4-propoxyphenyl-4-pyridinemethanol (m.p. 138-140C.); alpha-phenyl-alpha-4-propoxyphenyl-4-piperi-dinemethanol; dehydrated without isolation to 4-(4-propoxydi-phenylmethylene)-piperidine (m.p. 70-71C.);
- alpha-4-chlorophenyl-alpha-3'-methylphenyl-4-pyridinemethanol (m.p. 184-185C.); alpha-4-chlorophenyl-alpha-3'-methylphenyl-4-piperidinemethanol; dehydrated without isolation to 4-(4-chloro-3'-methyl-diphenylmethylene)-piperidine (b.p.
154-156GC./0.001 mm.Hg.).
~ -7-11~1426 Preparation of the 4-diphenylmethylene-1-hydroxybenzyl-piperi-dines accordin~ to the invention.
Example 1. First proc_ss.
1. 4-(4-tert.-sutyl-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine .a) A mixture of 18.4 g. of 4-(4-tert.-butyldiphenyl-methylene)-piperidine, 20 g. of 4-benzoyloxybenzyl bromide and 9.5 g. anhydrous sodium carbonate in 50 ml. xylene is heated for 4 hours at 120C. After cooling, the reaction mixture is filtered to separate the sodium bromide formed and the filtrate is extracted with dilute hydrochloric acid ~15 ml.
of concentrated hydrochloric acid diluted with 40 ml. of water).
1-(4-Benzoyloxybenzyl)-4-(4-tert.-butyl-diphenylmethylene)-piperidine, precipitates out in the form of its sparingly soluble hydrochloride, which is filtered off and recrystallized from isopropanol; m.p. 259-261C. Yield: 85~.
Y C36 37N02.HC
calculated: Cl 6.42% N 2.53 found : 6.35~ 2.60%
b) A mixture of 10 g. of the compound obtained according to a) above and 10 g. of potassium hydroxide in 200 ml. of ethanol is heated under reflux. The ethanol is allowed to distil off and is progressively replaced by water. After distillation of the ethanol, dilute hydrochloric a~id (20 ml.
of concentrated hydrochloric acid diluted with 25 ml. of water) is slowly added. The sparingly soluble hydrochloride precipitates out and is separated by decanting the reaction mixture. The precipitate is washed twice with lukewarm water and then re-crystallized from isopropanol to give 4-(4-tert.-butyl-diphenyl-methylene)-1-(4-hydroxybenzyl)-piperidine hydrochloride; m.p.
202-204C. (recrystallized from isopropanol).
Yield: 72%
` 1101426 lysis C2sTI33No.Hcl calculated: Cl 7.91% N 3.13 found : 8.04% 3.30~
The following compounds are prepared in an analogous manner. The melting points are, unless stated to the contrary, those of the hydrochlorides. The melting points are often not very sharp (margin of error 1-5C.) due to the fact that the compounds prepared frequently contain a small quantity of solvent.
2. 4-(4-tert.Butyl-diphenylmethylenej-1-(2-hydroxybenzy _ -piperidine .
) C36 37 2 HCl calculated: Cl 6.42% N 2.53%
found : 6.55~ 2.64%
m.p. 205-207C. (recrystallized from isopropanol).
b) C29H33NO-HCl calculated: Cl 7.91% N 3.13%
found : 8.13% 3.18%
m.p. 150-152C. (recrystallized from acetonitrile) 3. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine ) C32 29NO2.HCl calculated: Cl 7.14% N 2.80%
20found : 7.08% 2.78%
m.p. 246-248C. (recrystallized from isopropanol) bj C25H25NO-HCl calculated: Cl 9.04% N 3.57%
found : 9.20~ 3.56%
m.p. 244-246C. (recrystallized from isopropanol) 4. 4-Diphenylmethylene--l-(3-hydroxy-enzyl)-piperidine a) C32 29NO2.HCl calculated: Cl 7.14% N 2.80%
found : 7.31% 2.88%
m.p. 249-251C.
b) C25 25NO-HCl calculated: Cl 9.04% N 3.57%
found : 9.05% 3.69%
m.p. 148-150C. (recrystallized from acetonitrile)
- alpha-phenyl-alpha-2-trifluoromethylphenyl-4-pyridinemethanol (m.p. 224-225C.); alpha-phenyl-alpha-2-trifluoromethylphenyl-4-piperidinemethanol (m.p. 173-174C.);
4-(2-trifluoromethyl-diphenylmethylene)-piperidine (b.p. 128-130C./0.001 mm.Hg.);
.
- alpha-3-fluorophenyl-alpha-phenyl-4-pyridinemethanol (m.p. 194-195C.); alpha-3-fluorophenyl-alpha-phenyl-4-piperi-dinemethanol (m.p. 149-150C.); 4-~3-fluoro-diphenylmethylene)-piperidine (b.p. 142-144C./0.001 mm.Hg.; m.p. 45-46C.);
- alpha-4-fluorophenyl-alpha-4'-trifluoromethylphenyl-4-pyridinemethanol m.p. 157-158C.); alpha-4-fluorophenyl-alpha-4'-trifluoromethylphenyl-4-piperidinemethanol (m.p. of HCl salt: 262-263C.); 4-(4-fluoro-4'-trifluoromethyl-diphenyl-methylene)-piperidine (b.p. 130-134C./0.001 mm.Hg.);
- alpha,alpha-bis-(4-chlorophenyl)-4-pyridinemethanol (m.p. 202-205C.); alpha,alpha-bis-(4-chlorophenyl)-4-piperi-dinemethanol (m.p. 175-177C.); 4-(4,4'-dichlorodiphenyl-methylene)-piperidine (m.p. 115-117C.);
- alpha-4-isopropylphenyl-alpha-phenyl-4-pyridinemethanol (m.p.-151-153C); alpha-4-isopropylphenyl-alpha-phenyl-4-piperi-dinemethanol (m.p. 216-218C.); 4-(4-isopropyl-diphenylmethylene)-piperidine (m.p. 55-56C.);
- alpha-2-fluorophenyl-alpha-phenyl-4-pyridinemethanol (m.p. 200-201C.); alpha-2-fluorophenyl-alpha-phenyl-4-piperi-dinemethanol; dehydrated without isolation to 4-(2-fluorodi-phenylmethylene)-piperidine (b.p. 122-124C./0.001 mm.Hg.;
m.p. 65-66C.);
- alpha-phenyl-alpha-4-propoxyphenyl-4-pyridinemethanol (m.p. 138-140C.); alpha-phenyl-alpha-4-propoxyphenyl-4-piperi-dinemethanol; dehydrated without isolation to 4-(4-propoxydi-phenylmethylene)-piperidine (m.p. 70-71C.);
- alpha-4-chlorophenyl-alpha-3'-methylphenyl-4-pyridinemethanol (m.p. 184-185C.); alpha-4-chlorophenyl-alpha-3'-methylphenyl-4-piperidinemethanol; dehydrated without isolation to 4-(4-chloro-3'-methyl-diphenylmethylene)-piperidine (b.p.
154-156GC./0.001 mm.Hg.).
~ -7-11~1426 Preparation of the 4-diphenylmethylene-1-hydroxybenzyl-piperi-dines accordin~ to the invention.
Example 1. First proc_ss.
1. 4-(4-tert.-sutyl-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine .a) A mixture of 18.4 g. of 4-(4-tert.-butyldiphenyl-methylene)-piperidine, 20 g. of 4-benzoyloxybenzyl bromide and 9.5 g. anhydrous sodium carbonate in 50 ml. xylene is heated for 4 hours at 120C. After cooling, the reaction mixture is filtered to separate the sodium bromide formed and the filtrate is extracted with dilute hydrochloric acid ~15 ml.
of concentrated hydrochloric acid diluted with 40 ml. of water).
1-(4-Benzoyloxybenzyl)-4-(4-tert.-butyl-diphenylmethylene)-piperidine, precipitates out in the form of its sparingly soluble hydrochloride, which is filtered off and recrystallized from isopropanol; m.p. 259-261C. Yield: 85~.
Y C36 37N02.HC
calculated: Cl 6.42% N 2.53 found : 6.35~ 2.60%
b) A mixture of 10 g. of the compound obtained according to a) above and 10 g. of potassium hydroxide in 200 ml. of ethanol is heated under reflux. The ethanol is allowed to distil off and is progressively replaced by water. After distillation of the ethanol, dilute hydrochloric a~id (20 ml.
of concentrated hydrochloric acid diluted with 25 ml. of water) is slowly added. The sparingly soluble hydrochloride precipitates out and is separated by decanting the reaction mixture. The precipitate is washed twice with lukewarm water and then re-crystallized from isopropanol to give 4-(4-tert.-butyl-diphenyl-methylene)-1-(4-hydroxybenzyl)-piperidine hydrochloride; m.p.
202-204C. (recrystallized from isopropanol).
Yield: 72%
` 1101426 lysis C2sTI33No.Hcl calculated: Cl 7.91% N 3.13 found : 8.04% 3.30~
The following compounds are prepared in an analogous manner. The melting points are, unless stated to the contrary, those of the hydrochlorides. The melting points are often not very sharp (margin of error 1-5C.) due to the fact that the compounds prepared frequently contain a small quantity of solvent.
2. 4-(4-tert.Butyl-diphenylmethylenej-1-(2-hydroxybenzy _ -piperidine .
