GB1569249A

GB1569249A – 2-(2,2-diarylalkyl)1-azabicyclo(2.2.2)octane and compounds
– Google Patents

GB1569249A – 2-(2,2-diarylalkyl)1-azabicyclo(2.2.2)octane and compounds
– Google Patents
2-(2,2-diarylalkyl)1-azabicyclo(2.2.2)octane and compounds

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Publication number
GB1569249A

GB1569249A
GB14965/78A
GB1496578A
GB1569249A
GB 1569249 A
GB1569249 A
GB 1569249A
GB 14965/78 A
GB14965/78 A
GB 14965/78A
GB 1496578 A
GB1496578 A
GB 1496578A
GB 1569249 A
GB1569249 A
GB 1569249A
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Prior art keywords
azabicyclol
loctane
acid addition
addition salts
general formula
Prior art date
1977-04-18
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GB14965/78A
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GD Searle LLC

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GD Searle LLC
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1977-04-18
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1978-04-17
Publication date
1980-06-11

1978-04-17
Application filed by GD Searle LLC
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GD Searle LLC

1980-06-11
Publication of GB1569249A
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patent/GB1569249A/en

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Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids

C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring 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

Description

PATENT SPECIFICATION ( 11) 1569249
( 21) Application No 14965/78 ( 22) Filed 17 April 1978 ( 31) Convention Application No 788189 ( 19 ( 32) Filed 18 April 1977 in i ( 33) United States of America (US) ( 44) Complete Specification published 11 June 1980 ( 51) INT CL 3 C 07 D 453/02 A 61 K 31/44 ( 52) Index at acceptance C 2 C 1173 1175 1547 200 214 220 221 225 226 22 Y 246 250 251 Y 29 X 29 Y 30 Y 313 31 Y 338 351 352 386 43 X 47 X 625 699 760 776 77 X 802 80 Y AA TY ZF ( 72) Inventor CHUNG HWAI YEN ( 54) 2-( 2,2-DIARYLALKYL) 1-AZAB ICYCLOl 2 2 2 l OCTANE AND RELATED COMPOUNDS ( 71) We, G D SEARLE & CO, a corporation organised under the laws of the State of Delaware, United States of America, of P O Box 5110, Chicago, Illinois, 60680, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to
be performed, to be particularly described in and by the following statement: 5
This invention relates to 2-( 2,2-diarylalkyl)-l-azabicyclol 2 2 2 loctane and related compounds; more particularly, it relates to certain azabicyclooctane compounds, to processes for the preparation thereof, to pharmaceutical and veterinary compositions containing them and to the use thereof as antidiarrhoeal agents having little or no analgesic activity 10 In one aspct, the present invention provides a compound corresponding to the following general formula (I):
Rll (CH 2)n C RI FII R wherein R and R’, which may be the same or different, each represents a phenyl, a pyridyl, a mono-substituted halophenyl or a mono-substituted alkylphenyl group in 15 which the alkyl radical has from 1 to 4 carbon atoms; R” represents an alkyl radical having from 1 to 8 carbon atoms, an alkenyl radical having from 3 to 6 carbon atoms, a cycloalkyl radical having from 3 to 6 carbon atoms, a cycloalkyl alkyl radical in which the cycloalkyl moiety has from 3 to 6 carbon atoms and the alkyl moiety has from 1 to 3 carbon atoms or a cycloalkenyl radical having from 4 to 7 20 carbon atoms; and N represents an integer of from 1 to 3; and acid addition salts thereof.
The halo substituents included within the scope of above general formula (I) are fluoro, chloro, bromo and iodo atoms.
The alkyl radicals included within the scope of above general formula (I) are 25 exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and, where appropriate, the corresponding branched isomers thereof.
The alkenyl radicals included within the scope of above general formula (I) are exemplified by butenyl, propenyl, pentenyl, hexenyl and the corresponding branched isomers thereof 30 The cycloalkyl radicals included within the scope of above general formula (I) are exemplified by cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The cycloalkenyl radicals are exemplified by cyclobutenyl, cyclopentenyl and cyclohexenyl.
