CA1067498A - 5-(1,1-diphenyl-3-(4-hydroxy-4-phenylpiperidino) propyl-2-methyl-1,3,4-alkadiazole compounds - Google Patents
5-(1,1-diphenyl-3-(4-hydroxy-4-phenylpiperidino) propyl-2-methyl-1,3,4-alkadiazole compoundsInfo
- Publication number
- CA1067498A CA1067498A CA223,485A CA223485A CA1067498A CA 1067498 A CA1067498 A CA 1067498A CA 223485 A CA223485 A CA 223485A CA 1067498 A CA1067498 A CA 1067498A
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- CA
- Canada
- Prior art keywords
- diphenyl
- propyl
- hydroxy
- methyl
- carbon atoms
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention is concerned with 1,1-diaryl-1-oxadiazol-alkylamines. These compounds are prepared by reacting the tetrazoles of the present invention in the presence of a solvent such as pyridine with a suitable anhydride or acid chloride to give the oxadiazoles. The compounds of the present invention possess potent anti-diarrheal utility as evidenced by their ability to inhibit gastro-intestinal motility.
These subject compounds also possess a moderately high degree of analgesia.
The present invention is concerned with 1,1-diaryl-1-oxadiazol-alkylamines. These compounds are prepared by reacting the tetrazoles of the present invention in the presence of a solvent such as pyridine with a suitable anhydride or acid chloride to give the oxadiazoles. The compounds of the present invention possess potent anti-diarrheal utility as evidenced by their ability to inhibit gastro-intestinal motility.
These subject compounds also possess a moderately high degree of analgesia.
Description
~0~7~98 l,l-DIARYL-l-OXADIAZOL-ALKYLAMINES
The present invention relates to compounds ;~
o~ the general ~ormula R
N~O~ : ' (Alk)-( l_Ar X~
::
wherein~Alk is stra1ght~or branched chain alkylene~
5~ ~ oontalning 2-4 carbon atoms; R is an alkyl r~adical oontaining from 1-7 oarbon aboms; Ar ls phenyl or pyrldyl; X and X'~are;hydrogèn or halogen; Z is hydroxy, lower alkanoyloxy wherein the lower alkanoyl group contains l to 7 carbon atoms, carboxy and lower alkoxy carbonyl wherein the lower alkoxy group contalns l to 7 carbon atoms.
The alkylene radicals encompassed by the term AlK are exemplified by ethylene, propylene, or trimethylene. The term alkyl radical ls exemplified by methyl, ethyl, propyl and~butyl. The term halogen is exemplified by ~luoro, chloro, bromo, or iodo. The term alkanoyloxy ls exempli~ied by acetoxy. The term alkoxycarbonyl is exemplified by methoxycarbonyl and ethoxycarbonyl. The amine moiety is exemplified by .
~6749~3 4-phenyl-4-carboxypiperidino, 4-phenyl-4-carbethoxy_ piperidino, 4-phenyl-4-hydroxypiperidino and 4-phenyl-4-acetoxypiperidino. 4-phenyl-4-hydroxypipe:ridino is a preferred embodiment.
The organie bases of this invention form non-toxic acid-addition salts with a variety of organic and inorganic acids. Such salts are formed with acids ::
such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic,` sulfamic, citric, lactic 3 maleic, malio, succinic, tartaric, cinnamic, acetic, benzoic, glucZ~nic~
ascorbic and related acids.
The compounds of the present invention can be conveniently prepared by reacting a t~etrazole of the general formula N ~ -H
wherein Alk, Ar, X, X' and Z are defined as before ~ith an acylating compound of the general formula O
(R"' CO)20 or R"'C-Cl ~067~8 wherein Rl~lis an alkyl radical of 1-7 carbon atoms in a suitable solvent suCh as pyridine or any inert solvent SUCh as toluene, benzene, methylene chlorlde or cyclohexane in the presence of an acid scavenger sùch as triethylamine, piperidine, or potassium carbonate to give the oxadiazole Of the formula I. When Z is lower alkanoyloxy, the above procedurecan;be followed by hydrolysis to giv~e thè corresponding~hydroxy dompound.
ThiS procedure is used for the preparation of the hydroxy compounds beoause, during the reaotion of the~
tetrazole With the acylating agent, any free hydroxy group is ~converted to the corresponding eSter.
The starting material of formula II can be prepared bl reactlng compound~o` th-~g~nera. formu,a~
CN
lk)-C-Ar ~
15~ wherein Ar, Alk, X, xt and Z are defined~as before :
with an azide ion by methods similar to those des-~ ~ cribed by G. Moersch and D. Morrow, J.~Med. Chem., ; 10, 149 (1967).
In an alternate process for the preparation :
of the compounds of this invention, a hydrazide of ' -4~
~67498 :
:
the formula .