) C36 37 2 HCl calculated: Cl 6.42% N 2.53%
found : 6.55~ 2.64%
m.p. 205-207C. (recrystallized from isopropanol).
b) C29H33NO-HCl calculated: Cl 7.91% N 3.13%
found : 8.13% 3.18%
m.p. 150-152C. (recrystallized from acetonitrile) 3. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine ) C32 29NO2.HCl calculated: Cl 7.14% N 2.80%
20found : 7.08% 2.78%
m.p. 246-248C. (recrystallized from isopropanol) bj C25H25NO-HCl calculated: Cl 9.04% N 3.57%
found : 9.20~ 3.56%
m.p. 244-246C. (recrystallized from isopropanol) 4. 4-Diphenylmethylene--l-(3-hydroxy-enzyl)-piperidine a) C32 29NO2.HCl calculated: Cl 7.14% N 2.80%
found : 7.31% 2.88%
m.p. 249-251C.
b) C25 25NO-HCl calculated: Cl 9.04% N 3.57%
found : 9.05% 3.69%
m.p. 148-150C. (recrystallized from acetonitrile)
5. 4-Diphenylmethylene-1-(2-hydroxybenzyl)-piperidine ` 11~14Z6 a) C32H29N2 HCl calculated: Cl 7.14% N 2.80%
found : 7.12%2.88%
m.p. 214-216C.
) 25 25 Cl calculated: Cl 9.04% N 3.57 Eound : 9.00'~ 3.58~
m.p. 156-158C. (recrystallized from acetonitrile) (softened at 132C.).
found : 7.12%2.88%
m.p. 214-216C.
) 25 25 Cl calculated: Cl 9.04% N 3.57 Eound : 9.00'~ 3.58~
m.p. 156-158C. (recrystallized from acetonitrile) (softened at 132C.).
6. 4-(2-Chloro-dipheny_methylenej~ 4-hydroxybenzyl)-piperidine.
a) C32H28ClNO2.HCl calculated: Cl 13.36% C1 6.68% N 2.64%
found : 13.25~ 6.75% 2.63%
m.p~ 264-266C. (recrystallized from isopropanol) b) C25H24ClN0-HCl calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.30% 8.36~ 3.34%
m.p. 248-250C. (recrystallized from isopropanol); 193-194C.
(free base)
a) C32H28ClNO2.HCl calculated: Cl 13.36% C1 6.68% N 2.64%
found : 13.25~ 6.75% 2.63%
m.p~ 264-266C. (recrystallized from isopropanol) b) C25H24ClN0-HCl calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.30% 8.36~ 3.34%
m.p. 248-250C. (recrystallized from isopropanol); 193-194C.
(free base)
7. 4-(2-Chloro-diphenylmethylene)-1-(3-hydroxybenzyl)-piperidine.
a) C32H28ClN02.HCl calculated: Cl 13.36% Cl 6.68~ N 2.64%
fo~nd : 13.50% 6.72% 2.72%
m.p. 254-256C. (recrystallized from isopropanol) b) C25 24ClNO.HCl calculated: Cl 16.63% Cl 8.31~ N 3.28%
found : 16.75% 8.25% 3.39%
m.p. 242-244C.
a) C32H28ClN02.HCl calculated: Cl 13.36% Cl 6.68~ N 2.64%
fo~nd : 13.50% 6.72% 2.72%
m.p. 254-256C. (recrystallized from isopropanol) b) C25 24ClNO.HCl calculated: Cl 16.63% Cl 8.31~ N 3.28%
found : 16.75% 8.25% 3.39%
m.p. 242-244C.
8. 4-(2-Chloro-diphenylmethylene)-1-(2-hydroxybenzyl)-piperidine.
a) C32H28ClNO2.HCl calculated: Cl 13.36~ Cl 6.68% N 2.64%
found : 13.10~ 6.85% 2.86%
m.p. 200-202C.
~" 11(~14Z6 ~`
) C25H24ClNO.HCl calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.28% 8.20% 3.23%
m.p . 240-242c.
a) C32H28ClNO2.HCl calculated: Cl 13.36~ Cl 6.68% N 2.64%
found : 13.10~ 6.85% 2.86%
m.p. 200-202C.
~" 11(~14Z6 ~`
) C25H24ClNO.HCl calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.28% 8.20% 3.23%
m.p . 240-242c.
9. 4-(3-Chloro-diphenylmethyiene)-1-14-hydroxybenzyl~-piperidine.
a) C32H28ClNO2.HCl calculated: Cl 13.36% Cl 6.68% N 2.64%
found : 12.92~ 6.85% 2.70 m.p. 242-244C. (recrystallized from isopropanol) ' ) C25 24ClNO HCl calculated: Clttal 16.63% Cl 8 31% N 3 28%
found : 16.57% 8.30~ 3.36%
m.p. 234-236C. (recrystalllzed from isopropanol)
a) C32H28ClNO2.HCl calculated: Cl 13.36% Cl 6.68% N 2.64%
found : 12.92~ 6.85% 2.70 m.p. 242-244C. (recrystallized from isopropanol) ' ) C25 24ClNO HCl calculated: Clttal 16.63% Cl 8 31% N 3 28%
found : 16.57% 8.30~ 3.36%
m.p. 234-236C. (recrystalllzed from isopropanol)
10. 4-(3-Chloro-diphenylmethylene)-1-~3-hydroxybenzyl)-piperidine.
a) C32H28.ClNo2.HCl calculated: Cl 13.36% Cl 6.68% N 2.64%
found : 13.18% 6.55% 2.67%
m.p. 221-223C.
) C25 24ClNO.HCl calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.53% 8.31% 3.22 m.p. 156-157C. (recrystallized from isopropanol)
a) C32H28.ClNo2.HCl calculated: Cl 13.36% Cl 6.68% N 2.64%
found : 13.18% 6.55% 2.67%
m.p. 221-223C.
) C25 24ClNO.HCl calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.53% 8.31% 3.22 m.p. 156-157C. (recrystallized from isopropanol)
11. 4-(4-Chloro-diphenylmethylene)-1-(4-hydcoxybenzyl)-piperidine.
a) C32H28ClNO2-E~Cl calculated: Cl 13.36% Cl 6068% N 2.64~
found : 13.10% 6.95~ 2.73%
m~p. 244-246C.
) C25 24ClNO HCl calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.40~ 8.35% 3.33 11(~1426 m.p. 232-233C. (recrystallized from isopropanol)
a) C32H28ClNO2-E~Cl calculated: Cl 13.36% Cl 6068% N 2.64~
found : 13.10% 6.95~ 2.73%
m~p. 244-246C.
) C25 24ClNO HCl calculated: Cl 16.63~ Cl 8.31% N 3.28%
found : 16.40~ 8.35% 3.33 11(~1426 m.p. 232-233C. (recrystallized from isopropanol)
12. 4-(4-Chloro-diphenylmethylene)-1-(3-hydroxybenzyl)-piperidine.
a) C32H28ClNO2.HCl calculated: Cl 13.36% Cl 6.68% N 2.64%
found :13.10~ 6.75%2.68%
m.p. 192-194C.
) C25 24ClNO-HCl calculated: Cl 1 14.16%Cl 7.08% N 2.79~
(for 1/2 molecuIe of benzene of crystallization) found : 14.50% 7.20% 3.00%
m.p. 143-145C. (benzene)
a) C32H28ClNO2.HCl calculated: Cl 13.36% Cl 6.68% N 2.64%
found :13.10~ 6.75%2.68%
m.p. 192-194C.
) C25 24ClNO-HCl calculated: Cl 1 14.16%Cl 7.08% N 2.79~
(for 1/2 molecuIe of benzene of crystallization) found : 14.50% 7.20% 3.00%
m.p. 143-145C. (benzene)
13. 4-(4-Chloro-diphenylmethylene)-1-(2-hydroxybenzyl)-piperidine.
a) C32H28ClNO2.HCl calculated: Cl 12.04~ Cl 6~02% N 2.37%
(for 1 molecule of acetone of crystallization) found :12.00% 6.05%2.39%
m.p. 112-114C (acetone) ) 25 24ClNO.HCl calculated: Cl 16.63% Cl 8.31% N 3.28~
found :16.55% 8.42%3.28%
m.p. 240-241C.
a) C32H28ClNO2.HCl calculated: Cl 12.04~ Cl 6~02% N 2.37%
(for 1 molecule of acetone of crystallization) found :12.00% 6.05%2.39%
m.p. 112-114C (acetone) ) 25 24ClNO.HCl calculated: Cl 16.63% Cl 8.31% N 3.28~
found :16.55% 8.42%3.28%
m.p. 240-241C.
14. 4-(4-Fluoro-diphenylmethylene)-l-(4-hydroxybenzyl) pi~eridine.
a) C32H28FNo2.HCl calculated: Cl 6.90~ N 2.72%
found : 7.00% 2.72%
m.p. 233-234C. (recrystallized from isopropanol) ) C25 24 NO-HCl calculated: Cl 8.65% N 3.41%
found : 8.72% 3.42%
m.p. 230-232C. (recrystallized from benzene) ~ -12-" , ^`` 11al1426
a) C32H28FNo2.HCl calculated: Cl 6.90~ N 2.72%
found : 7.00% 2.72%
m.p. 233-234C. (recrystallized from isopropanol) ) C25 24 NO-HCl calculated: Cl 8.65% N 3.41%
found : 8.72% 3.42%
m.p. 230-232C. (recrystallized from benzene) ~ -12-" , ^`` 11al1426
15. 4-(4-Fluoro-diphenylmethylene)-1-~3-hydroxybenzyl)-piperidine.
a) C32H28FNO2.HCl calculated: C1 6.90% N 2.72%
found : 6.95~ 2.79%
m.p. 227-228C. (recrystallized from benzene) b) C25H24FNO-HCl calcuIated: Cl 8.65% N 3.41%
found : 8.54% 3.30%
m.p. 125-126C. (recrystallized from benzene) .
a) C32H28FNO2.HCl calculated: C1 6.90% N 2.72%
found : 6.95~ 2.79%
m.p. 227-228C. (recrystallized from benzene) b) C25H24FNO-HCl calcuIated: Cl 8.65% N 3.41%
found : 8.54% 3.30%
m.p. 125-126C. (recrystallized from benzene) .