The point of attachment of the halo or alkyl substituent in the compounds 35 corresponding to above general formula (I) when R and/or R’ represents a monosubstituted halophenyl or mono-substituted alkylphenyl is not critical Thus, the substituent may be in an ortho, meta or para position.
Preferred compounds according to the present invention are those corresponding to above general formula (I) wherein R and R’ each represents a phenyl group; R” prepresents an alkyl radical having from 1 to 8 carbon atoms; and n represents 1 2 ( 2,2 diphenyl pentyl) 1 azabicyclol 2 2 2 loctane, 2 ( 2,2 diphenylhexyl) 1 azabicyclol 2 2 2 loctane, 2( 2,2 diphenylpropyl) I 5 azabicyclol 2 2 2 loctane, 2 ( 2,2 diphenyloctyl) 1 azabicyclol 2 2 2 loctane and 2 ( 2,2 diphenylheptyl) I azabicyclol 2 2 2 loctane are particularly preferred.
Other preferred compounds according to the present invention are those corresponding to above general formula (I) wherein R and R’ each represents a 10 phenyl group; R” represents an alkenyl radical having from 3 to 6 carbon atoms; and N represents 1 2 ( 2,2 diphenylpent 4 enyl) 1 azabicyclol 2 2 2 loctane and 2 ( 5 methyl 2,2 diphenylhex 4 enyl) 1 azabicyclol 2 2 2 loctane are particularly preferred.
Further preferred compounds according to the present invention are those 15 corresponding to above general formula (I) wherein R and R’ each represents a phenyl group; R” represents a cycloalkyl radical having from 3 to 6 carbon atoms; and N represents 1 2 ( 2 cyclopentyl 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane maleate ( 1:1) and 2 ( 2 cyclohexyl 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane are particularly preferred 20 Another class of preferred compounds according to the present invention are those corresponding to above general formula (I) wherein R and R’ each represents a phenyl group; R” represents a cycloalkenyl radical having 3 to 6 carbon atoms; and N represents 1 2 ( 2 cyclohexenyl 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane is particularly preferred 25 Equivalent to the organic bases corresponding to above general formula (I) are the acid addition salts which are formed by the addition of a variety of organic acids and inorganic acids to the free base Such salts are formed with acids, such as sulphuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulphamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic and 30 ascorbic acids.
Acid addition salts which are not pharmaceutically or veterinarily acceptable may be so rendered by conventional metathetical reactions.
The compounds corresponding to above general formula (I), the pharmaceutically or veterinarily acceptable acid addition salts and pharmaceutical 35 or veterinary compositions containing them are useful in consequence of the valuable pharmacological properties thereof They are, for example, potent antidiarrhoeal agents as evidenced by the ability thereof to inhibit gastrointestinal motility as set out in the following tests:
Mouse Cecal Test 40 The method used for this assay is a modification of the techniques previously described by Macht and Barba-Gose, J Amer Pharm Ass, 20, 558 ( 1931), and Janssen and Jageneau, J Pharm Pharmacol, 9, 381 ( 1957) Details are as follows:
A group of six, male Charles River mice weighing from 20 to 25 g which have previously been fasted for 24 hours, are pretreated with the test compounds 45 administered orally either as a solution in water or suspended in O 5 % methyl cellulose A constant volume of 10 ml /kg is employed Thirty minutes after administration of the test compounds, the animals are given a single oral dose of charcoal which consists of 0 2 ml of 10 % charcoal suspended in 1 0 % methyl cellulose per mouse Three and half hours after charcoal administration, the 50 animals are sacrificed and the cecum is examined for the absence or presence of charcoal on an all-or-nothing basis.
The median effective dose (ED 50) is then calculated for each compound using the logistic method of Berkson ( 1953).
