CA1053672A - 1,1-diaryl-1-oxadiazol-alkylamines - Google Patents
1,1-diaryl-1-oxadiazol-alkylaminesInfo
- Publication number
- CA1053672A CA1053672A CA223,487A CA223487A CA1053672A CA 1053672 A CA1053672 A CA 1053672A CA 223487 A CA223487 A CA 223487A CA 1053672 A CA1053672 A CA 1053672A
- Authority
- CA
- Canada
- Prior art keywords
- azabicyclo
- propyl
- diphenyl
- oxadiazole
- oct
- 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
- 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 very low 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 very low degree of analgesia.
Description
l,l-DIARYL-]-OXAPIAZOI.-AL~YLAMINES
The present invention relates to compounds of the general formula R
~ ~ .
R' I
/ N-(Alk)-~-Ar ., ,13 .
-~ whereln Alk is stràight or branched chain alkylene ; containing 2-4 carbon atoms; R is hydrogen or an alkyl 1 5 radlcal containing from 1-7 carbon atoms; X is hydrogen, i halogen, or an alkyl radical containing from 1-7 carbon atoms; Ar is phenyl, pyridyl or monosubstituted phenyl, wherein the substituent is halogen or an alkyl radical containing from 1-7 carbon atoms; R' and R" together lQ wlth N ls an azabicycloalkane structure containing 6-8 carbon atoms and containing at least 5 atoms in each ring o~ the azabicycloalkane structure.
The alkylene radicals encompassed by the term Alk are exemplified by ethylene, propylene, or tri-¦ 15 methylene. The term alkyl radical is exemplified by ¦ methyl, ethyl, propyl and butyl. The term halogen is ~ exemplified by fluoro, chloro, bromo or iodo. R' and ¦ R" together wlth N fDrm a azabicycloalkane which is ,j`
~'. - ' ~ ' exemplified by 2-azabicyclo[2.2 2]octyl,6-azabicy-c10~3.2.1]octyl 3-azabicyclo[3.2.2]nonyl and 7-azabicy- :
clo[2.2.1]he~tyl.2-azabicyclor2.2.2]octyl is a preferred embodiment.
The organic bases of this invention form non-toxic acid-additlon salts with a variety of organic and inorganic acids. Such salts are formed wlth acids such as sulfurlc, phosphoric,'hydrochloric, hydrobromic, . hydriodlc, sulfamic, citric, lactic, maleie, malic, ~ 10 Succinic, tartaric,.cinnamic, acetic', benzoic, gluconic, : ascorbic, and related acids.
` The compounds or the present 'inve~tion can be ~: conveniently prepared by reacting a tetrazole of the general ~formula' ~F=Il, . .
` ~ H II
. ~ N ( ) ~
X/~
``~` ` ' ` . . , . .. .~:
'~5 whereln.A}k~ Ar, X, R~ and R" are derined as before wlth ~k`"~. an acylatlng compound of the general'formula . - (R~C0)20 or RrC-Cl "" .. wh`erein R"' 18 an alkyl radioal o~ 1-7 carbon atoms or ~- ~-. a group.readlly removed t~o leave hydrogen such as ~, . - ~ ~- - .
~ . . ~ .. ... . , - ~
.
.
.
. . . ~ ... ; . . ..
. .
` . . , .. - . . .. . . . .
carhethoxy in a sultable ~olvent such as pyridine or any lnert solvent ~uch as toluene, benzene, methylene chloride or cyclohexane in the presence of an acid scavenger such as triethylamine, piperidine, or potassium carbonate to give the oxadiazole of the formula I.
The starting material of formula II can be pre-pared by reacting a compound of the general formula - CN III
N-(Alk)-C-Ar R~
,. . , 13' . .
wh~rein Alk, Ar, X, R' and R" are de~lned as before wlth an azide ion by methods slmllar to tho~e desoribed by -G. Moersbh and D. Morrow, J. Med. Chem., 10, 149 (1967).
An alternate process for the preparation of the compounds o~ thls lnventlon comprlses reactlng a . haloalkyl compound oP the formula R .-) I IV
1. ' ~ '. ' ' ~ .
i ~ Ar-C.Alk-Z
-_4- -.~ :
: . .. . . ~ . ~ . :: . . :
. . - . . .
.
10536'7Z
whereln Ar, Al~, R ~nd X ~re (~efin~d as before and Z
ls chlorlne or brc)mine with an amine of the rormu1a I~NR'R" wherein NR'R" is de~ined as before in a suitable inert solvent such as toluene, benzene, methy-lene chloride, 4-methyl-2-pentanone or cyclohexane in the presence of an acid acceptor such as triethylamine, plperidine or potassium carbonate to give the oxadiazole of the formula I. It ls necessary to heat this-mixture to complete the reaction. Preferably, the mixture is heated ~or several hours at the reflux temperature of the solvent although the time and temperature can be varied.
In another process for the preparation of the compounds of this invention, a hydrazide of the formula O O
~IC-NHNH-CR
J Ar-C-Alk-NR'R"
V
` ~b ,.
f X~
wherein Ar, Alk, R, R', R" and X are defined as before i8 reacted with a dehydrating agent such as thionyl .. .
chlorlde or phosphoryl chloride in a suitable inert -solvent such as toluene, benzene, methylene chloride .. ..
or cyclohexane to glve the oxadiazole of the formula I.
The compound of the present inventlon possess valuable pharmocological propertles. They are ~" potent-antl-dlarr~eal agents. These compounds also Qssess only a very low degree of analgesia.
The anti-diarrheal properties and the anal-~f ~eaic aot.~vfity' of ~he instant compounds are speclfically ~ --5--i .
~ . : .
~`. .
.. . . . . . ..
.~. . .
.. . .
lOS36~7Z
illustrated by the activity of the representative species 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole in the following test procedures.
Anti-diarrheal utility of the instant compounds is evidenced by their ability to inhibit gastrointestinal motility as set out in the following tests.
Charcoal Meal Test 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) previously fasted for 24 hours were pretreated with the test compounds adminis-tered orally as a solution in water or suspended in 0.5%
methyl cellulose. A constant volume of 10 ml/kg was employed. Thirty minutes following administration of the teQt compounds, the animals were qiven 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 after charcoal administration, the animals were sacrificed and ; 20 the cecum examined for the absence or presence of char-coal on an all-or-none basis.
The median effective dose (ED ) was calculated for each compound using the logistic method of Berkson (1953).
Castor Oil Induced Diarrhea in the Rat Adult Charles River male rats were fasted in community cages for 24 hours prior to the test, with free ` access to water. The compound was administered intra-gastrically (suspended on 0.05% methyl cellulose) one hour ... ... . . . .. . .. .
prior to the administration of castor oil at the dose of l.Oml/rat IG. The rats were then observed for the presence or absence of diarrhea, at hourly intervals for up to 8 hours past administration of castor oil. The median effective dose values at each hourly interval was calcu-lated for the compound using the method of Berkson (1953).
The assessment of the analgesic effect of the instant compound was conducted in the mouse hot plate and tail clip tests.
Mouse Hot Plate Test A mouse (adult male weighing 18-25 grams) is placed in a restraining cylinder on a hot plate with the temperature controlled at 55+0.3~C. The reaction time of the mouse to lick a foot or jump is measured at 60, 40 and 20 minutes before and 30, 60, 90, and 120 minutes after administration of the test compound. The "normal"
reaction time is measured as the median of the three pretreatment reaction times. A positive response consists of a reaction time greater than twice the normal time at any of the post treatment times. A dose (50mg/kg administered intraperitoneally) of the test compound is considered active when 5~ per cent or more of the animals used show a positive response.
. .
Tail Clip Test 3 25 A special clip is applied to the base of the tail of the mouse (adult male weighing 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 included in the experiment. The test compound is then administered intra-peritoneally and the response to placemRnt of the clip is determined at 30, ~0, 90, and 120 minutes after treat-ment. A response is considered positive if the animal takes more than 2 times the pre-drug time to bite at the ~-clip at any of these time intervals. A test compound is considered active when 50 percent or more of the animals used show a positive response.
The following examples describe in detail com-pounds illustrative of the present invention and methods -for their preparation. Throughout the examples herein-after set forth, temperatures are given in degrees Centigrade and relative amounts of materials in parts by weight, except as otherwise noted.