16. 4-(4-Fluoro-diphen~lmethylene)-1-(2-hydroxybenzyl)-piperidine.
a) C32H28FN2 HCl calculated: Cl 6.90% N 2.72%
found : 6.85% 2.50%
m.p. 100-102C. (recrystallized from benzene) ) 25 24 - Cl calculated: Cl 8.65% N 3.41%
found : 9.00% 3.30%
m.p. 211-213C.
.
a) C32H28FN2 HCl calculated: Cl 6.90% N 2.72%
found : 6.85% 2.50%
m.p. 100-102C. (recrystallized from benzene) ) 25 24 - Cl calculated: Cl 8.65% N 3.41%
found : 9.00% 3.30%
m.p. 211-213C.
.
17. 4-(3-Fluoro-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine.
a) C32H28FN2'HCl calculated: Cl 6.90% N 2.72%
found : 6.9S% 2.74%
m.p. 254-256C. (recrystallized from benzene) b) C25H24FNO'HCl calculated: Cl 8.65% N 3.41%
found : 8.84% 3.52%
m.p. 242-246C. ~recrystallized from isopropanol)
a) C32H28FN2'HCl calculated: Cl 6.90% N 2.72%
found : 6.9S% 2.74%
m.p. 254-256C. (recrystallized from benzene) b) C25H24FNO'HCl calculated: Cl 8.65% N 3.41%
found : 8.84% 3.52%
m.p. 242-246C. ~recrystallized from isopropanol)
18. 4-(3-Fluoro-diphenylmethylene)-1-(3-hydroxybenzyl)-piperidine.
a) C32H28FNO2.HC1 calculated: Cl 6.90% N 2.72%
found : 7.00% 2.80%
m.p. 241-243C. (recrystallized from xylene) 30b) C25 24 Cl calculated: Cl 8.65%N 3.41~
found : 8.91% 3.44%
m.p. 145-147C. (recrystallized from acetonitrile)
a) C32H28FNO2.HC1 calculated: Cl 6.90% N 2.72%
found : 7.00% 2.80%
m.p. 241-243C. (recrystallized from xylene) 30b) C25 24 Cl calculated: Cl 8.65%N 3.41~
found : 8.91% 3.44%
m.p. 145-147C. (recrystallized from acetonitrile)
19. 4-(2-Fluoro-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine.
a) C32H28FNO2.Hcl calculated: Cl 6.90% N 2.72%
found : 7.07% 2.84%
m.p. 267-269C. (recrystallized from isopropanol) b) C25H24FNO'HCl calculated: Cl 8.65% N 3.41%
found : 8.87% 3.52%
m.p~ 245-247C.
a) C32H28FNO2.Hcl calculated: Cl 6.90% N 2.72%
found : 7.07% 2.84%
m.p. 267-269C. (recrystallized from isopropanol) b) C25H24FNO'HCl calculated: Cl 8.65% N 3.41%
found : 8.87% 3.52%
m.p~ 245-247C.
20. 1-(4-Hydroxybenzyl)-4-(4-trifluoromethyl-diphenylmethylene)-piperidine.
a) C33H28F3NO2.HCl calculated: Cl6.28% N 2.48%
found : 6.53% 2.56%
m.p. 242-244C.
b) C26H24F3N'HCl calculated: Cl 7.70% N 3.06%
found : 7.75% 3.08%
m.p. 228-229C (recrystallized from ethyl acetate)
a) C33H28F3NO2.HCl calculated: Cl6.28% N 2.48%
found : 6.53% 2.56%
m.p. 242-244C.
b) C26H24F3N'HCl calculated: Cl 7.70% N 3.06%
found : 7.75% 3.08%
m.p. 228-229C (recrystallized from ethyl acetate)
21. ~(3-Hydroxybenzyl)-4-(4-trifluoromethyl-diphenylmethylene)-piperidine.
a) C33H28F3NO2.HCl calculated: Cl 6.28% N 2.48%
found : 6.48% 2.54%
m.p. 201-203C. (recrystallized from ethyl acetate) b) C26 24 3 calculated: Cl 7.70% N 3.06%
found : 7.44% 2.92%
m.p. 129-131C.
a) C33H28F3NO2.HCl calculated: Cl 6.28% N 2.48%
found : 6.48% 2.54%
m.p. 201-203C. (recrystallized from ethyl acetate) b) C26 24 3 calculated: Cl 7.70% N 3.06%
found : 7.44% 2.92%
m.p. 129-131C.
22. 1-(4-Hydroxybenzyl)-4-(3-trifluoromethyl-diphenylmethylene)-piperidine a) C33H28F3No2-Hcl calculated: Cl 6.28% N 2.48%
found : 6.35% 2.61%
m.p. 229-231C. (recrystallized from methanol) ) 26 24 3 calculated: Cl 7.70% N 3.06%
found : 7.65% 3.17%
m.p. 229-230C. (recrystallized from ethyl acetate) ~-14-
found : 6.35% 2.61%
m.p. 229-231C. (recrystallized from methanol) ) 26 24 3 calculated: Cl 7.70% N 3.06%
found : 7.65% 3.17%
m.p. 229-230C. (recrystallized from ethyl acetate) ~-14-
23. 1-(3-~ydroxybenzyl)-4-(3-trifluoromethyl-diphenylmethylene) piperidine.
a) C33H28F3NO2.HCl calculated: Cl 6.28~ N 2.48%
found : 6.34% 2.55%
m.p. 215-217C.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found- : 7.58% 3.01%
m.p. 148-150C.
a) C33H28F3NO2.HCl calculated: Cl 6.28~ N 2.48%
found : 6.34% 2.55%
m.p. 215-217C.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found- : 7.58% 3.01%
m.p. 148-150C.
24. 1-(2-Hydroxybenzyl)-4-(3-trifluoromethyl-diphenylmethylene)-piperidine.
The benzoyloxy derivative was hydrolyzed without isolation.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found : 7.40% 2.92%
m.p. 158-160C. (recrystallized from isopropanol)
The benzoyloxy derivative was hydrolyzed without isolation.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found : 7.40% 2.92%
m.p. 158-160C. (recrystallized from isopropanol)
25. 1-(4-Hydroxybenzyl)-4-(2-trifluoromethyl-diphenylmethylene)-piperidine.
a) C33H28F3NO2.HCl calculated: Cl 6.28% N 2.48%
found : 6.18% 2.49%
m.p. 242-244C.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found : 7.95% 3.l4%
m.p. 250-252C. (recrystallized from methanol)
a) C33H28F3NO2.HCl calculated: Cl 6.28% N 2.48%
found : 6.18% 2.49%
m.p. 242-244C.
b) C26 24F3NO.HCl calculated: Cl 7.70% N 3.06%
found : 7.95% 3.l4%
m.p. 250-252C. (recrystallized from methanol)
26. 1-(2-Hydroxybenzyl)-4-(2-trifluoromethyl-diphenylmethylene)-piperidine.
a) C33H28F3NO2~HCl calculated: Cl 6.28% N 2.48%
found : 6.04% 2.51%
m.p. 125-127C.
b) C26 24 3NO HCl calculated: Cl 7.70% N 3.06%
found : 7.75% 3.05%
m.p. 132-134C.
a) C33H28F3NO2~HCl calculated: Cl 6.28% N 2.48%
found : 6.04% 2.51%
m.p. 125-127C.
b) C26 24 3NO HCl calculated: Cl 7.70% N 3.06%
found : 7.75% 3.05%
m.p. 132-134C.
27. 1-(4-Hydroxybenzyl)-4-(4-methoxy-diphenylmethylene)-piperidine.
~10~4Z~i a) C33H31~3-HCl calculated: Cl 6.73% N 2.65%
found : 6.82~ 2.68 m.p. 243-245C.
26 27 2 calculated: Cl 8.40% N 3.31%
found : 8.45% 3.29 m.p. 222-223C.
~10~4Z~i a) C33H31~3-HCl calculated: Cl 6.73% N 2.65%
found : 6.82~ 2.68 m.p. 243-245C.
26 27 2 calculated: Cl 8.40% N 3.31%
found : 8.45% 3.29 m.p. 222-223C.
28. 1-(2-Hydroxybenzyl)-4-(4-methoxy-diphenylmethylene)-pi~eridine.
a) C33H31N3-HCl calculated: Cl 6.73% N 2.65%
found : 6.55% 2.51%
m.p. 115-120C. (approximate) (recrystallized from ethyl acetate) b) C26H27N2 HCl calculated: Cl 8.40% N 3.31 ~ found : 8.54% 3.32 m.p. 223-224C.
a) C33H31N3-HCl calculated: Cl 6.73% N 2.65%
found : 6.55% 2.51%
m.p. 115-120C. (approximate) (recrystallized from ethyl acetate) b) C26H27N2 HCl calculated: Cl 8.40% N 3.31 ~ found : 8.54% 3.32 m.p. 223-224C.