O O
C-NHNH-C-R
(Alk)-l-Ar~
IV
1 : ~
, wherein Ar, Alk, R, X, X) and Z are defined as before is reaoted with a dehydrating agent suoh as;thionyl chloride or phosphoryl chloride in a~suitable inert ~:
5~ ~ solvent such as toluene;, benzene, methylene chloride :~
or cyclohexane to~glve:the oxadiazo]eof the~formula I.~
; The anti-diarrheal properties Or the instant :
compounds are specifically ilIustrated~by the activity of the representative species 5-~1?1-diphenyl-3- ::
10 ~4-hydroxy-4-phenylpiperidino)propyl3-2-methyl-1:,3,4-oxadiazole. :: :~
Anti-diarrheal utility of the lnstant compounds is evidenced:by their ability to inh~bit ::
:~ gastrointestinal motility as set out in the following `~ 15 test.
.:: : :
CHARCOAL MEAL ~EST
: ~ The method used in the present study has ~ : been adapted from techniques previously described : (Macht and Barba-Gose, 1931 and Janssen and Jageneau, :
1957). Male Charles River mice (20-25 g, n 6) pre-viously fasted for 24 hours were pretreated~with the test compounds administerèd orally as a solution in water or suspended in 0.5% methyl cellulose. A constant volume of 10 ml/kg~was employed. Thirty minutes follow-ing administration of the test compounds, the animals were given a single oral dose of charcoal (0.2 ml per mouse of a 10% charcoal suspended~in 1.0% methyl cellulose). Three and a half hours a~ter charcoal :!
administration, ~he animals were sacrificed and the cecum examined for the absence or presence of charcoal on an all-or-none basis. The median effeotive dose (ED50) was calculated for each compound usi~ng the logistic method of Berkson (1953).
, ~15 In addition to their anti-diarrheal activity, the compounds of the present invention also possess strong analgesic activityO The assessment of this activity was conducted by the tail clip test.
: : : :
TAIL CLIP TEST
A special clip is applied to the base of the tail of the mouse (adult male welghing 18-25 grams) and the time for the animal to turn around to bite at it is measured. The sensitivity of each mouse is determined one-half hour prior to drug administration.
Only those mice attempting to bite the clip are in-cluded in the experiment. The test compound is then administered intraperitoneally and the response to placement of the clip is determined at 30, 60, 90 ~ 67498 and 120 minutes a~ter treatment. A response is con-sidered positive lf the animal takes more than 2 times the pre-drug time to bite at the clip at an;y of these time intervals. A test compound ls considered active when 50 percent or more of the animals used show a positive response.
The following examples describe ln detail compounds illustrative of the present invention and methods for thelr preparation. Throughout the examples hereinafter set forth, temperatures are given in degrees Centigrade and relative amounts of materiaIs in parts by weight, except as otherwise noted.
: :
--- .
A mixture of l5 parts of 2,2-dlphenyl-4-bromobutyronitrile, 8.9 part~s of 4-hydroxy-4-phenyl~
piperidine and 400 parts by volumc Or ethylene glycol monomethyl ether were heated together at reflux for 18 hours under nitrogen. The solution was cooled and the volume was reduced 50% at 60C. under pressure. The concentrated mlxture was diiuted with 1200 parts of water, made basic with sodium hydroxide and extracted with ether. The ether solution was then extracted with dilute hydrochloric acid. The gummy solid which formed was separated by filtration7 washed with water, and then ether, and air dried. The pro-duct thus obtained was 2,2-diphenyl-4-(4-hydroxy-4-phenylpiperidino)butyronitrile, melting at 221-223C.
1067~9~3 ~
8.0 parts of this nitrile, 2.0 parts of sodium azide, 1.6 parts of ammonium chlorlde, 0~03 part of lithium chloride and 20 parts by volume of~dimethyl-.
formamide were combined and heated at 125C. ~or 12 hours. The mixture was then cooled and the solid wasfiltered from the dimethylformamide. The solid was then washed with dlmethylformamide and water. The dried solid was 5-[1,1-diphenyl-3-(4-hydroxy-4-: :
phenylpiperidino)propyl]-lH-tetrazole.
3.16 parts of this lH-tetrazole and 7.1 parts of acetic anhydride were refluxed in 36 parts by volume of pyridlne for 1 hour. The reactlon mixture was then cooled. The pyridlne was removed by evapora-tion at reduced pressure to provide~a residue. The residue was taken up in ether. The ether solution was washed with sodium bicarbonate solution. After wash-~ing with base, the ether was removed to leave a crudeproduct. This product was recrystallized from pentane to glve 5-~1,1-diphenyl-3-(4-acetoxy~4-phenyI_ plperidino)propyl]-2-methyl-1,3,4 oxadia~zole, meltlng at 157.5-160C.
Substitution of aoetyl chloride for the acetic anhydride used above and substantial repetition of the foregoing procedure afforded the same product 5-[l,l~diphenyl-3-(4-acetoxy-4-phenylpiperidino)pro-pyl]-2-methyl-1,3,4-oxadiazole.
Substitution of 4-hydroxy-L~-(4-chloro-phenyl)piperidine for 4-hydroxy-4-phenylpiperidine used above and substantial repetition of the fore---S--~167498 going procedure afforded 5-{1-1-diphenyl-3-[4-acetoxy-4-(4-chlorophenyl)piperidino]propyl~-2-methyl-1,3,4 oxa-diazole melting at 155-158C.