The median effective dose + Standard Error (ED 5 o+SE) for the following 55 representative compounds according to the present invention in the Mouse Cecal Test are 1,569,249 E Dso+S E.
mg/kg, IG 2-( 2,2-diphenyloctyl) 1 azabicyclol 2 2 21 octane maleate 20 67 _ 12 3 2-( 2,2-diphenylheptyl)1 azabicyclol 2 2 2 loctane maleate 5 84 + 1 94 2-( 2,2-diphenvlhexvl) 1azabicyclol 2 2 21 octane 8 74 + 3 95 2-( 2,2-diphenylpropyl) 1 1 O azabicyclol 22 21 octane 43 10 _ 15 54 10 2-( 5-methyl-2,2-diphenylhexazabicyclol 2 2 2 loctane 1 45 0 66 2-( 2,2-diphenyl-4-pentenyl) 1 4-enyl)1 -azabicyclol 2 2 2 l octane 1 82 0 45 Diphenoxylate À HCI (standard) 312 + 1 29 15 Castor Oil-Induced Diarrhoea in the Rat Adult Charles River male rats are fasted in community cages for 24 hours prior to the test, with free access to water The test compound is then administered intragastrically (suspended on 0 5 % methyl cellulose) one hour prior to the intragastric administration of a dose of 1 0 ml castor oil per rat The rats are then 20 observed for the presence or absence of diarrhoea at hourly intervals for up to 8 hours past the castor oil administration Using the method of Berkson ( 1953), the median effective dose (E Dso) values are calculated at each hourly interval for the test compound.
The median effective dose at 2 hours past the castor oil administration for the 25 following representative compounds according to the present invention in the castor oil-induced diarrhoea in the rat test are:
E Dso S E.
mg/kg IG 2-( 2,2-diphenylheptyl)1azabicyclol 2 2 2 loctane maleate 10 18 + 1 43 30 2-( 2,2-diphenylhexyl) 1 azabicyclol 2 2 21 octane 4 57 + 0 21 2-( 5-methyl-2,2-diphenylhex-4enyl) l-azabicyclol 2 2 2 loctane 1 74 + 0 53 2-( 2,2-diphenyl-4-pentenyl)1 35 azabicyclol 2 2 2 loctane 1 13 + 0 18 The compounds according to the present invention advantageously demonstrate little or no analgesic activity at the test doses The assessment of this activity is conducted by the following assay: 40 Tail Clip Test A special clip is applied to the base of the tail of the mouse 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 45 administered and the response to placement of the clip is determined at 30, 60, 90 and 120 minutes after treatment A response is considered positive if the animal takes more than twice 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 50 Mouse Hot Plate Test A mouse 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 5 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 posttreatment times A dose of test compound is considered active when 50 percent or more of the animals used show a positive response.
1,569,249 Compounds according to the present invention may be prepared by treating a compound corresponding to the following general formula (VI):
(dl) (C H 2)n H C R (RVT) N R wherein R and R’, which may be the same or different, each represents a phenyl, a pyridyl, a monosubstituted halophenyl, or a monosubstituted alkylphenyl group in 5 which the alkyl radical has from 1 to 4 carbon atoms; and N represents an integer of from 1 to 3; first with a strong base, such as n-butyl lithium, and optionally with N,N,N,’N’-tetramethylethylenediamine (TMEDA) and then with a compound corresponding to the following general formula (VII):
R”X (VII) 10 wherein RW represents an alkyl radical having 1 to 8 carbon atoms, an alkenyl radical having from 3 to 6 carbon atoms, a cycloalkyl radical having from 3 to 6 carbon atoms, a cycloalkyl alkyl radical in which the cycloalkyl moiety has from 3 to 6 carbon atoms and the alkyl moiety has from 1 to 3 carbon atoms or a cycioalkenyl radical having from 4 to 7 carbon atoms; and X represents chloro, 15 bromo or iodo The optional addition of N,N,N’,N’tetramethylethylenediamine to the reaction mixture general results in better yield of the desired compound.
Accordingly, the present invention also provides a process for the preparation of a compound corresponding to the above general formula (I) and acid addition salts thereof which comprises treating a compound corresponding to the following 20 general formula (VI):
(dl) (CH 2)n CH R’ () R wherein R, R’ and N are as defined above; with a strong base, optionally in the presence of N,N,N’,N’-tetramethylethylenediamine, and then with a compound corresponding to the following general formula (VII): 25 R”X (VII) wherein R” is as defined above; and X represents an iodine, a chlorine or a bromine atom.