29. 1-~4-Hydroxybenzyl)-4-(2-methoxy-diphenylmethylene)-pi-_eridine.
a) C33H31N3-HCl calculated: Cl 6.73% N 2.65~
found : 6.35~ 2.49%
m.p. 242-423C. (recrystallized from isopropanol) b) C26H27N2'HCl calculated: Cl 8.40% N 3.31%
found : 8.45~ 3.30 m.p. 251-252C.
a) C33H31N3-HCl calculated: Cl 6.73% N 2.65~
found : 6.35~ 2.49%
m.p. 242-423C. (recrystallized from isopropanol) b) C26H27N2'HCl calculated: Cl 8.40% N 3.31%
found : 8.45~ 3.30 m.p. 251-252C.
30. 1-(3-llydroxybenzyl)-4-(2-methoxy-diphenylmethylene)-piperidine.
a) C33H31N3'HCl calculated: Cl 6.73% N 2.65%
found : 6.85% 2.64%
m.p. 210-212C. (recrystallized from benzene) ) C26 27 2 Cl calculated: Cl 8.40% N 3.31%
found : 8.45% 3.31 m.p. 220-222C. (recrystallized from isopropanol)
a) C33H31N3'HCl calculated: Cl 6.73% N 2.65%
found : 6.85% 2.64%
m.p. 210-212C. (recrystallized from benzene) ) C26 27 2 Cl calculated: Cl 8.40% N 3.31%
found : 8.45% 3.31 m.p. 220-222C. (recrystallized from isopropanol)
31. 1-(2-Hydroxybenzyl)-4-(2-methoxy-diphenylmethylene)-~.
1~014Z6 piperidine.
) C33 31NO3.HCl calculated: Cl 6.73% N 2.65%
found : 6.70% 2.62%
m.p. 181 182C.
b) C26ll27NO2-llCl calculated: Cl 8.40~ N 3.31 found : 8.58% 3.38%
m.p. 128-130C. (recrystallized-from benzene)
1~014Z6 piperidine.
) C33 31NO3.HCl calculated: Cl 6.73% N 2.65%
found : 6.70% 2.62%
m.p. 181 182C.
b) C26ll27NO2-llCl calculated: Cl 8.40~ N 3.31 found : 8.58% 3.38%
m.p. 128-130C. (recrystallized-from benzene)
32. 4-(3t4-Dimethy~-diphenylmethylene)-l-(4-hydroxybenzyl) piperid-lne~
10) C34 33NO2.HCl calculated: Cl 6.76% N 2.72%
found : 6.72% 2.71%
m.p. 267-268C. (recrystallized from methanol) ) 27 29 -HCl calculated: Cl 8.44% N 3.33%
found : 8.80% 3.36%
m.p. 248-250C.
10) C34 33NO2.HCl calculated: Cl 6.76% N 2.72%
found : 6.72% 2.71%
m.p. 267-268C. (recrystallized from methanol) ) 27 29 -HCl calculated: Cl 8.44% N 3.33%
found : 8.80% 3.36%
m.p. 248-250C.
33. 4-(3,4-Dimethyl-diphenylmethylene)~ 3-hydroxybenzyl) piperidine .
a) C34H33N2 HCl calculated: Cl 6.76% N 2.72%
found : 6.89% 2.71%
20m.p. 235-236C. (recrystallized from isopropanol) b) C27H29NO-HCl calculated: Cl 8.44% N 3.33%
found : 8.33% 3.35%
m.p. 147-149C. (recrystallized from benzene)
a) C34H33N2 HCl calculated: Cl 6.76% N 2.72%
found : 6.89% 2.71%
20m.p. 235-236C. (recrystallized from isopropanol) b) C27H29NO-HCl calculated: Cl 8.44% N 3.33%
found : 8.33% 3.35%
m.p. 147-149C. (recrystallized from benzene)
34. 4-(3,4-Dimethyl-diphenylmethylene)-1-(2-hydroxybenzyl)-piperidine.
) 34 33 O2.HCl calculated: Cl 6.76% N 2.72~
found : 6.55%2.60%
m.p. 162-164C.
) 27 29NO.HCl calculated: Cl 8.44% N 3.33%
found : 8.68%3.34 m.p. 203-205C. (recrystallized from ethyl acetate)
) 34 33 O2.HCl calculated: Cl 6.76% N 2.72~
found : 6.55%2.60%
m.p. 162-164C.
) 27 29NO.HCl calculated: Cl 8.44% N 3.33%
found : 8.68%3.34 m.p. 203-205C. (recrystallized from ethyl acetate)
35. 4-(4-Chloro-4'-fluoro-diphenylmethylene3-1-(4-hydroxy-110~4Z6 benzyl)-piperidine.
a) C32H27ClFNO2.HCl calculated: Cl 12.92~ Cl 6.46% N 2.55%
found : 13.18~ 6.57% 2.52%
m.p. 221-222C. (recrystallized from benzene) b) C25H23ClFNO-HCl calculated: Cl 13~58% Cl 6.78% N 2.70 (for 1 molecule of benzene of crystallization) found : 13~30% 6.88% 2.72%
m.p. 134-316C. (benzene)
a) C32H27ClFNO2.HCl calculated: Cl 12.92~ Cl 6.46% N 2.55%
found : 13.18~ 6.57% 2.52%
m.p. 221-222C. (recrystallized from benzene) b) C25H23ClFNO-HCl calculated: Cl 13~58% Cl 6.78% N 2.70 (for 1 molecule of benzene of crystallization) found : 13~30% 6.88% 2.72%
m.p. 134-316C. (benzene)
36. 4-(4-Chloro-4'-f]uoro-diphenylmethylene)-1-(3-hydroxy-benzyl)-piperidine.
a) C32H27ClFNo2.HCl calculated: Cl 12.92% Cl 6.46% N 2.55%
found : 12.54% 6.57~ 2.54%
m.p. 236-238C. (recrystallized from isopropanol) b) C25H23ClFNo.HCl calculated: Cl 15.95% Cl 7.97% N 3.15%
found : 16.30% 8.10% 3.21 m.p. 229-230C.
a) C32H27ClFNo2.HCl calculated: Cl 12.92% Cl 6.46% N 2.55%
found : 12.54% 6.57~ 2.54%
m.p. 236-238C. (recrystallized from isopropanol) b) C25H23ClFNo.HCl calculated: Cl 15.95% Cl 7.97% N 3.15%
found : 16.30% 8.10% 3.21 m.p. 229-230C.
37. 4-(4-Fluoro-4'-trifluoromethyl-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine.
a) C33H27F4NO2.HCl calculated: Cl 6.49% N 2.40~
found : 6.50% 2.39%
m.p. 228-229C. (recrystallized from isopropanol) ) 26 23 4 C calculated: Cl 7.41% N 2.93 found : 7.35% 2.98 m.p. 223-225C. (recrystallized from benzene)
a) C33H27F4NO2.HCl calculated: Cl 6.49% N 2.40~
found : 6.50% 2.39%
m.p. 228-229C. (recrystallized from isopropanol) ) 26 23 4 C calculated: Cl 7.41% N 2.93 found : 7.35% 2.98 m.p. 223-225C. (recrystallized from benzene)
38. 4-(4-Fluoro-4'-trifluoromethyl-diphenylmethylene)-1-(3-hydroxybenzyl)-piperidine.
Thebenzoyloxy derivative was hydrolyzed without isolation.
b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93~
found : 7.20~ 2.88%
m.p. 134-315C. (rccrystallized from acctonitrilc)
Thebenzoyloxy derivative was hydrolyzed without isolation.
b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93~
found : 7.20~ 2.88%
m.p. 134-315C. (rccrystallized from acctonitrilc)
39. 4-(4-Fluoro-3'-trifluoromethyl-diphenylmcthylene) 1-(4-hydro~ybcnzyl)-pip~ridin~.
a) C~3H27F4NO2.HCl calculated: Cl 6.49% N 2.40%
found : 6.20~ 2.47%
m.p. 216-218C. (recrystallized from benzene) b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93%
found : - 7.84% 3.11%
m.p. 234-235C.
a) C~3H27F4NO2.HCl calculated: Cl 6.49% N 2.40%
found : 6.20~ 2.47%
m.p. 216-218C. (recrystallized from benzene) b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93%
found : - 7.84% 3.11%
m.p. 234-235C.
40. 4-(4-Fluoro-3'-trifluoromethyl-diphenylmethylene)-1-(3-hydrozybenzyl)-piperidine.
a) C33H27F4NO2.HCl calculated: Cl 6.49% N 2.40%
found : 6.15% 2.50%
m.p. 174-176C. (recrystallized from ethyl acetate) b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93%
found : 7.44% 2.94%
m.p. 133-135C.
a) C33H27F4NO2.HCl calculated: Cl 6.49% N 2.40%
found : 6.15% 2.50%
m.p. 174-176C. (recrystallized from ethyl acetate) b) C26H23F4NO-HCl calculated: Cl 7.41% N 2.93%
found : 7.44% 2.94%
m.p. 133-135C.