` A mixture of 26.3 parts of 2,2-diphenyl-4-t 20 (2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 9.0 parts of ~odium azide,7.4 parts of ammonium chloride and 0.12 part of lithium chloride in 60 parts by volume of di-j methylformamide was refluxed for 12 hours. A solid formed and this was separated by filtration to ~ive 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyll-lH-tetrazole. 11.2 Parts of this tetrazole and 13.04 parts of acetic anhydride were dissoved in 50 parts by volume of pyridine and refluKed for 2 hours. The solution was cooled and filtered to remove extraneous solid material.
~.
The filtrates were then evaporated to dryness. The re-sultant residue was suspended in aqueous potassium carbonate. This aqueous suspension was extracted with methylene chloride. The methylene chloride extracts were washed with water and dried. Concentration of the extracts gave a solid material which was ta~en up in ether. Upon standing, the ether solution gave a crys-talline material which was 5-11,1-diphenyl-3-~2-azabi-cyclo[2O2.21oct-2yl)propyl]-2-methyl-1,3,4-oxadiazole melting at 100-102C.
Substitution of 16.3 parts of acetyl chloride for the acetic anhydride used above and substantial repetition of the foregoing procedure affordea the same product, 5-[1,1-diphenyl-3-(2-azabicyclol2.2.21oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole.
11.2 Parts of 5-11.1-diphenyl-3-(2-azabicy-clol2.2.Z]oct-2-yl)propyl]-1~-tetrazole was reacted with 13.5 parts of propionic anhydride by the methods described in Example 1 to provide 5-11.1-diphenyl-3-(2-azabicyclo12.2.2]oct-2-yl)propyl]-2-ethyl-1,3,4-oxa-diazole melting at 96-98.5 C. Dissolving 0.9 part of this compound in 0~25 part of 85% phosphoric acid and 30 parts by volume of acetone and removing the solvent by evaporation at reduced pressure gave a slurry which upon recrystallization from methanol provided 5-[1,1-diphenyl-3-(2-azabicyclo12.2.2[oct-2-yl)propyl[-2-ethyl-1,3,4-oxadiazole phosphate melting at 175-178 C.
1053~7Z
36 Parts of 2,2-diphenyl-4-(3-azabicyclo[3.2.2]
non-3-yl)butyronitrile, 9.8 parts of sodium azide, 3.06 parts of ammonium chloride, and 0.15 part of lithium chloride were placed in 50 parts by volume of dimetAyl-formamide and heated at 125 C. for 12 hours. The solution was cooled and a white solid was filtered off. The solid was washed with dimethylformamide and water and then dried. This procedure provided 5-[1,1-diphenyl-3-(3-azabicyclol3.2.2]non-3-yl)propyl]-lH-tetrazole melting at 284-286C.
10.0 Parts of this l~-tetrazole and 20.5 parts of acetic anhydride were refluxed for 1 hour in 100 parts by volume of pyridine. The solution was cooled and the pyridine was removed by evaporation at reduced pressure.
The residue was taken up in ether and the ether solution was then washed with dilute sodium bicarbonate. The ether was then removed by evaporation at reduced pressure and the residual solid was recrystallized from a mixture of ether and n-pentane and dried in vacuum to provide 5-[1,1-diphenyl-3-(3-azabicyclo[3.2.2]non-3-yl)-propyl]-2-methyl-1,3,4-oxadiazole melting at 137-140 C.
When the procedure of Example 3 was repeated using equivalent quantities of the appropriate re-actants so that the appropriate nitrile was converted to the tetrazole and then to the oxadiazole, the follow-ing products were obtained:
5-[1-phenyl-1-(2-pyridyl)-3-(3-azabicyclo [3.2.2]non-3-yl)propyl]-2-methyl-1,3,4-oxadiazole melting at about 117.5-120C.
5-[1-phenyl-1-(2-pyridyl)-4-(3-azabicyclo[3.2.2]-non-3-ylbutyl]-2-methyl-1,3,4-oxadiazole.
5-[1,1-diphenyl-3-(8-azabicyclo[4.3.0]non-8-yl)-propyl]-2-methyl-1,3,4-oxadiazole.
EXAMPLE S
15 Parts of 2,2-diphenyl-4-bromobutyronitrile were condensed with 12.9 parts of 7-azabicyclo[2.2.1]hep-tane by reflux in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture was cooled and extracted with dilute hydrochloric acid.
The aqueous hydrochloric acid extract was made basic with sodium hydroxide solution and extracted with ether.
The ether extracts were dried over anhydrous sodium sulfate. Filtration and removal of the ether by evapo-ration at reduced pressure provided 2,2-diphenyl-4-(7-azabicyclo[2.2.1]hept-7-yl)butyronitrile melting at 79-81C. 4.9 parts of this butyronitrile, 1.5 parts of sodium azide, 1.2 parts of ammonium chloride, and 0.023 part of lithium chloride were placed in 50 parts by volume of dimethylformamide and heated at 125C. for 12 hours. The mixture was cooled and the solid was filtered from the dimethylformamide. The solid was washed with dimethylformamide and water. The dried solid was 5-11,1-diphenyl-3-(7-azabicyclo[2.2.1]hept-7-yl)propyl]-lH-tetrazole, melting at 284-286C.
The present invention relates to compounds of the general formula R
~ ~ .
R' I
/ N-(Alk)-~-Ar ., ,13 .
-~ whereln Alk is stràight or branched chain alkylene ; containing 2-4 carbon atoms; R is hydrogen or an alkyl 1 5 radlcal containing from 1-7 carbon atoms; X is hydrogen, i halogen, or an alkyl radical containing from 1-7 carbon atoms; Ar is phenyl, pyridyl or monosubstituted phenyl, wherein the substituent is halogen or an alkyl radical containing from 1-7 carbon atoms; R' and R" together lQ wlth N ls an azabicycloalkane structure containing 6-8 carbon atoms and containing at least 5 atoms in each ring o~ the azabicycloalkane structure.
The alkylene radicals encompassed by the term Alk are exemplified by ethylene, propylene, or tri-¦ 15 methylene. The term alkyl radical is exemplified by ¦ methyl, ethyl, propyl and butyl. The term halogen is ~ exemplified by fluoro, chloro, bromo or iodo. R' and ¦ R" together wlth N fDrm a azabicycloalkane which is ,j`
~'. - ' ~ ' exemplified by 2-azabicyclo[2.2 2]octyl,6-azabicy-c10~3.2.1]octyl 3-azabicyclo[3.2.2]nonyl and 7-azabicy- :
clo[2.2.1]he~tyl.2-azabicyclor2.2.2]octyl is a preferred embodiment.
The organic bases of this invention form non-toxic acid-additlon salts with a variety of organic and inorganic acids. Such salts are formed wlth acids such as sulfurlc, phosphoric,'hydrochloric, hydrobromic, . hydriodlc, sulfamic, citric, lactic, maleie, malic, ~ 10 Succinic, tartaric,.cinnamic, acetic', benzoic, gluconic, : ascorbic, and related acids.
` The compounds or the present 'inve~tion can be ~: conveniently prepared by reacting a tetrazole of the general ~formula' ~F=Il, . .
` ~ H II
. ~ N ( ) ~
X/~
``~` ` ' ` . . , . .. .~:
'~5 whereln.A}k~ Ar, X, R~ and R" are derined as before wlth ~k`"~. an acylatlng compound of the general'formula . - (R~C0)20 or RrC-Cl "" .. wh`erein R"' 18 an alkyl radioal o~ 1-7 carbon atoms or ~- ~-. a group.readlly removed t~o leave hydrogen such as ~, . - ~ ~- - .
~ . . ~ .. ... . , - ~
.
.
.
. . . ~ ... ; . . ..
. .
` . . , .. - . . .. . . . .
carhethoxy in a sultable ~olvent such as pyridine or any lnert solvent ~uch as toluene, benzene, methylene chloride or cyclohexane in the presence of an acid scavenger such as triethylamine, piperidine, or potassium carbonate to give the oxadiazole of the formula I.