1 Part of the above 5-~1,].-diphenyl-3-(4-acetoxy-4-phenylpiperidino)propyl]-2-methyl-1,3,4-oxadiazole was converted to the 4-hydroxy compound by hydrolysis in 55 parts methanol and 15 parts of 20%
sodium hydroxide. The product was isolat~d by evaporating the methanol under reduced pressure, diluting with water, adding sodium hydroxide, and then extracting the product into methylene chloride.
After removing the methylene chloride, the product was recrystallized from ether to provide 5-[1,1-di-phenyl-3-(4-hydroxy-4-phenylpiperidinojpropyl]-2-methyl-1,3,4-oxadiazole, melting at 160-162C.
Using equivalent quantities and following the procedure set out in Example 1, 2,2~diphenyl-4-(4-carbethoxy-4-phenylpiperidino)butyronitrile was converted to 5-~1,1-diphenyl-3-(4-carbethoxy-4-phenylpiperidino)propyl]-lH-tetrazole. Also accord-ing to Example 1, and using equivalent quantities, the lH tetrazole was converted to 5-[1,1-diphenyl-3-(4-carbethoxy-4-phenylpiperidino)propyl]-2-methyl-1,3,4-oxadiazole.
Hydrolysis of 1 part of this ester in 50 parts of methanol containing 15 parts of 20% aqueous sodium hydroxide and isolation provided 5-[1,1-di-phenyl-3-(4-carboxy-4-phenylpiperidino)propyl]-2-~6~67498 methyl-1,3,4-oxadiazole.
Using equivalent quantities and followlng the procedure set out in Example 1, 2,2-diphenyl-4-(4-hy~
droxy-4-phenylpiperidinobutyronitrile was converted to 5-~ diphenyl-3-(4-hydroxy-4-phenylpiperidino)pro~- ;
~ pyl]-lH-tetrazole. Substitution of propionic anhydride ; for the acetic anhydride in Example 1 and substantial repetition of the procedure of Example1converted the lH-tetrazole to 5-[1,1-diphenyl-3-(4-propionyloxy-4-phenylpiperidino)propyl]-2-ethyl-1,3,4-oxadiazole.
:
Pharmaceutical formulations were prepared in the following manner with amounts indicating the relative amount per tablet.; Thus,;2.5 parts of 5-[1,1-diphenyl-3-(4-hyaroxy-4-phenylpiperidino)pro-pyl]-2-methyl-1,3,4-oxadiazole were mixed thoroughly with 41.0 parts of polyvinylpyrrolidone and then :
screened. The~mixture was granulated with isopropyl alcohol, spread on trays and dried at 50C. for 16 hours. The granules were mixed thoroughly with I~0 parts o~ magnesium steara~e and the mixture compressed into tablets. The tablets weigh 90.0 mg and contain
The present invention relates to compounds ;~
o~ the general ~ormula R
N~O~ : ' (Alk)-( l_Ar X~
::
wherein~Alk is stra1ght~or branched chain alkylene~
5~ ~ oontalning 2-4 carbon atoms; R is an alkyl r~adical oontaining from 1-7 oarbon aboms; Ar ls phenyl or pyrldyl; X and X'~are;hydrogèn or halogen; Z is hydroxy, lower alkanoyloxy wherein the lower alkanoyl group contains l to 7 carbon atoms, carboxy and lower alkoxy carbonyl wherein the lower alkoxy group contalns l to 7 carbon atoms.
The alkylene radicals encompassed by the term AlK are exemplified by ethylene, propylene, or trimethylene. The term alkyl radical ls exemplified by methyl, ethyl, propyl and~butyl. The term halogen is exemplified by ~luoro, chloro, bromo, or iodo. The term alkanoyloxy ls exempli~ied by acetoxy. The term alkoxycarbonyl is exemplified by methoxycarbonyl and ethoxycarbonyl. The amine moiety is exemplified by .
~6749~3 4-phenyl-4-carboxypiperidino, 4-phenyl-4-carbethoxy_ piperidino, 4-phenyl-4-hydroxypiperidino and 4-phenyl-4-acetoxypiperidino. 4-phenyl-4-hydroxypipe:ridino is a preferred embodiment.
The organie bases of this invention form non-toxic acid-addition salts with a variety of organic and inorganic acids. Such salts are formed with acids ::
such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic,` sulfamic, citric, lactic 3 maleic, malio, succinic, tartaric, cinnamic, acetic, benzoic, glucZ~nic~
ascorbic and related acids.
The compounds of the present invention can be conveniently prepared by reacting a t~etrazole of the general formula N ~ -H
wherein Alk, Ar, X, X' and Z are defined as before ~ith an acylating compound of the general formula O
(R"' CO)20 or R"'C-Cl ~067~8 wherein Rl~lis an alkyl radical of 1-7 carbon atoms in a suitable solvent suCh as pyridine or any inert solvent SUCh as toluene, benzene, methylene chlorlde or cyclohexane in the presence of an acid scavenger sùch as triethylamine, piperidine, or potassium carbonate to give the oxadiazole Of the formula I. When Z is lower alkanoyloxy, the above procedurecan;be followed by hydrolysis to giv~e thè corresponding~hydroxy dompound.