41. 4-(4-Fluoro-4'-methoxy-diphenylmethylene)-1-(4-hydroxy-benzyl)-piperidine.
a) C33H30FNO3-HCl calculated: Cl 6.53~ N 2.57%
found : 6.25% 2.66%
m.p. 223-225C. (recrystallized from ethyl acetate) b) C26H26FN2 HCl calculated: Cl 8.05% N 3.18%
found : 8.50% 3.22%
m.p. 219-220C. (recrystallized from isopropanol)
a) C33H30FNO3-HCl calculated: Cl 6.53~ N 2.57%
found : 6.25% 2.66%
m.p. 223-225C. (recrystallized from ethyl acetate) b) C26H26FN2 HCl calculated: Cl 8.05% N 3.18%
found : 8.50% 3.22%
m.p. 219-220C. (recrystallized from isopropanol)
42. 4-(4-Fluoro-4'-methoxy-diphenylmethylene)-1-(3-hydroxy-benzyl)-piperidine.
a) C33H30FNO3-HCl calculated: Cl 6.53% N 2.57%
found : 6.68% 2.66%
m.p. 195-197C. (recrystallized from ethyl acetate) ,~," . --1 9--11~1426 ) C26H26FNO2.HCl calculated: Cl 8.05~ N 3.18 found : 7.95% 3.24 m.p. 140-141C. (recrystallized from isopropanol)
a) C33H30FNO3-HCl calculated: Cl 6.53% N 2.57%
found : 6.68% 2.66%
m.p. 195-197C. (recrystallized from ethyl acetate) ,~," . --1 9--11~1426 ) C26H26FNO2.HCl calculated: Cl 8.05~ N 3.18 found : 7.95% 3.24 m.p. 140-141C. (recrystallized from isopropanol)
43. 1-(4-Hydroxybenzyl)-4-(4-propoxy-diphenylmethylene)-piperidine.
) 35 35 3 calculated: Cl 6.39% N 2.52 found : 6.41% 2.64 m.p. 204-206C. (recrystallized from acetonitrile) b) C28 31 O3 HCl calculated: Cl 7.87% N 3.11%
~ found : 7.81% 3.20 m.p. 225-227C. (recrystallized from acetonitrile) Example 2. Second process.
) 35 35 3 calculated: Cl 6.39% N 2.52 found : 6.41% 2.64 m.p. 204-206C. (recrystallized from acetonitrile) b) C28 31 O3 HCl calculated: Cl 7.87% N 3.11%
~ found : 7.81% 3.20 m.p. 225-227C. (recrystallized from acetonitrile) Example 2. Second process.
44. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine.
a) 26.3 g. of alpha,alpha-diphenyl-4-pyridinemethanol in 60 ml. of dioxan are boiled under reflux and treated dropwise, while stirring mechanically, with a solution of 29.5 g of 4-benzoyloxybenzyl bromide in 50 ml. of dioxan. When the addltion of this solution is finished, the reaction mixture is further heated under reflux for 1.5 hours, whereafter excess solvent is evaporated off under vacuum and the 1-(4-benzoyloxybenzyl)-4-(alpha-hydroxy-diphenylmethyl)-pyridinium bromide thus ob-tained is crystallized from benzene; m.p. 210-213C. Yield:
69.5%.
~nalysis: C32ll26~rNO3 calculated: Br 14.46% N 2.53%
found : 14.21~ 2.70%
b) 33 g. of the compound obtained under a) above is subse-quently reduced catalytically in 1 liter of ethanol in the presence of 1 g. of platinum oxide under a hydrogen pressure of 4 kg.
in a Parr bomb at 3~C. The reduction product, 1-(4-benzoyloxy-benzyl)-alpha,alpha-diphenyl-4-piperidinemethanol (not isolated) obtained after filtering off the platinum oxide and evaporating the solvent, i5 subsequently dehydrated in 500 ml. of a solution ' "'5 `' -20-, 11(;~1426 of ethanol saturated in the cold with gaseous hydrogen chloride.
After heating the reaction mixture under reflux for 3 hours and ~vaporatin~ under vacuum to remove the solvent and exc~ss hydrogen chloride, the evaporation residue, dissolved in 250 ml.
oE cthanol wiLI~ ~he addikion oE 15 g. r~o~assiu~n hydroxlde, ls treated and isolated in the same manner as in step b) of Example 1 (firs~ process). ~Eter r~crystallization ~rom lsopropanol, 4-diphenylmethylene-1-(4-hydroxybenzyl)-piperidine hydrochloride is obtained; m.p. 245-246C. Yield: 82.5~.
Analysis C25H25NO-HCl calculated: Cl 9.04% N 3.57~
found : 9.28% 3.70%
There is no melting point depression when this product is mixed with the same compound of Example 1 (compound 3).
The following compounds were prepared in the same manner.
a) 26.3 g. of alpha,alpha-diphenyl-4-pyridinemethanol in 60 ml. of dioxan are boiled under reflux and treated dropwise, while stirring mechanically, with a solution of 29.5 g of 4-benzoyloxybenzyl bromide in 50 ml. of dioxan. When the addltion of this solution is finished, the reaction mixture is further heated under reflux for 1.5 hours, whereafter excess solvent is evaporated off under vacuum and the 1-(4-benzoyloxybenzyl)-4-(alpha-hydroxy-diphenylmethyl)-pyridinium bromide thus ob-tained is crystallized from benzene; m.p. 210-213C. Yield:
69.5%.
~nalysis: C32ll26~rNO3 calculated: Br 14.46% N 2.53%
found : 14.21~ 2.70%
b) 33 g. of the compound obtained under a) above is subse-quently reduced catalytically in 1 liter of ethanol in the presence of 1 g. of platinum oxide under a hydrogen pressure of 4 kg.
in a Parr bomb at 3~C. The reduction product, 1-(4-benzoyloxy-benzyl)-alpha,alpha-diphenyl-4-piperidinemethanol (not isolated) obtained after filtering off the platinum oxide and evaporating the solvent, i5 subsequently dehydrated in 500 ml. of a solution ' "'5 `' -20-, 11(;~1426 of ethanol saturated in the cold with gaseous hydrogen chloride.
After heating the reaction mixture under reflux for 3 hours and ~vaporatin~ under vacuum to remove the solvent and exc~ss hydrogen chloride, the evaporation residue, dissolved in 250 ml.
oE cthanol wiLI~ ~he addikion oE 15 g. r~o~assiu~n hydroxlde, ls treated and isolated in the same manner as in step b) of Example 1 (firs~ process). ~Eter r~crystallization ~rom lsopropanol, 4-diphenylmethylene-1-(4-hydroxybenzyl)-piperidine hydrochloride is obtained; m.p. 245-246C. Yield: 82.5~.
Analysis C25H25NO-HCl calculated: Cl 9.04% N 3.57~
found : 9.28% 3.70%
There is no melting point depression when this product is mixed with the same compound of Example 1 (compound 3).
The following compounds were prepared in the same manner.
45. 4-Diphenylmethylene-1-(3-hydroxybenzyl)-piperidine.
; a) 1-(3-Benzoyloxybenzyl)-4-(alpha-hydroxy-diphenylmethyl)-pyridinium bromide melts at 219-221C., after recrystallization from dioxan.
C32H26BrN3 calculated: Br 14.46% N 2.53~
found : 14.19% 2.57%
b) After reduction 1-(3-benzoyloxybenzyl)-alpha,alpha-diphenyl-4-piperidine-methanol hydrobromide is obtained, which melts at 218-219C., after recrystallization from acetonitrile.
C32H31NO3.HBr calculated: Br 14.31% N 2.50~
found : 14.60% 2.64%
4-Diphenylmethylene-1-(3-hydroxybenzyl)-piperidine hydro-chloride, obtained after dehydration and hydrolysis, melts at 148-150C. It does not show a melting point depression when mixed with the same compound prepared according to Example 1 (compound 4).
C25H25N HCl calculated: Cl 9.04% N 3.57%
found : 8.95% 3.57 .
11~14Z6
; a) 1-(3-Benzoyloxybenzyl)-4-(alpha-hydroxy-diphenylmethyl)-pyridinium bromide melts at 219-221C., after recrystallization from dioxan.
C32H26BrN3 calculated: Br 14.46% N 2.53~
found : 14.19% 2.57%
b) After reduction 1-(3-benzoyloxybenzyl)-alpha,alpha-diphenyl-4-piperidine-methanol hydrobromide is obtained, which melts at 218-219C., after recrystallization from acetonitrile.
C32H31NO3.HBr calculated: Br 14.31% N 2.50~
found : 14.60% 2.64%
4-Diphenylmethylene-1-(3-hydroxybenzyl)-piperidine hydro-chloride, obtained after dehydration and hydrolysis, melts at 148-150C. It does not show a melting point depression when mixed with the same compound prepared according to Example 1 (compound 4).
C25H25N HCl calculated: Cl 9.04% N 3.57%
found : 8.95% 3.57 .
11~14Z6
46. 4-Diphenylmethylene-1-(2-hYdroxybenzyl)-piperidine.
a) l-(2-Benzoyloxybenzyl)-4 (alpha-hydroxy-diphenylmethyl)-pyridinium bromide melts at 197-198C., after recrystallization from benzene.
C32ll26~rNO3 calculated: Br 14.46~ N 2.53%
found : 13.90% 2.44%
b) ~fter reduction, dehydration and hydrolysis, there is obtained 4-diphenylmethylene-1-(2-hydroxybenzyl)-piperidine hydrochloride, which melts at 156-158C., after recrystallization from acetonitrile. It is to be noted that this compound already softens at 132-134C., as does the same compound (compound 5) prepared according to Example 1. The free base, after liberation from the hydrochloride, melts at 149-150C.