The starting material of formula II can be pre-pared by reacting a compound of the general formula - CN III
N-(Alk)-C-Ar R~
,. . , 13' . .
wh~rein Alk, Ar, X, R' and R" are de~lned as before wlth an azide ion by methods slmllar to tho~e desoribed by -G. Moersbh and D. Morrow, J. Med. Chem., 10, 149 (1967).
An alternate process for the preparation of the compounds o~ thls lnventlon comprlses reactlng a . haloalkyl compound oP the formula R .-) I IV
1. ' ~ '. ' ' ~ .
i ~ Ar-C.Alk-Z
-_4- -.~ :
: . .. . . ~ . ~ . :: . . :
. . - . . .
.
10536'7Z
whereln Ar, Al~, R ~nd X ~re (~efin~d as before and Z
ls chlorlne or brc)mine with an amine of the rormu1a I~NR'R" wherein NR'R" is de~ined as before in a suitable inert solvent such as toluene, benzene, methy-lene chloride, 4-methyl-2-pentanone or cyclohexane in the presence of an acid acceptor such as triethylamine, plperidine or potassium carbonate to give the oxadiazole of the formula I. It ls necessary to heat this-mixture to complete the reaction. Preferably, the mixture is heated ~or several hours at the reflux temperature of the solvent although the time and temperature can be varied.
In another process for the preparation of the compounds of this invention, a hydrazide of the formula O O
~IC-NHNH-CR
J Ar-C-Alk-NR'R"
V
` ~b ,.
f X~
wherein Ar, Alk, R, R', R" and X are defined as before i8 reacted with a dehydrating agent such as thionyl .. .
chlorlde or phosphoryl chloride in a suitable inert -solvent such as toluene, benzene, methylene chloride .. ..
or cyclohexane to glve the oxadiazole of the formula I.
The compound of the present inventlon possess valuable pharmocological propertles. They are ~" potent-antl-dlarr~eal agents. These compounds also Qssess only a very low degree of analgesia.
The anti-diarrheal properties and the anal-~f ~eaic aot.~vfity' of ~he instant compounds are speclfically ~ --5--i .
~ . : .
~`. .
.. . . . . . ..
.~. . .
.. . .
lOS36~7Z
illustrated by the activity of the representative species 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole in the following test procedures.
Anti-diarrheal utility of the instant compounds is evidenced by their ability to inhibit gastrointestinal motility as set out in the following tests.
Charcoal Meal Test 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) previously fasted for 24 hours were pretreated with the test compounds adminis-tered orally as a solution in water or suspended in 0.5%
methyl cellulose. A constant volume of 10 ml/kg was employed. Thirty minutes following administration of the teQt compounds, the animals were qiven 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 after charcoal administration, the animals were sacrificed and ; 20 the cecum examined for the absence or presence of char-coal on an all-or-none basis.
The median effective dose (ED ) was calculated for each compound using the logistic method of Berkson (1953).
Castor Oil Induced Diarrhea in the Rat Adult Charles River male rats were fasted in community cages for 24 hours prior to the test, with free ` access to water. The compound was administered intra-gastrically (suspended on 0.05% methyl cellulose) one hour ... ... . . . .. . .. .
prior to the administration of castor oil at the dose of l.Oml/rat IG. The rats were then observed for the presence or absence of diarrhea, at hourly intervals for up to 8 hours past administration of castor oil. The median effective dose values at each hourly interval was calcu-lated for the compound using the method of Berkson (1953).
The assessment of the analgesic effect of the instant compound was conducted in the mouse hot plate and tail clip tests.
Mouse Hot Plate Test A mouse (adult male weighing 18-25 grams) is placed in a restraining cylinder on a hot plate with the temperature controlled at 55+0.3~C. The reaction time of the mouse to lick a foot or jump is measured at 60, 40 and 20 minutes before and 30, 60, 90, and 120 minutes after administration of the test compound. The "normal"
reaction time is measured as the median of the three pretreatment reaction times. A positive response consists of a reaction time greater than twice the normal time at any of the post treatment times. A dose (50mg/kg administered intraperitoneally) of the test compound is considered active when 5~ per cent or more of the animals used show a positive response.
. .
Tail Clip Test 3 25 A special clip is applied to the base of the tail of the mouse (adult male weighing 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 included in the experiment. The test compound is then administered intra-peritoneally and the response to placemRnt of the clip is determined at 30, ~0, 90, and 120 minutes after treat-ment. A response is considered positive if the animal takes more than 2 times the pre-drug time to bite at the ~-clip at any of these time intervals. A test compound is considered active when 50 percent or more of the animals used show a positive response.
The following examples describe in detail com-pounds illustrative of the present invention and methods -for their preparation. Throughout the examples herein-after set forth, temperatures are given in degrees Centigrade and relative amounts of materials in parts by weight, except as otherwise noted.
` A mixture of 26.3 parts of 2,2-diphenyl-4-t 20 (2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 9.0 parts of ~odium azide,7.4 parts of ammonium chloride and 0.12 part of lithium chloride in 60 parts by volume of di-j methylformamide was refluxed for 12 hours. A solid formed and this was separated by filtration to ~ive 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyll-lH-tetrazole. 11.2 Parts of this tetrazole and 13.04 parts of acetic anhydride were dissoved in 50 parts by volume of pyridine and refluKed for 2 hours. The solution was cooled and filtered to remove extraneous solid material.
~.
The filtrates were then evaporated to dryness. The re-sultant residue was suspended in aqueous potassium carbonate. This aqueous suspension was extracted with methylene chloride. The methylene chloride extracts were washed with water and dried. Concentration of the extracts gave a solid material which was ta~en up in ether. Upon standing, the ether solution gave a crys-talline material which was 5-11,1-diphenyl-3-~2-azabi-cyclo[2O2.21oct-2yl)propyl]-2-methyl-1,3,4-oxadiazole melting at 100-102C.
Substitution of 16.3 parts of acetyl chloride for the acetic anhydride used above and substantial repetition of the foregoing procedure affordea the same product, 5-[1,1-diphenyl-3-(2-azabicyclol2.2.21oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole.
11.2 Parts of 5-11.1-diphenyl-3-(2-azabicy-clol2.2.Z]oct-2-yl)propyl]-1~-tetrazole was reacted with 13.5 parts of propionic anhydride by the methods described in Example 1 to provide 5-11.1-diphenyl-3-(2-azabicyclo12.2.2]oct-2-yl)propyl]-2-ethyl-1,3,4-oxa-diazole melting at 96-98.5 C. Dissolving 0.9 part of this compound in 0~25 part of 85% phosphoric acid and 30 parts by volume of acetone and removing the solvent by evaporation at reduced pressure gave a slurry which upon recrystallization from methanol provided 5-[1,1-diphenyl-3-(2-azabicyclo12.2.2[oct-2-yl)propyl[-2-ethyl-1,3,4-oxadiazole phosphate melting at 175-178 C.
1053~7Z
36 Parts of 2,2-diphenyl-4-(3-azabicyclo[3.2.2]
non-3-yl)butyronitrile, 9.8 parts of sodium azide, 3.06 parts of ammonium chloride, and 0.15 part of lithium chloride were placed in 50 parts by volume of dimetAyl-formamide and heated at 125 C. for 12 hours. The solution was cooled and a white solid was filtered off. The solid was washed with dimethylformamide and water and then dried. This procedure provided 5-[1,1-diphenyl-3-(3-azabicyclol3.2.2]non-3-yl)propyl]-lH-tetrazole melting at 284-286C.
10.0 Parts of this l~-tetrazole and 20.5 parts of acetic anhydride were refluxed for 1 hour in 100 parts by volume of pyridine. The solution was cooled and the pyridine was removed by evaporation at reduced pressure.
The residue was taken up in ether and the ether solution was then washed with dilute sodium bicarbonate. The ether was then removed by evaporation at reduced pressure and the residual solid was recrystallized from a mixture of ether and n-pentane and dried in vacuum to provide 5-[1,1-diphenyl-3-(3-azabicyclo[3.2.2]non-3-yl)-propyl]-2-methyl-1,3,4-oxadiazole melting at 137-140 C.
When the procedure of Example 3 was repeated using equivalent quantities of the appropriate re-actants so that the appropriate nitrile was converted to the tetrazole and then to the oxadiazole, the follow-ing products were obtained:
5-[1-phenyl-1-(2-pyridyl)-3-(3-azabicyclo [3.2.2]non-3-yl)propyl]-2-methyl-1,3,4-oxadiazole melting at about 117.5-120C.