ThiS procedure is used for the preparation of the hydroxy compounds beoause, during the reaotion of the~
tetrazole With the acylating agent, any free hydroxy group is ~converted to the corresponding eSter.
The starting material of formula II can be prepared bl reactlng compound~o` th-~g~nera. formu,a~
CN
lk)-C-Ar ~
15~ wherein Ar, Alk, X, xt and Z are defined~as before :
with an azide ion by methods similar to those des-~ ~ cribed by G. Moersch and D. Morrow, J.~Med. Chem., ; 10, 149 (1967).
In an alternate process for the preparation :
of the compounds of this invention, a hydrazide of ' -4~
~67498 :
:
the formula .
O O
C-NHNH-C-R
(Alk)-l-Ar~
IV
1 : ~
, wherein Ar, Alk, R, X, X) and Z are defined as before is reaoted with a dehydrating agent suoh as;thionyl chloride or phosphoryl chloride in a~suitable inert ~:
5~ ~ solvent such as toluene;, benzene, methylene chloride :~
or cyclohexane to~glve:the oxadiazo]eof the~formula I.~
; The anti-diarrheal properties Or the instant :
compounds are specifically ilIustrated~by the activity of the representative species 5-~1?1-diphenyl-3- ::
10 ~4-hydroxy-4-phenylpiperidino)propyl3-2-methyl-1:,3,4-oxadiazole. :: :~
Anti-diarrheal utility of the lnstant compounds is evidenced:by their ability to inh~bit ::
:~ gastrointestinal motility as set out in the following `~ 15 test.
.:: : :
CHARCOAL MEAL ~EST
: ~ The method used in the present study has ~ : been adapted from techniques previously described : (Macht and Barba-Gose, 1931 and Janssen and Jageneau, :
1957). Male Charles River mice (20-25 g, n 6) pre-viously fasted for 24 hours were pretreated~with the test compounds administerèd orally as a solution in water or suspended in 0.5% methyl cellulose. A constant volume of 10 ml/kg~was employed. Thirty minutes follow-ing administration of the test compounds, the animals were given a single oral dose of charcoal (0.2 ml per mouse of a 10% charcoal suspended~in 1.0% methyl cellulose). Three and a half hours a~ter charcoal :!
administration, ~he animals were sacrificed and the cecum examined for the absence or presence of charcoal on an all-or-none basis. The median effeotive dose (ED50) was calculated for each compound usi~ng the logistic method of Berkson (1953).
, ~15 In addition to their anti-diarrheal activity, the compounds of the present invention also possess strong analgesic activityO The assessment of this activity was conducted by the tail clip test.
: : : :
TAIL CLIP TEST
A special clip is applied to the base of the tail of the mouse (adult male welghing 18-25 grams) and the time for the animal to turn around to bite at it is measured. The sensitivity of each mouse is determined one-half hour prior to drug administration.
Only those mice attempting to bite the clip are in-cluded in the experiment. The test compound is then administered intraperitoneally and the response to placement of the clip is determined at 30, 60, 90 ~ 67498 and 120 minutes a~ter treatment. A response is con-sidered positive lf the animal takes more than 2 times the pre-drug time to bite at the clip at an;y of these time intervals. A test compound ls considered active when 50 percent or more of the animals used show a positive response.
The following examples describe ln detail compounds illustrative of the present invention and methods for thelr preparation. Throughout the examples hereinafter set forth, temperatures are given in degrees Centigrade and relative amounts of materiaIs in parts by weight, except as otherwise noted.
: :
--- .
A mixture of l5 parts of 2,2-dlphenyl-4-bromobutyronitrile, 8.9 part~s of 4-hydroxy-4-phenyl~
piperidine and 400 parts by volumc Or ethylene glycol monomethyl ether were heated together at reflux for 18 hours under nitrogen. The solution was cooled and the volume was reduced 50% at 60C. under pressure. The concentrated mlxture was diiuted with 1200 parts of water, made basic with sodium hydroxide and extracted with ether. The ether solution was then extracted with dilute hydrochloric acid. The gummy solid which formed was separated by filtration7 washed with water, and then ether, and air dried. The pro-duct thus obtained was 2,2-diphenyl-4-(4-hydroxy-4-phenylpiperidino)butyronitrile, melting at 221-223C.
1067~9~3 ~
8.0 parts of this nitrile, 2.0 parts of sodium azide, 1.6 parts of ammonium chlorlde, 0~03 part of lithium chloride and 20 parts by volume of~dimethyl-.
formamide were combined and heated at 125C. ~or 12 hours. The mixture was then cooled and the solid wasfiltered from the dimethylformamide. The solid was then washed with dlmethylformamide and water. The dried solid was 5-[1,1-diphenyl-3-(4-hydroxy-4-: :
phenylpiperidino)propyl]-lH-tetrazole.
3.16 parts of this lH-tetrazole and 7.1 parts of acetic anhydride were refluxed in 36 parts by volume of pyridlne for 1 hour. The reactlon mixture was then cooled. The pyridlne was removed by evapora-tion at reduced pressure to provide~a residue. The residue was taken up in ether. The ether solution was washed with sodium bicarbonate solution. After wash-~ing with base, the ether was removed to leave a crudeproduct. This product was recrystallized from pentane to glve 5-~1,1-diphenyl-3-(4-acetoxy~4-phenyI_ plperidino)propyl]-2-methyl-1,3,4 oxadia~zole, meltlng at 157.5-160C.