The compounds corresponding to above general formula (VI) may be prepared according to the procedure illustrated by scheme (A) below wherein R and R’ are 30 as defined above:
1,569,249 SCHEME A O R’ H -C-H R (IL) Me OH A KOH R KOH + HCI (IE) C-=C H i R (T Va) trans (EV b) cis and R’-CH-CH X and R R (J Vc) trans (Cd) cis Et OH 50/o Pd/CH 2 H 2 NNH 2 H 20 KOH KOH (dl) Rm-CH-C 2 R (v) (dl) R’ CH CH 2, RN By way of illustration, the first step of Scheme A is shown as the condensation of diphenylacetaldehyde with l-azabicyclol 2 2 2 loctan 3 one This reaction is conveniently conducted in an organic solvent, a particularly preferred solvent being methanol This reaction produces a mixture of isomers illustrated by general formulae (IV)(a)-(IV)(d) which when subjected to catalytic hydrogenation, produce the 2 ( 2,2 diarylethyl) 1 azabicyclol 2 2 2 loctan 3 ones corresponding to general formula (V).
The oxo group of the compound corresponding to general formula (V) is then reduced using a hydrazine hydrate and a base according to the WolffKishner method.
1,569,249 Scheme A illustrates the preparation of compounds and acid addition salts thereof corresponding to general formula (I) wherein R, R’, and R’ are as defined above; and N represents 1 It would be obvious to one skilled in the art that Scheme A also serves to illustrate the preparation of compounds corresponding to general formula (I) wherein N represents 2 or 3 by beginning with the appropriate starting 5 material in order to obtain the desired compounds.
Examples I and 2 illustrate the preparation of starting materials for the purposes of the present invention Examples 3 to 21 describe in more detail the preparation of compounds according to the present invention (Throughout the Examples, temperatures are given in degrees Centigrade (“C) and relative amounts 10 in parts, by weight, unless parts, by volume, is specified The relationship between parts, by weight, and parts, by volume, is the same as that existing between grams and millilitres) Example 1
64 8 parts of 1 azabicyclol 2 2 2 loctan 3 one hydrochloride and 100 parts 15 of diphenylacetaldehyde were suspended in 600 parts, by volume, of methanol and heated to boiling to form a solution 40 0 parts of potassium hydroxide in 200 parts, by volume, of hot methanol was then added with stirring The hot solution was filtered and the solid which was collected was rinsed with 100 parts by volume, of methanol The filtrate was diluted with 1000 parts, by volume, of toluene and this 20 mixture was distilled until 1660 parts, by volume, of distillate was collected and a head temperature of 1000 C was reached The pot residue was then diluted with 500 parts, by volume, of xylene, heated to reflux under a Dean-Stark collector for 40 minutes, cooled to room temperature and the brown gum was removed by filtration The filtrate was decanted from the gummy precipitate which formed 25 during standing, washed with water and dried over anhydrous sodium sulphate.
Removal of the solvent under reduced pressure afforded an oily residue which was dissolved in 180 parts, by volume, of ethyl ether The vessel containing the solution was then scratched to induce crystallization The resulting crystals were filtered, washed with diethyl ether and air-dried to give a first crop melting at from 141 to 30 1490 C Reducing the volume of the mother liquor to 100 parts, by volume, diluting it with 15 parts, by volume, of n-pentane and subsequently cooling provided a second crop of crystals, melting at from 110 to 11 1 C Both crops of crystals were mixtures containing various amounts of the two isomers (cis and trans) of 2 ( 2,2 diphenylethylidenyl) 1 azabicyclol 2 2 2 loctan3 one and 2 ( 2,2 35 diphenylethenyl) 1 azabicyclol 2 2 2 loctan 3 one.
Example 2
25.7 parts of a mixture of the isomers (cis and trans) of 2 ( 2,2 diphenylethylidenyl) 1 azabicyclol 2 2 2 l octan 3 one and 2 ( 2,2 diphenylethenyl) 1 azabicyclol 2 2 21 octan 3 one was dissolved in 1000 40 parts, by volume, of ethanol Then, 5 parts of 5 % palladium-on-carbon was added and the mixture was hydrogenated using a Parr low-pressure hydrogenator, at room temperature and at a pressure of from 60 to 30 psi for 4 hours After the hydrogenation was completed, the catalyst was removed by filtration The solution was then stripped in vacuum to give a solid which was dissolved in 500 parts, by 45 volume, of hot diethyl ether The solution was filtered and then concentrated on a steam bath to about 150 parts, by volume The concentrated solution was cooled in an ice-bath to afford a precipitate which was filtered off from the solvent, washed with cold ethyl ether and dried in vacuo to provide a white solid This solid was recrystallized from ethyl ether to afford 2 ( 2,2 diphenylethyl) 1 50 azabicyclol 2 2 2 loctan 3 one melting at from 103 to 1070 C.