5-[1-phenyl-1-(2-pyridyl)-4-(3-azabicyclo[3.2.2]-non-3-ylbutyl]-2-methyl-1,3,4-oxadiazole.
5-[1,1-diphenyl-3-(8-azabicyclo[4.3.0]non-8-yl)-propyl]-2-methyl-1,3,4-oxadiazole.
EXAMPLE S
15 Parts of 2,2-diphenyl-4-bromobutyronitrile were condensed with 12.9 parts of 7-azabicyclo[2.2.1]hep-tane by reflux in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture was cooled and extracted with dilute hydrochloric acid.
The aqueous hydrochloric acid extract was made basic with sodium hydroxide solution and extracted with ether.
The ether extracts were dried over anhydrous sodium sulfate. Filtration and removal of the ether by evapo-ration at reduced pressure provided 2,2-diphenyl-4-(7-azabicyclo[2.2.1]hept-7-yl)butyronitrile melting at 79-81C. 4.9 parts of this butyronitrile, 1.5 parts of sodium azide, 1.2 parts of ammonium chloride, and 0.023 part of lithium chloride were placed in 50 parts by volume of dimethylformamide and heated at 125C. for 12 hours. The mixture was cooled and the solid was filtered from the dimethylformamide. The solid was washed with dimethylformamide and water. The dried solid was 5-11,1-diphenyl-3-(7-azabicyclo[2.2.1]hept-7-yl)propyl]-lH-tetrazole, melting at 284-286C.
2.15 parts of the above tetrazole and 4.9 parts of acetic anhydride were refluxed in 20 parts .
by volume of pyridine for 1 hour. ~he reaction mixture was cooled. The pyridine was removed by evaporation at reduced pressure to leave a residue which was taken up in ether. The ether was washed with sodium bicarbonate ~olution. The ether was then removed to provide a crude product which upon recrystallization from pentane provided 5-[1,1-diphenyl-3-~7-azabicyclo[2.2.1]hept-7-yl)propyl]-2-methyl-1,3,4 -oxaaiazole, melting at 130-132C.
2.0 Parts of 5-11-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-lH-tetrazole was reacted with 4.0 parts of acetic anhydride by the method described in Example 1 to provide 5-[1-phenyl-1-(3-py-ridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole.
0.54 parts of the above oxadiazole was com-bined with 0.215 parts of oxalic acid in 6.0 parts of methanol to give a solution. This solution was diluted with 6.0 parts of ether to give a white percipitate which was filtered from the liquors. This precipitate was washed with methanol-ether and ether and then dried in vacuum to give 5-[1-phenyl-1-(3-pyridyl)-3-(2-aza bicyclo[2.2.21oct-2-yl)propyll-2-methyl-1,3,4-oxa-diazole oxalate meltin~ at 171-172 C.
1.6 Parts by volume ethyl chloroglyoxylate was added to a stirred suspension of 5-11,1-diphenyl-3-(2-azabicyclo~2.2.21oct-2-yl)propyl]-lH-tetrazole in --1~--lOS367Z
pyridine. After the reaction mixture was stirred for fifteen minutes at -6C., it was heated with stirring to 60and kept at that temperature for about 2 hours.
The reaction mixture was then cooled and stripped to give a residue which was dissolved in water. Treatment of the solution with excess potassium carbonate in water gave a solid. This solid was dissolved in ether.
The ether solution was washed with water, dried over sodium sulfate, treated with charcoal and filtered. The filtrates were stripped in vacuum to give a brown gum.
This gum was dissolved in ethanol and treated with excess hydrogen chloride. The precipitate which formed was filtered off, washed with a mixture of ethanol and ether and air-dried. This procedure provided ethyl-5-1l,l-diphenyl-3-~2-azabicyclo[2.2.2]oct-2-yl)propyl~
1,3,4-oxadiazole-2-carboxylate hydrochloride which melted at 198.0-200C.
8.0 Parts of the above oxadiazole was SU8-pended in 200 parts by volume of 5~ sodium hydroxide.
mis suspensioA wa~ heated to reflux temperature for five minutes. Upon cooling the ~olution to room temperature, a gum precipitated. This gum was dissolved in water. The resultant solution was extracted with ether. Adjustment of the aqueoue phase of the extrac-tion to p~ 6 gave a gum. This gum was extracted several times with methylene chloride and the extracts were combined and then stripped in vacuum to give a solid.
The solid now was taken up in methylene chloride. The resultant solution was filterea. The filtrates were ~053672 concentrated to a lower volume. Dilution of these fil-trates with methanol caused the formation of a solid material. This solid material was filtered off, washed with an ether/methanol mixture and dried to give 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylic acid hydrate, melting at about 128-129C.
by volume of pyridine for 1 hour. ~he reaction mixture was cooled. The pyridine was removed by evaporation at reduced pressure to leave a residue which was taken up in ether. The ether was washed with sodium bicarbonate ~olution. The ether was then removed to provide a crude product which upon recrystallization from pentane provided 5-[1,1-diphenyl-3-~7-azabicyclo[2.2.1]hept-7-yl)propyl]-2-methyl-1,3,4 -oxaaiazole, melting at 130-132C.
2.0 Parts of 5-11-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-lH-tetrazole was reacted with 4.0 parts of acetic anhydride by the method described in Example 1 to provide 5-[1-phenyl-1-(3-py-ridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole.
0.54 parts of the above oxadiazole was com-bined with 0.215 parts of oxalic acid in 6.0 parts of methanol to give a solution. This solution was diluted with 6.0 parts of ether to give a white percipitate which was filtered from the liquors. This precipitate was washed with methanol-ether and ether and then dried in vacuum to give 5-[1-phenyl-1-(3-pyridyl)-3-(2-aza bicyclo[2.2.21oct-2-yl)propyll-2-methyl-1,3,4-oxa-diazole oxalate meltin~ at 171-172 C.
1.6 Parts by volume ethyl chloroglyoxylate was added to a stirred suspension of 5-11,1-diphenyl-3-(2-azabicyclo~2.2.21oct-2-yl)propyl]-lH-tetrazole in --1~--lOS367Z
pyridine. After the reaction mixture was stirred for fifteen minutes at -6C., it was heated with stirring to 60and kept at that temperature for about 2 hours.
The reaction mixture was then cooled and stripped to give a residue which was dissolved in water. Treatment of the solution with excess potassium carbonate in water gave a solid. This solid was dissolved in ether.
The ether solution was washed with water, dried over sodium sulfate, treated with charcoal and filtered. The filtrates were stripped in vacuum to give a brown gum.
This gum was dissolved in ethanol and treated with excess hydrogen chloride. The precipitate which formed was filtered off, washed with a mixture of ethanol and ether and air-dried. This procedure provided ethyl-5-1l,l-diphenyl-3-~2-azabicyclo[2.2.2]oct-2-yl)propyl~
1,3,4-oxadiazole-2-carboxylate hydrochloride which melted at 198.0-200C.
8.0 Parts of the above oxadiazole was SU8-pended in 200 parts by volume of 5~ sodium hydroxide.
mis suspensioA wa~ heated to reflux temperature for five minutes. Upon cooling the ~olution to room temperature, a gum precipitated. This gum was dissolved in water. The resultant solution was extracted with ether. Adjustment of the aqueoue phase of the extrac-tion to p~ 6 gave a gum. This gum was extracted several times with methylene chloride and the extracts were combined and then stripped in vacuum to give a solid.
The solid now was taken up in methylene chloride. The resultant solution was filterea. The filtrates were ~053672 concentrated to a lower volume. Dilution of these fil-trates with methanol caused the formation of a solid material. This solid material was filtered off, washed with an ether/methanol mixture and dried to give 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1,3,4-oxadiazole-2-carboxylic acid hydrate, melting at about 128-129C.
3.1 Parts of the above oxadiazole was heated in an oil bath for fifteen minutes during which time the oxadiazole melted and gave off gas. The glass which resulted from this procedure was extracted with ether.