Substitution of aoetyl chloride for the acetic anhydride used above and substantial repetition of the foregoing procedure afforded the same product 5-[l,l~diphenyl-3-(4-acetoxy-4-phenylpiperidino)pro-pyl]-2-methyl-1,3,4-oxadiazole.
Substitution of 4-hydroxy-L~-(4-chloro-phenyl)piperidine for 4-hydroxy-4-phenylpiperidine used above and substantial repetition of the fore---S--~167498 going procedure afforded 5-{1-1-diphenyl-3-[4-acetoxy-4-(4-chlorophenyl)piperidino]propyl~-2-methyl-1,3,4 oxa-diazole melting at 155-158C.
1 Part of the above 5-~1,].-diphenyl-3-(4-acetoxy-4-phenylpiperidino)propyl]-2-methyl-1,3,4-oxadiazole was converted to the 4-hydroxy compound by hydrolysis in 55 parts methanol and 15 parts of 20%
sodium hydroxide. The product was isolat~d by evaporating the methanol under reduced pressure, diluting with water, adding sodium hydroxide, and then extracting the product into methylene chloride.
After removing the methylene chloride, the product was recrystallized from ether to provide 5-[1,1-di-phenyl-3-(4-hydroxy-4-phenylpiperidinojpropyl]-2-methyl-1,3,4-oxadiazole, melting at 160-162C.
Using equivalent quantities and following the procedure set out in Example 1, 2,2~diphenyl-4-(4-carbethoxy-4-phenylpiperidino)butyronitrile was converted to 5-~1,1-diphenyl-3-(4-carbethoxy-4-phenylpiperidino)propyl]-lH-tetrazole. Also accord-ing to Example 1, and using equivalent quantities, the lH tetrazole was converted to 5-[1,1-diphenyl-3-(4-carbethoxy-4-phenylpiperidino)propyl]-2-methyl-1,3,4-oxadiazole.
Hydrolysis of 1 part of this ester in 50 parts of methanol containing 15 parts of 20% aqueous sodium hydroxide and isolation provided 5-[1,1-di-phenyl-3-(4-carboxy-4-phenylpiperidino)propyl]-2-~6~67498 methyl-1,3,4-oxadiazole.
Using equivalent quantities and followlng the procedure set out in Example 1, 2,2-diphenyl-4-(4-hy~
droxy-4-phenylpiperidinobutyronitrile was converted to 5-~ diphenyl-3-(4-hydroxy-4-phenylpiperidino)pro~- ;
~ pyl]-lH-tetrazole. Substitution of propionic anhydride ; for the acetic anhydride in Example 1 and substantial repetition of the procedure of Example1converted the lH-tetrazole to 5-[1,1-diphenyl-3-(4-propionyloxy-4-phenylpiperidino)propyl]-2-ethyl-1,3,4-oxadiazole.
:
Pharmaceutical formulations were prepared in the following manner with amounts indicating the relative amount per tablet.; Thus,;2.5 parts of 5-[1,1-diphenyl-3-(4-hyaroxy-4-phenylpiperidino)pro-pyl]-2-methyl-1,3,4-oxadiazole were mixed thoroughly with 41.0 parts of polyvinylpyrrolidone and then :
screened. The~mixture was granulated with isopropyl alcohol, spread on trays and dried at 50C. for 16 hours. The granules were mixed thoroughly with I~0 parts o~ magnesium steara~e and the mixture compressed into tablets. The tablets weigh 90.0 mg and contain
2.5 mg of active ingredients per tablet.
In the preparation of tablets from the compounds of the present invention, a variety of excipients can be used. These are summarized as ~,o67~98 :
follows: sugars such as lactose, sucrose9 or mannitol; starches such as corn starch, tapioca starch, or potato starch; cellulose derivatives such as ethyl cellulose, methyl cellulose,~gelatin cellu-lose, acetate phthalate~ calcium phosphates such asdlcalcium phosphate or tricalcium phosphate; sodium sulfate, sodium bicarbonate, calcium sulfate, poly-vinylpyrrolidone, polyvinyl alcohol,~ polyvinyl acetate phthalate, stearic acid; alkaline earth metal stearates such as magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil; surfactants (nonionic, cationic, : anionic); ethylene glycol polymers; ~-cyclodextrin;
~;~ fatty alcohols, as well as other nontoxic compatible fillers, binders, disintegrants, and lubricants commonly used in pha~maceutlcal ~ormulations.
., :
In the preparation of tablets from the compounds of the present invention, a variety of excipients can be used. These are summarized as ~,o67~98 :
follows: sugars such as lactose, sucrose9 or mannitol; starches such as corn starch, tapioca starch, or potato starch; cellulose derivatives such as ethyl cellulose, methyl cellulose,~gelatin cellu-lose, acetate phthalate~ calcium phosphates such asdlcalcium phosphate or tricalcium phosphate; sodium sulfate, sodium bicarbonate, calcium sulfate, poly-vinylpyrrolidone, polyvinyl alcohol,~ polyvinyl acetate phthalate, stearic acid; alkaline earth metal stearates such as magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil; surfactants (nonionic, cationic, : anionic); ethylene glycol polymers; ~-cyclodextrin;
~;~ fatty alcohols, as well as other nontoxic compatible fillers, binders, disintegrants, and lubricants commonly used in pha~maceutlcal ~ormulations.