C25H25NO.HCl calculated: Cl 9.04% N 3.57%
found : 9.11% 3.54%
Example 3. Third_process.
a) l-(2-Benzoyloxybenzyl)-4 (alpha-hydroxy-diphenylmethyl)-pyridinium bromide melts at 197-198C., after recrystallization from benzene.
C32ll26~rNO3 calculated: Br 14.46~ N 2.53%
found : 13.90% 2.44%
b) ~fter reduction, dehydration and hydrolysis, there is obtained 4-diphenylmethylene-1-(2-hydroxybenzyl)-piperidine hydrochloride, which melts at 156-158C., after recrystallization from acetonitrile. It is to be noted that this compound already softens at 132-134C., as does the same compound (compound 5) prepared according to Example 1. The free base, after liberation from the hydrochloride, melts at 149-150C.
C25H25NO.HCl calculated: Cl 9.04% N 3.57%
found : 9.11% 3.54%
Example 3. Third_process.
47. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine.
A solution of 12.5 g. of 4-diphenylmethylene-piperidine and of 20 g. of 4-hydroxybenzaldehyde in 120 ml. of ethanol is reduced in the presence of 1 g. of platinum oxide in a Parr bomb under a hydrogen pressure of 4 kg. at a temperature of 30-35C. After filtering the reaction mixture, 4-diphenyl-methylene-l-(4-hydroxybenzyl)-piperidine crystallizes in the form of the base upon concentration of the filtrate. After recrystallization from ethanol, it has a melting point of 189-190C.
25 25 calculated: N 3.94%
found : 4.03%
The corresponding hydrochloride, after recrystallization from isopropanol, melts at 244-246C. and does not show any melting point depression when mixed with the same compound prepared according to the two other Examples (compounds 3 and 44)-11(~1426
A solution of 12.5 g. of 4-diphenylmethylene-piperidine and of 20 g. of 4-hydroxybenzaldehyde in 120 ml. of ethanol is reduced in the presence of 1 g. of platinum oxide in a Parr bomb under a hydrogen pressure of 4 kg. at a temperature of 30-35C. After filtering the reaction mixture, 4-diphenyl-methylene-l-(4-hydroxybenzyl)-piperidine crystallizes in the form of the base upon concentration of the filtrate. After recrystallization from ethanol, it has a melting point of 189-190C.
25 25 calculated: N 3.94%
found : 4.03%
The corresponding hydrochloride, after recrystallization from isopropanol, melts at 244-246C. and does not show any melting point depression when mixed with the same compound prepared according to the two other Examples (compounds 3 and 44)-11(~1426
48. 4-Diphenylmethylene-l-t2-hydroxybenzyl)-piperidine.
This compound is obtained in an analogous manner.
After recrystallization from ethanol, it has a melting point of 148-149C. (free base). When mixed with the same compound prepared according to Example 2 (compound 46), it does not show any melting point depression.
25 25 calculated: N 3.94~
found : 3.90%
The corresponding hydrochloride, after recrystallization from acetonitrile, melts at 156-158C. but already softens at about 132-134C., as aLready observed for the same compound prepared according to the other Examples (compounds 5 and 46).
This compound is obtained in an analogous manner.
After recrystallization from ethanol, it has a melting point of 148-149C. (free base). When mixed with the same compound prepared according to Example 2 (compound 46), it does not show any melting point depression.
25 25 calculated: N 3.94~
found : 3.90%
The corresponding hydrochloride, after recrystallization from acetonitrile, melts at 156-158C. but already softens at about 132-134C., as aLready observed for the same compound prepared according to the other Examples (compounds 5 and 46).
49. 1-(4-Hydroxybenzyl)-4-(4-isopropyl-diphenylmethylene)-piperidlne .
A solution of 15 g. of 4-(4-isopropanol-diphenyl-methylene)-piperidine and of 20 g. of 4-hydroxybenzaldehyde in 100 ml. of ethanol is reduced in the same manner as des-cribed above. After the reaction, the reaction mixture is filtered and excess solvent evaporated off under vacuum on a waterbath. The evaporation residue is taken up in 100 ml.
of benzene, filtered and extracted with dilute hydrochloric acid (15 ml. of concentrated hydrochloric acid diluted with
A solution of 15 g. of 4-(4-isopropanol-diphenyl-methylene)-piperidine and of 20 g. of 4-hydroxybenzaldehyde in 100 ml. of ethanol is reduced in the same manner as des-cribed above. After the reaction, the reaction mixture is filtered and excess solvent evaporated off under vacuum on a waterbath. The evaporation residue is taken up in 100 ml.
of benzene, filtered and extracted with dilute hydrochloric acid (15 ml. of concentrated hydrochloric acid diluted with
50 ml. of water). 1-(4-Hydroxybenzyl)-4-(4-isopropyldiphenyl-methylene)-piperidine hydrochloride thus obtained, after crystal-lization from ethanol, melts at 253-254C. Yield: 60%.
28 3lNo.Hcl calculated: Cl 8.17~ N 3.22%
found : 8.43~ 3.27~
The following two compounds are prepared in the same manner as compound 49:
50. 4-(4-Chloro-3'-methyl-diphenylmethylene)~1-(4-h~droxy-benzyl)-piperidine.
C26H26ClNo.HCl 11(1 14Z6 calculated: Cl 16.10~ Cl 8.05% N 3.18~
found : 15.87% 8.32% 3.26%
A~ter recrystallization from ethyl acetate, it melts at 221-223C.
28 3lNo.Hcl calculated: Cl 8.17~ N 3.22%
found : 8.43~ 3.27~
The following two compounds are prepared in the same manner as compound 49:
50. 4-(4-Chloro-3'-methyl-diphenylmethylene)~1-(4-h~droxy-benzyl)-piperidine.
C26H26ClNo.HCl 11(1 14Z6 calculated: Cl 16.10~ Cl 8.05% N 3.18~
found : 15.87% 8.32% 3.26%
A~ter recrystallization from ethyl acetate, it melts at 221-223C.
51. 4-(4,4'-Dichloro-diphenyl~ethylene)-1-~4-hydroxybenzyl)-piperidine.
C25 23cl2No-llcl calculated: Cl 23.08% Cl 7.69% N 3.03%
found : 23.29~ 7.93% 3.10%
After recrystallization from isopropanol, the product melts at 166-168C.
Salts of compound 6 mentioned above can also be prepared:
C25 23cl2No-llcl calculated: Cl 23.08% Cl 7.69% N 3.03%
found : 23.29~ 7.93% 3.10%
After recrystallization from isopropanol, the product melts at 166-168C.
Salts of compound 6 mentioned above can also be prepared:
52. 4-(2-Chloro-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine fumarate.
c25H24ClNo~c4H4o4 calculated: N 2.76% Cl 7.00%
found : 2.74~ 7.07%
m.p. 130-140C.
c25H24ClNo~c4H4o4 calculated: N 2.76% Cl 7.00%
found : 2.74~ 7.07%
m.p. 130-140C.
53. 4-(2-Chloro-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine maleate.
c25H24ClNo~c4H4o4 calculated: N 2.76% Cl 7.00%
found : 2.76% 7.4%
m.p. 110-112C.
Pharmacological properties.
1. Activity on the blood circulation.
_______ _________________________ The hemodynamic effects of compounds of general formula 1 were studied on the anesthetized dog subjected to artificial respiration under the experimental conditions described by D. WELLENS and E. WAUTERS (Arch. Int. Pharmacodyn., 171, (1968), 245-250). The measurement of the musculo-cutaneous, cardiac and cerebral outputs, carried out by means of probes places around the femoral (A), carotid (B), coronary (C) and vertebral (D) arteries, showed that the compounds of general formula I
~ -24-11~14Z6 considerably increase the blood circulation.
In these experiments, the maximum score " 2" is assigned to a compound that brings about an increase of circulation of at least 20~ for at least 20 minutes. The maximum score per experiment carried out on two dogs is " 4" , with the possibility of the intermediates form " 0" to " 4" .
For the purpose of comparison, the corresponding values for two known compounds,~papaverine (X) andtheophylline (Y) are also given. The results obtained are given in the following Table I:
TABLE I
Output scores CompoundDoses in mg/kg (i.v.) A B C D
X 2 1.5 2 2 1.5 Y 20 0 1.5 1 4 6 2 2.0 2.8 3.10 3.0 14 2 1.10 2.20 3.0 4 2 1.2 2.2 3.2 3.2 2 1 2 2.5 2.5 37 Z 1.2 1 3.2 4 44 2 0.8 1.6 2.6 3.2 In this Table I, when the output scores for each of the tested compound are added up, it can be seen that the total vasodilatatory activity of the compounds according to the invention is markedly superior to that of the reference compounds (X) and (Y); they also show a certain specificity of action where the reference compounds are deficient.
The compounds according to the invention are thus useful in the treatment of diseases resulting from central or peripheral circulatory deficiencies.
2. Activity on the central nervous system.
.
Some of the compounds of general formula I were tested for their anti-convulsive activity using the method described by M.A. DAVIS et al. (J. Med. Chem. 7, (1964), 88-94).
The object of the test was to provide evidence of antagonism to convulsions caused by the administration of a convulsive agent (pentetrazol) which makes it possible to determine a possible anti-epileptic potentiality of the tested compounds.