The extracts were then stripped in vacuum. The gum which resulted was treated with excess hydrogen chloride in 2-propanol and cooled to o. The precipitate which formed was filtered off, washed with acetone and dried in vacuum to give 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]
oct-2-yl)propyl]-1,3,4 oxadiazole hydrochloride melting at 233-234.5C.
A mixture of 5.69 parts of 2-phenyl-2-(2-pyridyl)-4-(2-azabicyclo~2.2.2]oct-2-yl)butyronitrile, 1.67 parts of sodium azide, 1.38 parts of ammonium chloride and 0.025 parts of lithium chloride in 30 parts by volume of dimethylformamide was stirred for 12 hours under nitrogen at 120C. After the reaction time was completed, the material was cooled and fil-, tered. The collected precipitate was washed with ; dimethylformamide and water. The precipitate was then dissolved in 100 parts by volume of 0.2N NaO~. The resultant solution was filtered. The filtrates were - : .
- . . .. ~ .. ..
lOS367Z
neutralized with dilute hydrochloric acid. The product which separated was recrystallized from ethanol. The procedure afforded 5-Ll-phenyl--1-(2-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-lH-tetrazole melting at about 253-254C.
The extracts were then stripped in vacuum. The gum which resulted was treated with excess hydrogen chloride in 2-propanol and cooled to o. The precipitate which formed was filtered off, washed with acetone and dried in vacuum to give 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]
oct-2-yl)propyl]-1,3,4 oxadiazole hydrochloride melting at 233-234.5C.
A mixture of 5.69 parts of 2-phenyl-2-(2-pyridyl)-4-(2-azabicyclo~2.2.2]oct-2-yl)butyronitrile, 1.67 parts of sodium azide, 1.38 parts of ammonium chloride and 0.025 parts of lithium chloride in 30 parts by volume of dimethylformamide was stirred for 12 hours under nitrogen at 120C. After the reaction time was completed, the material was cooled and fil-, tered. The collected precipitate was washed with ; dimethylformamide and water. The precipitate was then dissolved in 100 parts by volume of 0.2N NaO~. The resultant solution was filtered. The filtrates were - : .
- . . .. ~ .. ..
lOS367Z
neutralized with dilute hydrochloric acid. The product which separated was recrystallized from ethanol. The procedure afforded 5-Ll-phenyl--1-(2-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-lH-tetrazole melting at about 253-254C.
4.62Parts of the above tetrazole, 40 parts by volume of pyridine, and 14 parts by volume of acetic anhydride were refluxed for 2.5 hours. The solution was cooled and decomposed by the addition of water. The solvent was stripped off and the resultant residue was taken up in a saturated aqueous solution of sodium bi-carbonate and ether. This aqueous solution was ex-tracted several times with ether. The ether extracts were washed neutral with water and then dried over sodium sulfate. The extracts were then filtered and the filtrates were evaporated. The residue was taken up in ether and filtered. Addition of excess hydrogen chloride in isopropanol to this solution caused the for-mation of a precipitate. The precipitate was collected, dissolved in water, and washed with ether. The aqueous solution was then made alkaline. The product was then extracted with ether. The e;ther extracts were washed neutral, dried over sodium sulfate, filtered and eva-porated. Evaporation of the solvent gave a crystalline product which was 5-[1-phenyl-1-(2-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl~-2-methyl-1,3,4-oxa diazole melting at 109-110C.
;
; . ' , 1053~;7Z
EXA~lPLE 9 4.08 Parts of 2-(4-chlorophenyl)-2-phenyl-4-~2-azabicyclo[2.2.2]oct-2yl)butyronitrile, 50 parts by volume of dimethylformamide, 1.09 parts of sodium azide, 0.90 parts of ammonium chloride, and 0.030 parts of lithium chloride were heated with stirring at 110C.
for 13 hours. The product which was isolated as in Example 8 was 5-[1-(4-chlorophenyl)-1-phenyl-3-(2-azabicyclo[2.2.2~oct-2-yl)propyl]-lH-tetrazole melting at about 277-278C. The resultant tetrazole from the above procedure 25 parts by volume of pyridine, and 5.0 parts by volume of acetic anhydride were refluYed to-gether for 2.5 hours. After the reaction time was completed, the solution was cooled and the mixture was hydrolyzed by the addition of water. The reaction mix-ture was stripped of solvent and the resultant residue was taken up in a saturated aqueous solution of sodium bicarbonate and ether. The ether layer was separated and the solvent evaporated to leave a residue which crystallized to give 5-[1-(4-chlorophenyl)-1-phenyl-3-(2-aza~icyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole melting at 97-102C.
7.32 Parts of 2,2-bis(4-chlorophenyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 1.77 parts of sodium azide, 1.45 parts of ammonium chloride, 0.020 parts of lithium chloride and 60 parts by volume of dimethylformamide were combined and stirred under .
105367~
nitrogen at 1~0C. overnight. Cooling of this reaction mixture afforded a solid material which was filtered off. The solid was washed with water and dried to give 5-[l,l-bis-(4-chlorophenyl)-3-(2-azabicyclo[2.2.2]
oct-2-yl)propyl]tetrazole, melting at 263-264 C.
;
; . ' , 1053~;7Z
EXA~lPLE 9 4.08 Parts of 2-(4-chlorophenyl)-2-phenyl-4-~2-azabicyclo[2.2.2]oct-2yl)butyronitrile, 50 parts by volume of dimethylformamide, 1.09 parts of sodium azide, 0.90 parts of ammonium chloride, and 0.030 parts of lithium chloride were heated with stirring at 110C.
for 13 hours. The product which was isolated as in Example 8 was 5-[1-(4-chlorophenyl)-1-phenyl-3-(2-azabicyclo[2.2.2~oct-2-yl)propyl]-lH-tetrazole melting at about 277-278C. The resultant tetrazole from the above procedure 25 parts by volume of pyridine, and 5.0 parts by volume of acetic anhydride were refluYed to-gether for 2.5 hours. After the reaction time was completed, the solution was cooled and the mixture was hydrolyzed by the addition of water. The reaction mix-ture was stripped of solvent and the resultant residue was taken up in a saturated aqueous solution of sodium bicarbonate and ether. The ether layer was separated and the solvent evaporated to leave a residue which crystallized to give 5-[1-(4-chlorophenyl)-1-phenyl-3-(2-aza~icyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole melting at 97-102C.
7.32 Parts of 2,2-bis(4-chlorophenyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 1.77 parts of sodium azide, 1.45 parts of ammonium chloride, 0.020 parts of lithium chloride and 60 parts by volume of dimethylformamide were combined and stirred under .
105367~
nitrogen at 1~0C. overnight. Cooling of this reaction mixture afforded a solid material which was filtered off. The solid was washed with water and dried to give 5-[l,l-bis-(4-chlorophenyl)-3-(2-azabicyclo[2.2.2]
oct-2-yl)propyl]tetrazole, melting at 263-264 C.
5.44 Parts of the above tetrazole, 50 parts by volume of pyridine, and 10 parts by volume of acetic anhydride were combined and refluxed for 2.5 hours.
The reaction mixture was decomposed with water and the solvent was evaporated. The residue was mixed with saturated aqueous sodium bicarbonate solution and ether. The ether solvent was evaporated and the residue was redissolved in ether and treated with excess hydrogen chloride in 2-pro~anol. The solid which formed was separated to give 5-[l,l-bis-(4-chlorophenyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxa-diazole hydrochloride hemihydrate melting at about 165-175C.
EXAMPLE ll Using equivalent amounts and following the procedure set out in Example 1, 1-phenyl-1-(3-tolyl)-4-(2-azabicyclo[2.2.2]oct-2-yl butyronitrile was con-verted to 5-[1-phenyl-l-(3-tolyl)-3-(2-azabicyclo [2.2.2]oct-2-yl)propyl]-lH-tetrazole and this tetra-zole was then converted to 5-[l-phenyl-l-(3-tolyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole.