., :
Claims (10)
1. The process for the preparation of compounds of the general formula (I) wherein AlK is straight or branched chain alkylene containing 2 to 4 carbon atoms; R is an alkyl radical containing from 1 to 4 carbon atoms; Ar is phenyl; X and X' are hydrogen or halogen;
Z is hydroxy, lower alkanoyloxy wherein the lower alkanoyl group contains 2 to 4 carbon atoms, carboxy and lower alkoxy carbonyl wherein the lower alkoxy group contains 1 to 4 carbon atoms which is characterized by reacting a compound of the general formula (II) wherein AlK, Ar, X, X' and Z are defined as before with a compound of the formula (R'''CO)2O or wherein R"' is an alkyl radical of 1 to 4 carbon atoms; and when Z is lower alkanoyloxy, the above procedure can be followed by hydrolysis to give the corresponding hydroxy compound.
Z is hydroxy, lower alkanoyloxy wherein the lower alkanoyl group contains 2 to 4 carbon atoms, carboxy and lower alkoxy carbonyl wherein the lower alkoxy group contains 1 to 4 carbon atoms which is characterized by reacting a compound of the general formula (II) wherein AlK, Ar, X, X' and Z are defined as before with a compound of the formula (R'''CO)2O or wherein R"' is an alkyl radical of 1 to 4 carbon atoms; and when Z is lower alkanoyloxy, the above procedure can be followed by hydrolysis to give the corresponding hydroxy compound.
2. A process according to claim 1 wherein the anhydride used is acetic anhydride.
3. A process for the preparation of 5-[1,1-diphenyl-3-(4-hydroxy-4-phenylpiperidine)propyl]-2-methyl-1,3,4-oxadiazole which is characterized by reacting 5-[1,1-diphenyl-3-(4-hydroxy-4-phenylpiperidino)propyl]-1H-tetrazole with acetic anhydride followed by hydrolysis to remove the 4-acetoxy group which is formed in the reaction.
4. A process for the preparation of 5-[1,1-diphenyl-3-(4-acetoxy-4-phenylpiperidino)propyl]-2-methyl-1,3,4-oxodiazole which is characterized by reacting 5-[1,1-diphenyl-3-(4-hydroxy-4-phenylpiperidino)propyl]-1H-tetrazole with acetic anhydride.
5. A process for the preparation of 5-{1,1-diphenyl-3-[4-acetoxy-4-(4-chlorophenyl)piperidlnolpropyl}-2-methyl-1,3,4-oxadiazole which is characterized by reacting 5-{1,1-diphenyl-3-[4-hydroxy-4-(4-chlorophenyl)piperidino]propyl}-1H-tetrazole with acetic anhydride.
6. A compound of the formula (I) wherein AlK is straight or branched chain alkylene containing 2 to 4 carbon atoms; R is an alkyl radical containing from 1 to 4 carbon atoms; Ar is phenyl; X and X' are hydrogen or halogen;
Z is hydroxyl lower alkanoyloxy wherein the lower alkanoyl group contains 2 to 4 carbon atoms, carboxy and lower alkoxy carbonyl wherein the lower alkoxy group contains 1 to 4 carbon atoms, whenever prepared by the process of claim 1.
Z is hydroxyl lower alkanoyloxy wherein the lower alkanoyl group contains 2 to 4 carbon atoms, carboxy and lower alkoxy carbonyl wherein the lower alkoxy group contains 1 to 4 carbon atoms, whenever prepared by the process of claim 1.
7. A compound of the formula (I) as defined in claim 6, whenever prepared by the process of claim 2.
8. 5-[1,1-Diphenyl-3-(4-hydroxy-4-phenyl?piperidino)-propyl]-2-methyl-1,3,4-oxadiazole, whenever prepared by the process of claim 3.
9. 5-[1,1-Diphenyl-3-(4-acetoxy-4-phenyl-piperidino)-propyl]-2-methyl-1,3,4-oxadiazole, whenever prepared by the process of claim 4.