Example 3
9.3 parts of 2 ( 2,2 diphenylethyl I azabicyclol 2 2 2 loctan 3 one, 1 3 parts of potassium hydroxide, 3 6 parts, by volume, of an 85 % solution of hydrazine in water and 59 parts diethylene glycol were refluxed together, with stirring, under 55 a nitrogen atmosphere for 2 75 hours Stirring and heating were then discontinued and the reaction mixture was allowed to stand overnight The mixture was then heated to distill under a nitrogen atmosphere until a head temperature of 2350 C.
was reached After cooling to room temperature, the mixture was partitioned between 900 parts, by volume, of 5 % sodium chloride solution and two 600 parts, by 60 volume, portions of ethyl ether The ethereal extracts were combined, washed with water, dried over anhydrous sodium sulphate and stripped in vacuo to give a 1,569,249 residual oil which solidified upon standing This solid was dissolved in 300 parts, by volume, of hot n-pentane and the solution was then concentrated on a steam bath to 45 parts, by volume, and cooled to room temperature to give a solid precipitate which was filtered off, washed with n-pentane and dried in vacuo to give a white solid 2 ( 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane, melting at from 87 5 to 5 89 C.
The white solid was dissolved in 100 parts, by volume, of dry ethyl ether and treated with an excess of a solution of hydrogen chloride in isopropanol The gum which precipitated solidified and was filtered off and washed with ethyl ether.
Recrystallization from a mixture of ethanol and ethyl ether afforded 2 ( 2,2 10 diphenylethyl) 1 azabicyclol 2 2 2 loctane hydrochloride melting at from 218 to 221 C.
Example 4
To a solution of 2 91 parts of 2 ( 2,2 diphenylethyl) I azabicyclol 2 2 2 loctane in 40 parts, by volume, of cyclohexane under a nitrogen 15 atmosphere was added 5 1 parts, by volume, of a 2 17 M solution of butyl lithium in hexane and 1 15 parts of TMEDA (N,N,N’,N’ tetramethylethylenediamine) This solution was then stirred under reflux for 1 25 hour The resulting brickred mixture was cooled in an ice-bath Then, 2 01 parts of n-butyl iodide was added and the solution was stirred without cooling for 18 hours A yellow mixture containing a 20 solid resulted and this was then washed with 5 portions of water and extracted with dilute hydrochloric acid This extraction resulted in the formation of three phases:
water, oil and cyclohexane The cyclohexane phase was siphoned off The aqueous phase and the oil phase were combined, washed with cyclohexane, treated with excess aqueous sodium hydroxide and extracted with ethyl ether The ethereal 25 extract was dried over anhydrous sodium sulphate and then stripped in vacuo to give a brown oil This brown oil was then chromatographed using neutral silica gel as the column adsorbent and a solvent mixture of benzene-ethanolconcentrated ammonium hydroxide ( 97:3:1/4) as the eluant The desired fractions were combined and stripped in vacuo to give an oil This oil was taken up in ethyl ether and 30 extracted with dilute hydrochloric acid Basifying the acidic extract with aqueous sodium hydroxide liberated another oil.
This oil was then extracted with ethyl ether and the ethereal extract was dried over sodium sulphate and stripped in vacuo to give an oil This oil was taken up in npentane and the solution was filtered to remove any trace of undissolved material 35 Evaporation of the filtrate left an oil which solidified upon standing The solid was dried in vacuo to give a white solid which is 2 ( 2,2 diphenylhexyl) 1 azabicyclol 2 2 2 loctane This compound melts at from 68 to 72 C.