, lOS367Z
Following the procedures set out in Example 1 27.3 parts of 2-(2-pyridyl)-2-(3-tolyl)-4-(2-azabi-cyclo[2.2.2]oct-2-yl)butyronitrile was reacted with 7.95 parts of ammonium chloride, 9.75 parts of sodium azide, and 0.15 part of lithium chloride in 75 parts by volume of dimethylformamide to provide 5-[1-t2-pyridyl)-1-t3-tolyl)-3-t2-azabicyclol2.2.2~oct-2-yl)propyl]-lH-tetrazole. Also following the procedures in Example 1, 1.1 parts of the above tetrazole is reacted with 1.15 parts of acetyl chloride in 10 parts by volume of pyridine to provide 5-[1-t2-pyridyl)-1-t3-tolyl)-3-t2-azabicyclol2.2.2]oct-2-yl)propyl]2-methyl-1,3,4-oxadiazole.
1.90 Parts of 2,2-diphenyl-4-t2-azabicyclo [2.2.2]oct-2-yl) valeronitrile, 1.13 parts of sodium azide, 0;93 parts of ammoniumchloride, 0.17 parts of lithium chloride and 20 parts by volume of dimethyl-formamide were com~ined and refluxed for 12 hours.
Upon refluxing a solid separate which was 5-[1,1-di-phenyl-3-(2-azabicyclo12.2.2]oct-2-yl)butyl]lH-tetra-zole.
0.800~Parts of this tetrazole intermediate and 1.6 parts of acetic anhydride were dissolved in 8.0 parts by volume of pyridine and refluxed for 2 hours.
The solvent was stripped off and the residue was ex-tracted with ether. The ether extracts were washed with water and dried over sodium sulfate. Concentration of the extracts gave a solid material which was re-crystallized from an ether/n-pentane mixture. This procedure afforded 5~ diphenyl-3-(2-azabicyclol2.2.2]
oct-2-yl)butyll2-methyl-1,3,4-oxadiazole melting at 128-133.
Substitution of equivalent amount of Z-2-di-phenyl-4-(2-azabicyclo12.2.2]oct-2-yl)3-methylbutyroni-trile for the 2-2-diphenyl-4-~2-azabicyclo[2.2.2]oct-2-yl) valeronitrile used above ana substantial repetition of the foregoing procedure afforded 5-[1~1-diphenyl-2-(2-azabicyclol2.2.2]oct-2-yl)-2-methylpropyll2-methyl-1,3,4-oxadiazole.
2.6 Parts of 5-11,1-diphenyl-3(6-azabi-cyclol3.2.1]oct-6-yl)propyl-1~-tetrazole was reactcd with 10 parts of acetic anhydride by the method ~escribed in Example 1 to provide 5-[1,1-diphenyl-3-(6-azabicyclo 13.2.1]oct-6-yl)propyl]-2-methyl-1,3,4oxadiazole melting at 98-101C.
A mixture of 1.07 parts ~f 5-(1,1-diphenyl-3-bromopropyl)-2-methyl-1,3,4-oxadiazole, 0.49 part of isoquinuclidine hydrochloride, 0.46 part of potassium carbonate, 0.17 part of potassium iodide, 1 part of water and 3.2 parts of 4-methyl-2-pentanone was re-fluxed for 2 hours. The solvent was then evaporated and the residue was partitioned between methylene chlo-ride and water. The organic layer was separated, washed with water and with saturated aqueous sodium chloride solution and then dried over sodium sulfate.
- :
10536~Z
Evaporation of the solvent left a semi-solid residue which was slurried in ether and then filtered to remove the solid. The solvent was evaporated from the filtrate leaving an oily residue which was ta~en up in refluxing hexane. The hexane solution was then decanted and cooled and the oily solid which formed was removed by filtra-tion. Evaporation of the solvent from the filtrate left 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)pro-pyl]-2-methyl-1,3,4-oxadiazole as an oily residue.
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-(2-azabicyclo[2.2.2]oct-2-yl)propyl[-2-methyl-1,3,4-oxadiazole was mixed thorougllly with 41.0 parts of poly-vinylpyrioli~one and then screened. The mixture was granulated with isopropyl alcohol, spread on trays, and dried at 50C. for 16 hours. The dried granulation was then screened. The granules were mixed thoroughly with 1.0 part of magnesium stearate and the mixture compressed into tablets. The tablets weigh 90.0 mg. and contain 2.5 mg. of active ingredient per tablet.
In the preparation of tablets from the com-pounds of the present invention, a variety of ex-cipients can be used. These are summarized as follows:
sugars such as lactose, sucrose, or mannitol; starches such as corn starch, tapioca starch, or potato starch;
cellulose derivatives such as ethyl cellulose, methyl cellulose, gelatin cellulose, acetate phthalate; cal-cium phosphates such as dicalcium phosphate or tri-1053~7Z
calcium phosphate; sodium sulfate, sodium bicarbonate, ~ ciuln sulfate, polyvirlylpyrrolidone, polyvinyl alcohol, polyvinyl acetate phthalate, stearic acid;
alkaline earth metal stearates such as magnesium stear-ate; vegetable oils such as peanut oil, cottonseed oil,sesame oil, olive oil, corn oil; surfactants (nonionic, cationic, anionic); ethylene glycol polymers; ~-cyclo-dextrin; fatty alcohols; as well as other nontoxic compatable fillers, binders, disintegrants, and lubri-cants commonly used in pharmaceutical formulations.
The reaction mixture was decomposed with water and the solvent was evaporated. The residue was mixed with saturated aqueous sodium bicarbonate solution and ether. The ether solvent was evaporated and the residue was redissolved in ether and treated with excess hydrogen chloride in 2-pro~anol. The solid which formed was separated to give 5-[l,l-bis-(4-chlorophenyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxa-diazole hydrochloride hemihydrate melting at about 165-175C.
EXAMPLE ll Using equivalent amounts and following the procedure set out in Example 1, 1-phenyl-1-(3-tolyl)-4-(2-azabicyclo[2.2.2]oct-2-yl butyronitrile was con-verted to 5-[1-phenyl-l-(3-tolyl)-3-(2-azabicyclo [2.2.2]oct-2-yl)propyl]-lH-tetrazole and this tetra-zole was then converted to 5-[l-phenyl-l-(3-tolyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole.
, lOS367Z
Following the procedures set out in Example 1 27.3 parts of 2-(2-pyridyl)-2-(3-tolyl)-4-(2-azabi-cyclo[2.2.2]oct-2-yl)butyronitrile was reacted with 7.95 parts of ammonium chloride, 9.75 parts of sodium azide, and 0.15 part of lithium chloride in 75 parts by volume of dimethylformamide to provide 5-[1-t2-pyridyl)-1-t3-tolyl)-3-t2-azabicyclol2.2.2~oct-2-yl)propyl]-lH-tetrazole. Also following the procedures in Example 1, 1.1 parts of the above tetrazole is reacted with 1.15 parts of acetyl chloride in 10 parts by volume of pyridine to provide 5-[1-t2-pyridyl)-1-t3-tolyl)-3-t2-azabicyclol2.2.2]oct-2-yl)propyl]2-methyl-1,3,4-oxadiazole.
1.90 Parts of 2,2-diphenyl-4-t2-azabicyclo [2.2.2]oct-2-yl) valeronitrile, 1.13 parts of sodium azide, 0;93 parts of ammoniumchloride, 0.17 parts of lithium chloride and 20 parts by volume of dimethyl-formamide were com~ined and refluxed for 12 hours.
Upon refluxing a solid separate which was 5-[1,1-di-phenyl-3-(2-azabicyclo12.2.2]oct-2-yl)butyl]lH-tetra-zole.
0.800~Parts of this tetrazole intermediate and 1.6 parts of acetic anhydride were dissolved in 8.0 parts by volume of pyridine and refluxed for 2 hours.
The solvent was stripped off and the residue was ex-tracted with ether. The ether extracts were washed with water and dried over sodium sulfate. Concentration of the extracts gave a solid material which was re-crystallized from an ether/n-pentane mixture. This procedure afforded 5~ diphenyl-3-(2-azabicyclol2.2.2]
oct-2-yl)butyll2-methyl-1,3,4-oxadiazole melting at 128-133.
Substitution of equivalent amount of Z-2-di-phenyl-4-(2-azabicyclo12.2.2]oct-2-yl)3-methylbutyroni-trile for the 2-2-diphenyl-4-~2-azabicyclo[2.2.2]oct-2-yl) valeronitrile used above ana substantial repetition of the foregoing procedure afforded 5-[1~1-diphenyl-2-(2-azabicyclol2.2.2]oct-2-yl)-2-methylpropyll2-methyl-1,3,4-oxadiazole.