'l'he convulsive agcn~ was administered intraperitoneally to mice (body weight 18-30 g.) in an amount which was sufficient to induce convulsions in 90 to 100~ of the experimental anima~ls:
in the case of pentetrazol, this is 125 mg./kg. The compound to be tested was administered orally one hour before administra-tion of the convulsive agent, using groups of 10 experimental animals. The ED50 was measured, this being the amount of tested compound which inhibits tonic crises in 50~ of the animals. The compound used for comparison was meprobamate.
The results obtained are given in the following Table II:
TABLE II
Compound ED in mg./kg.
0.24 0.30 36 0.18 37 0.10 41 0.18 12 0.032 meprobamate (comparison) 0.62 In the case of this compound, it is not the ED50 but rather the active dose for 3 animals out of 8. Consequently, the ED50 is somewhat greater than this value.
As can be seen from the preceding Table II,the anti-convulsive activity of the compounds according to the inventionis markedly superior to that of meprobamate.
3. Toxicology.
~,~
The -toxicity of the compounds of the invention is relatively low. As an examp]e, for compound 6, r4-(2-chloro-diphenylmethylene)~ 4-hydroxybenzyl)-piperidine hydrochloride~
the LD 50 in the rat is:
41 mg./]cg~ intravenously 1,230 mg./kg. intraperitioneally, 5,423 mg./kg. orally.
. Posolo~y.
The compounds according to the invention may be administered orally, reaetally or parenterally in unit doses of 10 to 50 mg. aceording to the mode of administration, in admixture with the usual pharmaceutieal liquid or solid excipients.
~ -27-
c25H24ClNo~c4H4o4 calculated: N 2.76% Cl 7.00%
found : 2.76% 7.4%
m.p. 110-112C.
Pharmacological properties.
1. Activity on the blood circulation.
_______ _________________________ The hemodynamic effects of compounds of general formula 1 were studied on the anesthetized dog subjected to artificial respiration under the experimental conditions described by D. WELLENS and E. WAUTERS (Arch. Int. Pharmacodyn., 171, (1968), 245-250). The measurement of the musculo-cutaneous, cardiac and cerebral outputs, carried out by means of probes places around the femoral (A), carotid (B), coronary (C) and vertebral (D) arteries, showed that the compounds of general formula I
~ -24-11~14Z6 considerably increase the blood circulation.
In these experiments, the maximum score " 2" is assigned to a compound that brings about an increase of circulation of at least 20~ for at least 20 minutes. The maximum score per experiment carried out on two dogs is " 4" , with the possibility of the intermediates form " 0" to " 4" .
For the purpose of comparison, the corresponding values for two known compounds,~papaverine (X) andtheophylline (Y) are also given. The results obtained are given in the following Table I:
TABLE I
Output scores CompoundDoses in mg/kg (i.v.) A B C D
X 2 1.5 2 2 1.5 Y 20 0 1.5 1 4 6 2 2.0 2.8 3.10 3.0 14 2 1.10 2.20 3.0 4 2 1.2 2.2 3.2 3.2 2 1 2 2.5 2.5 37 Z 1.2 1 3.2 4 44 2 0.8 1.6 2.6 3.2 In this Table I, when the output scores for each of the tested compound are added up, it can be seen that the total vasodilatatory activity of the compounds according to the invention is markedly superior to that of the reference compounds (X) and (Y); they also show a certain specificity of action where the reference compounds are deficient.
The compounds according to the invention are thus useful in the treatment of diseases resulting from central or peripheral circulatory deficiencies.
2. Activity on the central nervous system.
.
Some of the compounds of general formula I were tested for their anti-convulsive activity using the method described by M.A. DAVIS et al. (J. Med. Chem. 7, (1964), 88-94).
The object of the test was to provide evidence of antagonism to convulsions caused by the administration of a convulsive agent (pentetrazol) which makes it possible to determine a possible anti-epileptic potentiality of the tested compounds.
'l'he convulsive agcn~ was administered intraperitoneally to mice (body weight 18-30 g.) in an amount which was sufficient to induce convulsions in 90 to 100~ of the experimental anima~ls:
in the case of pentetrazol, this is 125 mg./kg. The compound to be tested was administered orally one hour before administra-tion of the convulsive agent, using groups of 10 experimental animals. The ED50 was measured, this being the amount of tested compound which inhibits tonic crises in 50~ of the animals. The compound used for comparison was meprobamate.
The results obtained are given in the following Table II:
TABLE II
Compound ED in mg./kg.
0.24 0.30 36 0.18 37 0.10 41 0.18 12 0.032 meprobamate (comparison) 0.62 In the case of this compound, it is not the ED50 but rather the active dose for 3 animals out of 8. Consequently, the ED50 is somewhat greater than this value.
As can be seen from the preceding Table II,the anti-convulsive activity of the compounds according to the inventionis markedly superior to that of meprobamate.
3. Toxicology.
~,~
The -toxicity of the compounds of the invention is relatively low. As an examp]e, for compound 6, r4-(2-chloro-diphenylmethylene)~ 4-hydroxybenzyl)-piperidine hydrochloride~
the LD 50 in the rat is:
41 mg./]cg~ intravenously 1,230 mg./kg. intraperitioneally, 5,423 mg./kg. orally.
. Posolo~y.
The compounds according to the invention may be administered orally, reaetally or parenterally in unit doses of 10 to 50 mg. aceording to the mode of administration, in admixture with the usual pharmaceutieal liquid or solid excipients.
~ -27-
Claims (24)
1. A process for the preparation of 4-diphenylmethylene-1-hydroxybenzyl-piperidines of the general formula wherein A1, A2, A3 and A4, taken separately, each represents hydrogen, halogen, trifluoromethyl, alkyl containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms, and the pharmaceu-tically acceptable acid addition salts thereof, which comprises a) condensing a 4-diphenylmethylene-piperidine of the formula in which A1, A2, A3 and A4 have the meanings given above, with a benzyl compound of the formula in which X is a halogen atom or an equivalent reactive group and A5 is a protective group for the hydroxyl group, which can be easily eliminated by hydrolysis, in the presence of an acid acceptor and in solution in an organic solvent and subjecting the resulting 1-benzyl-4-diphenylmethylene-piperidine of the formula in which A1, A2, A3, A4 and A5 have the meanings given above, to hydrolysis, or b) condensing an alpha, alpha-diphenyl-4-pyridinemethanol of the formula in which A1, A2, A3 and A4 have the meanings given above, with a benzyl compound of the formula:
in which X and A5 have the meanings given above, catalytically reducing the resulting 1-benzyl-4-(alpha-hydroxy-diphenylmethyl)-pyridinium compound of the formula in which A1, A2, A3, A4, A5 and X have the meanings given above, dehydrating with a dehydrating agent the resulting 1-benzyl-alpha, alpha-diphenyl-4-piperidinemethanol of the formula in which A1, A2, A3, A4 and A5 have the meanings given above, and subjecting the resulting 1-benzyl-4-diphenylmethylene-piperidine of the formula in which A1, A2, A3, A4 and A5 have the meanings given above, to hydrolysis, or c) condensing a 4-diphenylmethylene-piperidine of the formula in which A1, A2, A3 and A4 have the meanings given above,with a hydroxybenzaldehyde in an inert solvent in the presence of catalyti-cally activated hydrogen, and, if desired, d) converting the obtained 4-diphenylmethylene-1-hydroxybenzyl-piperidines into pharmaceuticaily acceptable acid addition salts thereof.
in which X and A5 have the meanings given above, catalytically reducing the resulting 1-benzyl-4-(alpha-hydroxy-diphenylmethyl)-pyridinium compound of the formula in which A1, A2, A3, A4, A5 and X have the meanings given above, dehydrating with a dehydrating agent the resulting 1-benzyl-alpha, alpha-diphenyl-4-piperidinemethanol of the formula in which A1, A2, A3, A4 and A5 have the meanings given above, and subjecting the resulting 1-benzyl-4-diphenylmethylene-piperidine of the formula in which A1, A2, A3, A4 and A5 have the meanings given above, to hydrolysis, or c) condensing a 4-diphenylmethylene-piperidine of the formula in which A1, A2, A3 and A4 have the meanings given above,with a hydroxybenzaldehyde in an inert solvent in the presence of catalyti-cally activated hydrogen, and, if desired, d) converting the obtained 4-diphenylmethylene-1-hydroxybenzyl-piperidines into pharmaceuticaily acceptable acid addition salts thereof.
2. A process according to claim 1, wherein each of A1, A2, A3 and A4 is hydrogen and the hydroxyl group is in the 4-posi-tion of the benzyl group.
3. A process according to claim 1, wherein A1 is 2-chloro, each of A2, A3 and A4 is hydrogen and the hydroxyl group is in the 4-position of the benzyl group.
4. A process according to claim 1, wherein A1 is 4-chloro, each of A2, A3 and A4 is hydrogen and the hydroxyl group is in the 3-position of the benzyl group.
5. A process according to claim 1, wherein A1 is 4-fluoro, each of A2, A3 and A4 is hydrogen and the hydroxyl group is in the 4-position of the benzyl group.
6. A process according to claim 1, wherein A1 is 4-fluoro, each of A2, A3 and A4 is hydrogen and the hydroxyl group is in the 3-position of the benzyl group.
7. A process according to claim 1, wherein A1 is 4-trifluoromethyl,each of A2, A3 and A4 is hydrogen and the hydroxyl group is in the 4-position of the benzyl group.