10. 5-?1,1-diphenyl-3-[4-acetoxy-4-(4-chlorophenyl)-piperidino]propyl?-2-methyl-1,3,4-oxadiazole, whenever prepared by the process of claim 5.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US456755A US3917615A (en) | 1974-04-01 | 1974-04-01 | 1,1-Diaryl-1-oxadiazol-alkylamines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1067498A true CA1067498A (en) | 1979-12-04 |
Family
ID=23814026
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA223,485A Expired CA1067498A (en) | 1974-04-01 | 1975-04-01 | 5-(1,1-diphenyl-3-(4-hydroxy-4-phenylpiperidino) propyl-2-methyl-1,3,4-alkadiazole compounds |
| CA223,487A Expired CA1053672A (en) | 1974-04-01 | 1975-04-01 | 1,1-diaryl-1-oxadiazol-alkylamines |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA223,487A Expired CA1053672A (en) | 1974-04-01 | 1975-04-01 | 1,1-diaryl-1-oxadiazol-alkylamines |
Country Status (26)
| Country | Link |
|---|---|
| US (2) | US3917615A (en) |
| JP (2) | JPS5936631B2 (en) |
| AR (2) | AR206425A1 (en) |
| AT (2) | AT340916B (en) |
| BE (2) | BE827324A (en) |
| CA (2) | CA1067498A (en) |
| CH (2) | CH613964A5 (en) |
| CS (1) | CS194718B2 (en) |
| DE (2) | DE2514229A1 (en) |
| DK (2) | DK137375A (en) |
| EG (1) | EG12104A (en) |
| ES (2) | ES436044A1 (en) |
| FI (2) | FI61895C (en) |
| FR (2) | FR2265376B1 (en) |
| GB (2) | GB1494943A (en) |
| HU (1) | HU170747B (en) |
| IE (2) | IE40894B1 (en) |
| IL (2) | IL46959A (en) |
| NL (2) | NL7503856A (en) |
| NO (2) | NO142174C (en) |
| OA (1) | OA04914A (en) |
| PH (1) | PH11423A (en) |
| PL (1) | PL99553B1 (en) |
| SE (2) | SE420491B (en) |
| YU (1) | YU39200B (en) |
| ZA (2) | ZA751193B (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4003904A (en) * | 1974-04-01 | 1977-01-18 | G. D. Searle & Co. | Anti-diarrheal oxadiazoles |
| US4086227A (en) * | 1975-04-16 | 1978-04-25 | G. D. Searle & Co. | Novel anti-diarrheal 4-azatricyclo[4.3.1.13,8 ] undecane derivatives |
| US3998832A (en) * | 1975-04-16 | 1976-12-21 | G. D. Searle & Co. | Anti-diarrheal compounds |
| US4057549A (en) * | 1975-04-16 | 1977-11-08 | G. D. Searle & Co. | Triarylpropyl-azabicyclooctanes |
| US4025524A (en) * | 1975-04-16 | 1977-05-24 | G. D. Searle & Co. | 2-{3-[4-Azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-5-methyl-1,3,4-oxadiazole and congeners |
| US3996214A (en) * | 1976-02-23 | 1976-12-07 | G. D. Searle & Co. | 5-(1,1-Diphenyl-4-(cyclic amino) but-2-trans-en-1-yl)-2-alkyl-1,3,4-oxadiazoles and intermediates thereto |
| US4013668A (en) * | 1976-03-10 | 1977-03-22 | G. D. Searle & Co. | 5-(1,1-diphenyl-3-(5- or 6-hydroxy-2-azabicyclo(2.2.2)oct-2-yl)propyl)-2-alkyl-1,3,4-oxadiazoles and related compounds |
| US4012393A (en) * | 1976-03-22 | 1977-03-15 | G. D. Searle & Co. | 2-[5-(CYCLIC AMINO) ETHYL-10,11-DIHYDRO-5H-dibenzo[a,d]-cyclohepten-5- yl]-5 |
| US4028364A (en) * | 1976-07-06 | 1977-06-07 | G. D. Searle & Co. | 2-Azabicyclo[2.2.2.]octan-2-yl-diphenyl-alkanones and related compounds |
| US4053477A (en) * | 1976-09-20 | 1977-10-11 | G. D. Searle & Co. | 5-(1,1-diphenyl-3-(4-phenylpiperidino)propyl)-2-methyl-1,3,4-oxadiazole and related compounds |
| US4194045A (en) * | 1977-12-27 | 1980-03-18 | G. D. Searle & Co. | 1-(3,3-Diaryl-3-oxadiazolalkyl)-4-phenyl-4-piperidinomethanols and related compounds |
| US4203989A (en) * | 1979-04-30 | 1980-05-20 | G. D. Searle & Co. | Anti-diarrheal diaryl-(1-azabicyclo(2.2.2)octan-2-yl)-alkanols and related compounds |
| US4203990A (en) * | 1979-04-30 | 1980-05-20 | G. D. Searle & Co. | Anti-diarrheal 2-substituted quinuclidines |
| US4596801A (en) | 1983-03-24 | 1986-06-24 | Chugai Seiyaku Kabushiki Kaisha | 4H-3,1-benzoxazine derivatives, process for producing the same and agricultural or horticultural fungicide containing the same |
| JPS61194917A (en) * | 1985-02-23 | 1986-08-29 | Matsushita Electric Works Ltd | Delay switch |
| JPS61195022A (en) * | 1985-02-25 | 1986-08-29 | Matsushita Electric Works Ltd | Delay switch |
| GB8830226D0 (en) * | 1988-12-23 | 1989-02-22 | Beecham Group Plc | Novel compounds |
| DK40890D0 (en) * | 1990-02-16 | 1990-02-16 | Ferrosan As | SUBSTITUTED URINARY COMPOUNDS, THEIR PREPARATION AND USE |