2.6 Parts of 5-11,1-diphenyl-3(6-azabi-cyclol3.2.1]oct-6-yl)propyl-1~-tetrazole was reactcd with 10 parts of acetic anhydride by the method ~escribed in Example 1 to provide 5-[1,1-diphenyl-3-(6-azabicyclo 13.2.1]oct-6-yl)propyl]-2-methyl-1,3,4oxadiazole melting at 98-101C.
A mixture of 1.07 parts ~f 5-(1,1-diphenyl-3-bromopropyl)-2-methyl-1,3,4-oxadiazole, 0.49 part of isoquinuclidine hydrochloride, 0.46 part of potassium carbonate, 0.17 part of potassium iodide, 1 part of water and 3.2 parts of 4-methyl-2-pentanone was re-fluxed for 2 hours. The solvent was then evaporated and the residue was partitioned between methylene chlo-ride and water. The organic layer was separated, washed with water and with saturated aqueous sodium chloride solution and then dried over sodium sulfate.
- :
10536~Z
Evaporation of the solvent left a semi-solid residue which was slurried in ether and then filtered to remove the solid. The solvent was evaporated from the filtrate leaving an oily residue which was ta~en up in refluxing hexane. The hexane solution was then decanted and cooled and the oily solid which formed was removed by filtra-tion. Evaporation of the solvent from the filtrate left 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)pro-pyl]-2-methyl-1,3,4-oxadiazole as an oily residue.
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-(2-azabicyclo[2.2.2]oct-2-yl)propyl[-2-methyl-1,3,4-oxadiazole was mixed thorougllly with 41.0 parts of poly-vinylpyrioli~one and then screened. The mixture was granulated with isopropyl alcohol, spread on trays, and dried at 50C. for 16 hours. The dried granulation was then screened. The granules were mixed thoroughly with 1.0 part of magnesium stearate and the mixture compressed into tablets. The tablets weigh 90.0 mg. and contain 2.5 mg. of active ingredient per tablet.
In the preparation of tablets from the com-pounds of the present invention, a variety of ex-cipients can be used. These are summarized as follows:
sugars such as lactose, sucrose, or mannitol; starches such as corn starch, tapioca starch, or potato starch;
cellulose derivatives such as ethyl cellulose, methyl cellulose, gelatin cellulose, acetate phthalate; cal-cium phosphates such as dicalcium phosphate or tri-1053~7Z
calcium phosphate; sodium sulfate, sodium bicarbonate, ~ ciuln sulfate, polyvirlylpyrrolidone, polyvinyl alcohol, polyvinyl acetate phthalate, stearic acid;
alkaline earth metal stearates such as magnesium stear-ate; vegetable oils such as peanut oil, cottonseed oil,sesame oil, olive oil, corn oil; surfactants (nonionic, cationic, anionic); ethylene glycol polymers; ~-cyclo-dextrin; fatty alcohols; as well as other nontoxic compatable fillers, binders, disintegrants, and lubri-cants commonly used in pharmaceutical formulations.
Claims (23)
1. A process for the preparation of a compound of the general formula I
wherein Alk is straight or branched chain alkylene containing 2-4 carbon atoms; R is hydrogen or an alkyl radical containing 1-4 carbon atoms; X is hydrogen, halogen, or an alkyl radical containing from 1-4 carbon atoms; Ar is phenyl, pyridyl or mono-substituted phenyl, wherein the substituent is halogen or an alkyl radical containing from 1-4 carbon atoms; R' and R" toget-her with N is an azabicycloalkane structure containing 6-8 carbon atoms and containing at least 5 atoms in each ring of the azabicycloalkane structure which is characterized by reacting:
a) a compound of the general formula II
wherein Alk, Ar, X, R' and R" are defined as above with a compound of the formula (R"' CO)2O or wherein R"' is an alkyl radical of 1-7 carbon atoms or a group readily removed to leave hydrogen, or b) a compound of the general formula IV
wherein Ar, Alk, R and X are defined as above and Z is chlorine or bromine with an amine of the formula HNR'R" wherein NR'R" is defined as above.
wherein Alk is straight or branched chain alkylene containing 2-4 carbon atoms; R is hydrogen or an alkyl radical containing 1-4 carbon atoms; X is hydrogen, halogen, or an alkyl radical containing from 1-4 carbon atoms; Ar is phenyl, pyridyl or mono-substituted phenyl, wherein the substituent is halogen or an alkyl radical containing from 1-4 carbon atoms; R' and R" toget-her with N is an azabicycloalkane structure containing 6-8 carbon atoms and containing at least 5 atoms in each ring of the azabicycloalkane structure which is characterized by reacting:
a) a compound of the general formula II
wherein Alk, Ar, X, R' and R" are defined as above with a compound of the formula (R"' CO)2O or wherein R"' is an alkyl radical of 1-7 carbon atoms or a group readily removed to leave hydrogen, or b) a compound of the general formula IV
wherein Ar, Alk, R and X are defined as above and Z is chlorine or bromine with an amine of the formula HNR'R" wherein NR'R" is defined as above.
2. A process for the preparation of a compound of the general formula VI
wherein Ar, Alk, X and R are defined as in claim 1 which is characterized by reacting:
a) a compound of the general formula VII
wherein Alk, Ar and X are defined as in claim 1 with a compound of the formula (R"' CO)2O or wherein R"' is defined as in claim 1, or b) a compound of the general formula IV
wherein Ar, Alk, R, X and Z are defined as in claim 1 with an amine of the formula
wherein Ar, Alk, X and R are defined as in claim 1 which is characterized by reacting:
a) a compound of the general formula VII
wherein Alk, Ar and X are defined as in claim 1 with a compound of the formula (R"' CO)2O or wherein R"' is defined as in claim 1, or b) a compound of the general formula IV
wherein Ar, Alk, R, X and Z are defined as in claim 1 with an amine of the formula
3. The process according to claim 1 wherein the anhydride used is acetic anhydride.
4. The process according to Claim 1 for the pre-paration of 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl) propyl]-2-methyl-1,3,4-oxadiazole which is characterized by reacting 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl) propyl]-1H-tetrazole with acetic anhydride.
5) The process according to claim 1 for the preparation of 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]1,3,4-oxadiazole which is characterized by reacting 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl) propyl]1H-tetrazole with ethyl chloroglyoxylate.
6) The process according to claim 1 for the preparation of 5-[1-phenyl-1-(2-pyridyl)-3-(3-azabicyclo [3.2.2]non-3-yl)propyl]-2-methyl-1,3,4-oxadiazole which is characterized by reacting 5-[1-phenyl-1-(3-pyridyl)-3-(3-azabicyclo[3.2.2]non-3-yl)propyl]-1H-tetrazole with acetic anhydride.
7) The process according to claim 1 for the preparation of 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo [2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole which is characterized by reacting 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole with acetic anhydride.
8) The process according to claim 1 for the preparation of 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]
oct-2-yl)propyl]-2-ethyl-1,3,4-oxadiazole which is characterized by reacting 5-[1,1-diphenyl-3-(2-azabicyclo [2.2.2]oct-2-yl)propyl]-1H-tetrazole with propionic anhydride.
oct-2-yl)propyl]-2-ethyl-1,3,4-oxadiazole which is characterized by reacting 5-[1,1-diphenyl-3-(2-azabicyclo [2.2.2]oct-2-yl)propyl]-1H-tetrazole with propionic anhydride.
9) The process according to claim 1 for the preparation of 5-[1,1-diphenyl-3-(7-azabicyclo[2.2.1]hept-7-yl)propyl]-2-methyl-1,3,4-oxadiazole which is characterized by reacting 5-[1,1-diphenyl-3-(7-azabicyclo[2.2.1]hept-7-yl) propyl]-1H-tetrazole with acetic anhydride.
10) The process according to claim 1 for the preparation of 5-[1,1-diphenyl-3-(3-azabicyclo[3.2.2]non-3-yl)propyl]-2-methyl-1,3,4-oxadiazole which is characterized by reacting 5-[1,1-diphenyl-3-(3-azabicyclo[3.2.2]non-3-yl) propyl]-1H-tetrazole with acetic anhydride.