Example 5
To a solution of 2 9 parts of 2 ( 2,2 diphenylethyl) I 40 azabicyclol 2 2 2 loctane in 40 parts, by volume, of cyclohexane were added under a nitrogen atmosphere 4 6 parts, by volume, of a 2 5 M solution of butyl lithium in hexane and 1 5 parts, by volume, of N,N,N’,N’-tetramethylethylenediamine The mixture was heated to reflux, with stirring, for 1 2/3 hours and then cooled to room temperature 1 45 parts of 3-bromopropene was then added during a 5-second 45 period Stirring was continued for about 6 minutes during which time the internal temperature reached a maximum of 43 C and then subsided The resulting yellow mixture was washed with seven portions of water and then extracted with dilute hydrochloride acid The acidic, aqueous extract was washed with ethyl ether and then basified with aqueous sodium hydroxide resulting in the liberation of an oil 50 This oil was extracted with ethyl ether and the ethereal extract was dried over anhydrous sodium sulphate and stripped in vacuo to give a light brown oil This oil was crystallized from methanol and water to afford as a white solid, 2 ( 2,2 diphenyl 4 pentenyl) I azabicyclol 2 2 2 l octane melting at from 95 5 to 98 C 55 Example 6
0.50 parts of 2 ( 2,2 diphenyl 4 pentenyl) I azabicyclol 2 2 21 loctane was dissolved in 50 parts, by volume, of ethanol This solution was then added to a Parr hydrogenation bottle which contained 0 05 parts of 5 O/ palladium-oncarbon.
The mixture was hydrogenated at room temperature and atmospheric pressure 60 using a 50 ml burette to measure hydrogen uptake After the hydrogenation was 1,569,249 completed, the catalyst was removed by filtration The solution was then stripped in vacuo to afford a gum Crystallization of this gum from methanol/water afforded a white solid which was dried in vacuo at 60 C for 4 hours to give 2 ( 2,2 diphenylpentyl) 1 azabicyclof 2 2 2 loctane This compound melts at from 115 to 117 5 C The compound was then dissolved in ethyl ether and the resulting ethereal 5 solution was treated with HCI/iso Pr OH solution The solid which precipitated was filtered, washed with ethyl ether and dried in vacuo to give 2 ( 2,2diphenylpentyl) I azabicyclol 2 2 21 octane hydrochloride melting at from 222 5 to 225 5 C.
Example 7 10
To a solution of 1 46 parts of 2 ( 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane in 20 parts, by volume, of cyclohexane was added under a nitrogen atmosphere 2 4 parts, by volume, of 2 5 M solution of n-butyl lithium The mixture was heated with stirring at reflux temperature for one hour After cooling this mixture to O C, 0 58 part of idomethane was added, and the reaction mixture 15 was then stirred at room temperature for 18 hours The resulting yellow mixture which contained a white solid and a gum was diluted with 100 parts, by volume, of ethyl ether and then washed with water The cyclohexane-ethyl ether layer, excluding the gum, was extracted with dilute hydrochloric acid The acidic, aqueous extract was basified with aqueous sodium hydroxide resulting in the 20 liberation of an oil This mixture was then extracted with ether The ethereal extract was dried over anhydrous sodium sulphate and stripped in vacuo to give an oil which is crude 2 ( 2,2 diphenylpropyl) I azabicyclol 2 2 21 octane This oil was then dissolved in ethyl ether Treating this ethereal solution with an H Cl/iso Pr OH solution resulted in the precipitation of a gum This gum was rinsed 25 with ethyl ether and then dissolved in acetone The acetone solution was concentrated and then cooled to induce crystallization The resulting crystals were filtered, washed with acetone and dried in vacuo to give 2 ( 2,2 diphenylpropyl) 1 azabicyclol 2 2 21 octane hydrochloride melting at from 261 to 264 C.
Example 8 30
Following the procedure described in Example 4, 2 91 parts of 2 ( 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane in 40 parts, by volume, of cyclohexane and 5 1 parts, by volume, of a 2 17 M solution of butyl lithium in hexane were reacted with 1 5 parts of TMEDA and 1 81 parts of n-hexyl bromide to provide 2 ( 2,2 diphenyloctyl) 1 azabicyclol 2 2 2 loctane This compound was then 35 treated with 0 730 parts of maleic acid to give 2 ( 2,2 diphenyloctyl) 1 azabicyclol 2 2 2 loctane maleate melting at from 180 to 181 C.