| US5889038A (en) * | 1996-03-20 | 1999-03-30 | Children's Hospital | Methods and products for treating diarrhea and scours: use of clotrimazole and related aromatic compounds |
| PT107888B (en) | 2011-05-27 | 2015-06-24 | Reliance Ind Ltd | PROCEDURE FOR THE PREPARATION OF AN ORGANIC CARBOXYLIC ACID ESTER BY ESTERIFICATION OF AN ORGANIC CARBOXYLIC ACID |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3141019A (en) * | 1964-07-14 | Chaohj | ||
| US3299044A (en) * | 1964-05-13 | 1967-01-17 | Searle & Co | Complex n-substituted azabicycloalkanes |
| FR1469022A (en) * | 1965-12-14 | 1967-02-10 | Chimie Et Synthese De Picardie | New oxadiazole derivatives and their preparation process |
| GB1174411A (en) * | 1966-03-02 | 1969-12-17 | Aspro Nicholas Ltd | Novel Benzothiophen Compounds, Compositions containing them and processes for their manufacture |
| GB1231829A (en) * | 1968-09-19 | 1971-05-12 | ||
| US3720685A (en) * | 1970-07-15 | 1973-03-13 | Squibb & Sons Inc | 3-amino-5-benzyl-1,2,4-oxadiazoles |
-
1974
- 1974-04-01 US US456755A patent/US3917615A/en not_active Expired - Lifetime
-
1975
- 1975-01-01 AR AR258169A patent/AR206425A1/en active
- 1975-02-26 ZA ZA00751193A patent/ZA751193B/en unknown
- 1975-03-26 ES ES436044A patent/ES436044A1/en not_active Expired
- 1975-03-28 FR FR7509996A patent/FR2265376B1/fr not_active Expired
- 1975-03-28 FR FR7509995A patent/FR2265367B1/fr not_active Expired
- 1975-03-28 BE BE154890A patent/BE827324A/en not_active IP Right Cessation
- 1975-03-28 HU HUSE1776A patent/HU170747B/hu unknown
- 1975-03-28 IL IL46959A patent/IL46959A/en unknown
- 1975-03-28 CS CS752162A patent/CS194718B2/en unknown
- 1975-03-28 BE BE154889A patent/BE827323A/en not_active IP Right Cessation
- 1975-03-31 JP JP50039025A patent/JPS5936631B2/en not_active Expired
- 1975-03-31 ES ES436160A patent/ES436160A1/en not_active Expired
- 1975-03-31 EG EG179/75A patent/EG12104A/en active
- 1975-03-31 JP JP50039024A patent/JPS5939434B2/en not_active Expired
- 1975-03-31 OA OA55456A patent/OA04914A/en unknown
- 1975-03-31 IL IL46966A patent/IL46966A/en unknown
- 1975-03-31 YU YU00816/75A patent/YU39200B/en unknown
- 1975-03-31 PH PH16986A patent/PH11423A/en unknown
- 1975-04-01 NO NO751104A patent/NO142174C/en unknown
- 1975-04-01 SE SE7503688A patent/SE420491B/en not_active IP Right Cessation
- 1975-04-01 DK DK137375A patent/DK137375A/da not_active Application Discontinuation
- 1975-04-01 NL NL7503856A patent/NL7503856A/en not_active Application Discontinuation
- 1975-04-01 PL PL1975179255A patent/PL99553B1/en unknown
- 1975-04-01 GB GB13184/75A patent/GB1494943A/en not_active Expired
- 1975-04-01 NO NO751103A patent/NO142173C/en unknown
- 1975-04-01 CH CH410875A patent/CH613964A5/xx not_active IP Right Cessation
- 1975-04-01 SE SE7503689A patent/SE420492B/en unknown
- 1975-04-01 DE DE19752514229 patent/DE2514229A1/en not_active Ceased
- 1975-04-01 CH CH410975A patent/CH614205A5/xx not_active IP Right Cessation
- 1975-04-01 CA CA223,485A patent/CA1067498A/en not_active Expired
- 1975-04-01 DK DK137275A patent/DK137275A/da not_active IP Right Cessation
- 1975-04-01 AT AT245175A patent/AT340916B/en not_active IP Right Cessation
- 1975-04-01 DE DE19752514183 patent/DE2514183A1/en not_active Withdrawn
- 1975-04-01 FI FI750966A patent/FI61895C/en not_active IP Right Cessation
- 1975-04-01 GB GB1318675A patent/GB1456943A/en not_active Expired
- 1975-04-01 CA CA223,487A patent/CA1053672A/en not_active Expired
- 1975-04-01 NL NL7503849A patent/NL7503849A/en not_active Application Discontinuation
- 1975-04-01 FI FI750965A patent/FI63572C/en not_active IP Right Cessation
- 1975-04-01 AT AT245275A patent/AT342045B/en not_active IP Right Cessation
- 1975-04-01 ZA ZA00751986A patent/ZA751986B/en unknown
- 1975-04-02 IE IE712/75A patent/IE40894B1/en unknown
- 1975-04-02 IE IE713/75A patent/IE40895B1/en unknown
-
1976
- 1976-07-15 AR AR20634176D patent/AR206341A1/en active
- 1976-09-02 US US05/719,775 patent/USRE29556E/en not_active Expired - Lifetime
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