11. The process according to claim 1 for the preparation of 5-[1,1-diphenyl-3-(6-azabicyclo[3.2.1]oct-6-yl)propyl-2-methyl-1,3,4-oxadiazole which is characterized by reacting 5-[1,1-diphenyl-3-(6-azabicyclo[3.2.1]oct-6-yl) propyl-1H-tetrazole with acetic anhydride.
12. The process according to claim 1 for the preparation of 5-[1,1-diphenyl-3(2-azabicyclo[2.2.2]oct-2-yl) propyl]2-methy-1,3,4-oxadiazole which is characterized by re-acting 5-(1,1-diphenyl-3-bromopropyl)-2-methyl-1,3,4-oxadiazole with isoquinuclidine hydrochloride.
13. A compound of the formula I
wherein Alk is straight or branched chain alkylene containing 2-4 carbon atoms; R is hydrogen or an alkyl radical containing from 1-4 carbon atoms; X is hydrogen, halogen, or an alkyl radical containing from 1-4 carbon atoms; Ar is phenyl, pyridyl or monosubstituted phenyl, wherein the substituent is halogen or an alkyl radical containing from 1-4 carbon atoms; R' and R" together with N is an azabicycloalkane structure containing 6-8 carbon atoms and containing at least 5 atoms in each ring of the azabicycloalkane structure whenever prepared by the process of Claim 1.
wherein Alk is straight or branched chain alkylene containing 2-4 carbon atoms; R is hydrogen or an alkyl radical containing from 1-4 carbon atoms; X is hydrogen, halogen, or an alkyl radical containing from 1-4 carbon atoms; Ar is phenyl, pyridyl or monosubstituted phenyl, wherein the substituent is halogen or an alkyl radical containing from 1-4 carbon atoms; R' and R" together with N is an azabicycloalkane structure containing 6-8 carbon atoms and containing at least 5 atoms in each ring of the azabicycloalkane structure whenever prepared by the process of Claim 1.
14. A compound of the general formula VI
wherein Ar, Alk, X, and R are defined as in claim 2 whenever prepared by the process of Claim 2.
wherein Ar, Alk, X, and R are defined as in claim 2 whenever prepared by the process of Claim 2.
15. 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl) propyl]-2-methyl-1,3,4-oxadiazole, whenever prepared by the process of Claim 4.
16. 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]1,3,4-oxadiazole, whenever prepared by the process of claim 5.
17. 5-[1-phenyl-1-(2-pyridyl)-3-(3-azabicyclo[3.2.2]-non-3-yl)propyll-2-methyl-1,3,4-oxadiazole, whenever prepared by the process of claim 6.
18. 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]-oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole, whenever prepared by the process of Claim 7.
19. 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2- ethyl-1,3,4-oxadiazole, whenever prepared by the process of Claim 8.
20. 5-[1,1-diphenyl-3-(7-azabicyclo[2.2.1]hept-7-yl)propyl]-2-methyl-1,3,4-oxadiazole, whenever pre-pared by the process of Claim 9.
21. 5-[1,1-diphenyl-3-(3-azabicyclo[3.2.2]non-3-yl)propyl]-2-methyl-1,3,4-oxadiazole, whenever pre-pared by the process of Claim 10.
22. 5-[1,1-diphenyl-3-(6-azabicyclo[3.2.1]oct-6-yl)propyl]-2-methyl-1,3,4-oxadiazole, whenever pre-pared by the process of Claim 11.
23. 5-[1,1-diphenyl-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole, whenever pre-pared by the process of Claim 12.
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 |
|---|---|
| CA1053672A true CA1053672A (en) | 1979-05-01 |
Family
ID=23814026
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA223,487A Expired CA1053672A (en) | 1974-04-01 | 1975-04-01 | 1,1-diaryl-1-oxadiazol-alkylamines |
| 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 |
Family Applications After (1)
| 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 |
Country Status (26)
| Country | Link |
|---|---|
| US (2) | US3917615A (en) |
| JP (2) | JPS5936631B2 (en) |
| AR (2) | AR206425A1 (en) |
| AT (2) | AT342045B (en) |
| BE (2) | BE827324A (en) |
| CA (2) | CA1053672A (en) |
| CH (2) | CH614205A5 (en) |
| CS (1) | CS194718B2 (en) |
| DE (2) | DE2514183A1 (en) |
| DK (2) | DK137375A (en) |
| EG (1) | EG12104A (en) |
| ES (2) | ES436044A1 (en) |
| FI (2) | FI63572C (en) |
| FR (2) | FR2265367B1 (en) |
| GB (2) | GB1456943A (en) |
| HU (1) | HU170747B (en) |
| IE (2) | IE40895B1 (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) | SE420492B (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 |
| US3998832A (en) * | 1975-04-16 | 1976-12-21 | G. D. Searle & Co. | Anti-diarrheal compounds |
| 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 |
| US4057549A (en) * | 1975-04-16 | 1977-11-08 | G. D. Searle & Co. | Triarylpropyl-azabicyclooctanes |
| US4086227A (en) * | 1975-04-16 | 1978-04-25 | G. D. Searle & Co. | Novel anti-diarrheal 4-azatricyclo[4.3.1.13,8 ] undecane derivatives |
| 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 |
| CN105330538A (en) | 2011-05-27 | 2016-02-17 | 瑞来斯实业有限公司 | Process for esterification by using ionic liquids |
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|---|---|---|---|---|
| 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 |
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1974
- 1974-04-01 US US456755A patent/US3917615A/en not_active Expired - Lifetime
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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 IL IL46959A patent/IL46959A/en unknown
- 1975-03-28 CS CS752162A patent/CS194718B2/en unknown
- 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 FR FR7509996A patent/FR2265376B1/fr not_active Expired
- 1975-03-28 HU HUSE1776A patent/HU170747B/hu 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 IL IL46966A patent/IL46966A/en unknown
- 1975-03-31 JP JP50039024A patent/JPS5939434B2/en not_active Expired
- 1975-03-31 OA OA55456A patent/OA04914A/en unknown
- 1975-03-31 EG EG179/75A patent/EG12104A/en active
- 1975-03-31 PH PH16986A patent/PH11423A/en unknown
- 1975-03-31 ES ES436160A patent/ES436160A1/en not_active Expired
- 1975-03-31 YU YU00816/75A patent/YU39200B/en unknown
- 1975-04-01 CH CH410975A patent/CH614205A5/xx not_active IP Right Cessation
- 1975-04-01 DK DK137375A patent/DK137375A/da not_active Application Discontinuation
- 1975-04-01 GB GB1318675A patent/GB1456943A/en not_active Expired
- 1975-04-01 NO NO751104A patent/NO142174C/en unknown
- 1975-04-01 ZA ZA00751986A patent/ZA751986B/en unknown
- 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 CA CA223,487A patent/CA1053672A/en not_active Expired
- 1975-04-01 DE DE19752514183 patent/DE2514183A1/en not_active Withdrawn
- 1975-04-01 NL NL7503856A patent/NL7503856A/en not_active Application Discontinuation
- 1975-04-01 AT AT245175A patent/AT340916B/en not_active IP Right Cessation
- 1975-04-01 DE DE19752514229 patent/DE2514229A1/en not_active Ceased
- 1975-04-01 CH CH410875A patent/CH613964A5/xx not_active IP Right Cessation
- 1975-04-01 DK DK137275A patent/DK137275A/da not_active IP Right Cessation
- 1975-04-01 NO NO751103A patent/NO142173C/en unknown
- 1975-04-01 PL PL1975179255A patent/PL99553B1/en unknown
- 1975-04-01 FI FI750966A patent/FI61895C/en not_active IP Right Cessation
- 1975-04-01 SE SE7503689A patent/SE420492B/en unknown
- 1975-04-01 CA CA223,485A patent/CA1067498A/en not_active Expired
- 1975-04-01 SE SE7503688A patent/SE420491B/en not_active IP Right Cessation
- 1975-04-01 GB GB13184/75A patent/GB1494943A/en not_active Expired
- 1975-04-01 NL NL7503849A patent/NL7503849A/en not_active Application Discontinuation
- 1975-04-02 IE IE713/75A patent/IE40895B1/en unknown
- 1975-04-02 IE IE712/75A patent/IE40894B1/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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