8. A process according to claim 1, wherein A1 is 2-trifluoromethyl,each of A2, A3 and A4 is hydrogen and the hydroxyl group is in the-4-position of the benzyl group.
9. A process according to claim 1, wherein A1 is 4-chloro, A3 is 4'-fluoro, each of A2 and A4 is hydrogen and the hydroxyl group is in the 4-position of the benzyl group.
10. A process according to claim 1, wherein A1 is 4-chloro, A3 is 4'-fluoro, each of A2 and A4 is hydrogen and the hydroxyl group is in the 3-position of the benzyl group.
11. A process according to claim 1, wherein A1 is 4-fluoro, A3 is 4'-trifluoromethyl, each of A2 and A4 is hydrogen and the hydroxyl group is in the 4-position of the benzyl group.
12. A process according to claim 1, wherein A1 is 4-fluoro, A3 is 4'-methoxy, each of A2 and A4 is hydrogen and the hydroxyl group is in the 4-position of the benzyl group.
13. 4-Diphenylmethylene-1-hydroxybenzyl-piperidines of the general formula wherein A1, A2, A3 and A4, taken separately, each represents hydrogen, halogen, trifluoromethyl, alkyl containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms, and the pharmaceutically acceptable acid addition salts thereof, whenever prepared by a process according to claim 1 or any obvious chemical equivalent thereof.
14. 4-Diphenylmethylene-1-(4-hydroxybenzyl)-piperidine, whenever prepared by a process according to claim 2 or any obvious chemical equivalent thereof.
15. 4-(2-Chloro-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine, whenever prepared by a process according to claim 3 or any obvious chemical equivalent thereof.
16. 4-(4-Chloro-diphenylmethylene)-1-(3-hydroxybenzyl)-piperidine, whenever prepared by a process according to claim 4 or any obvious chemical equivalent thereof.
17. 4-(4-Fluoro-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine, whenever prepared by a process according to claim 5 or any obvious chemical equivalent thereof.
18. 4-(4-Fluoro-diphenylmethylene)-1-(3-hydroxybenzyl)-piperidine, whenever prepared by a process according to claim 6 or any obvious chemical equivalent thereof.
19. 1-(4-Hydroxybenzyl)-4-(4-trifluoromethyl-diphenyl-methylene)-piperidine, whenever prepared by a process according to claim 7 or any obvious chemical equivalent thereof.
20. 1-(4-Hydroxybenzyl)-4-(2-trifluoromethyl-diphenyl-methylene)-piperidine, whenever prepared by a process according to claim 8 or any obvious chemical equivalent thereof.
21. 4-(4-Chloro-4'-fluoro-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine, whenever prepared by a process according to claim 9 or any obvious chemical equivalent thereof.
22. 4-(4-Chloro-4'-fluoro-diphenylmethylene)-1-(3-hydroxy-benzyl)-piperidine, whenever prepared by a process according to claim 10 or any obvious chemical equivalent thereof.
23. 4-(4-Fluoro-4'-trifluoromethyl-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine, whenever prepared by a process according to claim 11 or any obvious chemical equivalent thereof.
24. 4-(4-Fluoro-4'-methoxy-diphenylmethylene)-1-(4-hydroxybenzyl)-piperidine, whenever prepared by a process according to claim 12 or any obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB931/77A GB1542823A (en) | 1977-01-11 | 1977-01-11 | Piperidine derivatives |
| GB931/77 | 1977-01-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1101426A true CA1101426A (en) | 1981-05-19 |
Family
ID=9713045
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA294,674A Expired CA1101426A (en) | 1977-01-11 | 1978-01-10 | 4-diphenylmethylene-1-hydroxybenzyl-piperidine compounds |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS5387367A (en) |
| BE (1) | BE862769A (en) |
| BG (1) | BG28574A3 (en) |
| CA (1) | CA1101426A (en) |
| CS (1) | CS195652B2 (en) |
| DD (1) | DD134089A5 (en) |
| DE (1) | DE2800919A1 (en) |
| DK (1) | DK5778A (en) |
| ES (1) | ES465861A1 (en) |
| FI (1) | FI780028A (en) |
| FR (1) | FR2376846A1 (en) |
| GB (1) | GB1542823A (en) |
| IL (1) | IL53766A0 (en) |
| IT (1) | IT1103117B (en) |
| LU (1) | LU78839A1 (en) |
| NL (1) | NL7800146A (en) |
| NO (1) | NO780040L (en) |
| PL (1) | PL203912A1 (en) |
| PT (1) | PT67511B (en) |
| SE (1) | SE7800184L (en) |
| SU (2) | SU772482A3 (en) |
| ZA (1) | ZA78158B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4650874A (en) * | 1984-11-26 | 1987-03-17 | G. D. Searle & Co. | N-(aralkoxybenzyl)-4(benzhydryl) piperidines |
| US4628095A (en) * | 1985-06-05 | 1986-12-09 | G. D. Searle & Co. | Substituted N-benzyl-4-(benzhydryl) piperidines |
| EP0228893A3 (en) * | 1985-12-20 | 1990-01-03 | A.H. ROBINS COMPANY, INCORPORATED (a Delaware corporation) | Arylalkyl-heterocyclic amines, n-substituted by aryloxyalkyl group in allergy treatment |
| GB9000305D0 (en) * | 1990-01-06 | 1990-03-07 | Pfizer Ltd | Anticholinergic agents |
| WO1997022583A1 (en) * | 1995-12-20 | 1997-06-26 | Eckhart Pein | Novel 1-phenylalkyl/alkylene-4-(.alpha.-hydroxydiphenylmethyl)-piperidine derivatives and their use as serotonin antagonists |
| ES2237078T3 (en) * | 1998-01-16 | 2005-07-16 | Eisai Co., Ltd. | PROCEDURE TO PRODUCE DERIVATIVES OF DONEPEZILO. |
| AU2003296373A1 (en) * | 2002-12-18 | 2004-07-29 | Bayer Cropscience Ag | N-(substituted arylmethyl)-4-(disubstituted methyl)piperidines and piperazines |
| JP4730096B2 (en) * | 2003-05-20 | 2011-07-20 | 味の素株式会社 | Novel piperidine derivatives |
-
1977
- 1977-01-11 GB GB931/77A patent/GB1542823A/en not_active Expired
-
1978
- 1978-01-05 NL NL7800146A patent/NL7800146A/en not_active Application Discontinuation
- 1978-01-05 NO NO780040A patent/NO780040L/en unknown
- 1978-01-05 DK DK5778A patent/DK5778A/en unknown
- 1978-01-05 FI FI780028A patent/FI780028A/en not_active Application Discontinuation
- 1978-01-09 IL IL53766A patent/IL53766A0/en unknown
- 1978-01-09 BG BG7838343A patent/BG28574A3/en unknown
- 1978-01-09 CS CS78170A patent/CS195652B2/en unknown
- 1978-01-09 FR FR7800616A patent/FR2376846A1/en active Granted
- 1978-01-09 SE SE7800184A patent/SE7800184L/en unknown
- 1978-01-10 IT IT47573/78A patent/IT1103117B/en active
- 1978-01-10 LU LU78839A patent/LU78839A1/en unknown
- 1978-01-10 ZA ZA00780158A patent/ZA78158B/en unknown
- 1978-01-10 PL PL20391278A patent/PL203912A1/en unknown
- 1978-01-10 JP JP147578A patent/JPS5387367A/en active Granted
- 1978-01-10 PT PT67511A patent/PT67511B/en unknown
- 1978-01-10 DD DD78203161A patent/DD134089A5/en unknown
- 1978-01-10 CA CA294,674A patent/CA1101426A/en not_active Expired
- 1978-01-10 DE DE19782800919 patent/DE2800919A1/en not_active Withdrawn
- 1978-01-10 ES ES465861A patent/ES465861A1/en not_active Expired
- 1978-01-10 BE BE1008634A patent/BE862769A/en not_active IP Right Cessation
- 1978-01-10 SU SU782562702A patent/SU772482A3/en active
- 1978-07-17 SU SU782637199A patent/SU990761A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| IT1103117B (en) | 1985-10-14 |
| PT67511B (en) | 1979-06-11 |
| SU772482A3 (en) | 1980-10-15 |
| ZA78158B (en) | 1978-10-25 |
| GB1542823A (en) | 1979-03-28 |
| SE7800184L (en) | 1978-07-12 |
| DK5778A (en) | 1978-07-12 |
| NO780040L (en) | 1978-07-12 |
| IL53766A0 (en) | 1978-04-30 |
| SU990761A1 (en) | 1983-01-23 |
| BG28574A3 (en) | 1980-05-15 |
| BE862769A (en) | 1978-07-10 |
| DD134089A5 (en) | 1979-02-07 |
| NL7800146A (en) | 1978-07-13 |
| FR2376846B1 (en) | 1983-02-04 |
| PT67511A (en) | 1978-02-01 |
| JPS5387367A (en) | 1978-08-01 |
| ES465861A1 (en) | 1978-09-16 |
| JPS6125031B2 (en) | 1986-06-13 |
| PL203912A1 (en) | 1979-06-04 |
| IT7847573A0 (en) | 1978-01-10 |
| CS195652B2 (en) | 1980-02-29 |
| LU78839A1 (en) | 1978-09-18 |
| FR2376846A1 (en) | 1978-08-04 |
| DE2800919A1 (en) | 1978-07-13 |
| FI780028A (en) | 1978-07-12 |
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| MKEX | Expiry |