Example 9
Following the procedure described in Example 4, 2 91 parts of 2 ( 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane in 40 parts, by volume, of cyclohexane 40 and 5 1 parts, by volume, of a 2 17 M solution of n-butyl lithium in hexane were reacted with 1 5 parts, by volume, of TMEDA and 1 65 parts of 1bromopentane to provide 2 ( 2,2 diphenylhepty) 1 azabicyclol 2 2 2 loctane This compound was then treated with 0 570 parts of maleic acid to give 2 ( 2,2 diphenylheptyl) 1 azabicyclol 2 2 2 loctane maleate melting at from 177 to 178 5 C 45 Example 10
2.04 parts of 2 ( 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane and 3 6 parts, by volume, of a 2 17 M solution of n-butyl lithium in hexane were dissolved in parts, by volume, of dry cyclohexane This solution was refluxed with stirring under a nitrogen atmosphere for 1 hours and then cooled in an ice-bath To this 50 cooled mixture was added, with stirring, 1 16 parts of 1 bromo 3 methyl 2 butene The cooling bath was removed and the mixture was stirred at ambient temperature for 18 hours The resulting yellow-coloured mixture containing solid was washed with water and then extracted with diluted hydrochloric acid The acidic aqueous extract was basified with aqueous sodium hydroxide resulting in the 55 liberation of an oil This oil was then extracted with ethyl ether and the ethereal extract was dried over anhydrous sodium sulphate and stripped in vacuo to give a gum This gum was then chromatographed using neutral silica gel as the column adsorbent and a solvent mixture of benzene-ethanol-concentrated ammonium hydroxide ( 98:2:1/2) as the eluant The desired fractions from the chromatography 60 were combined and stripped in vacuo to leave a residue This residue was dissolved 1,569,249 in n-pentane and the solution was then washed with dilute potassium carbonate, dried over sodium sulphate and evaporated to give an oil which is 2 ( 5 methyl 2,2 diphenylhex 4 enyl) 1 azabicyclol 2 2 2 loctane This compound was then reacted with hydrogen chloride in dioxane to give ( 2 ( 5 methyl 2,2 diphenylhex 4 enyl) 1 azabicyclol 2 2 2 loctane hydrochloride The crude 5 product melts at from 118 to 130 C.
Example 11
To a solution of 2 91 parts of 2 ( 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane in 40 parts, by volume, of cyclohexane, was added, under a nitrogen atmosphere, 5 1 parts, by volume, of 2 17 M solution of n-butyl lithium in 10 hexane and 1 15 parts of TMEDA This solution was then stirred under reflux for 1 hour The resulting brick-red mixture was cooled in an ice-water bath Then, 1 64 parts of bromocyclopentane was added and the solution was stirred for 18 hours at room temperature After this time, a brown-yellow mixture resulted This mixture was washed with 7 portions of water and extracted with dilute hydrochloric acid 15 The acidic extract which contained a small amount of solid was basified with aqueous sodium hydroxide resulting in the formation of a gum This gum was extracted with ethyl ether The ether extract was dried over sodium sulphate and then stripped in vacuo to give a gum The gum was then chromatographed using neutral silica gel as the column absorbent and a solvent mixture of benzene 20 ethanol-ammonium hydroxide ( 96:4:1/4) as the eluant The desired fractions from the chromatography were combined and stripped in vacuo to leave an oil This oil was dissolved in ethyl ether and the ethereal extract was extracted with dilutehydrochloric acid The acidic extract which contained a fine solid was basified with aqueous sodium hydroxide and extracted with ethyl ether The ethereal extract was 25 washed with sodium chloride, dried over sodium sulphate, and stripped in vacuo to give a gum which is 2 ( 2 cyclopentyl 2,2 diphenylethyl) 1 azabicyclol 2 2 21 octane 1 40 parts of this gum and 0 460 parts of maleic acid were dissolved in 5 parts of methanol Diluting this solution with 10 parts of ether and seeding resulted in the formation of crystals These crystals were then 30 recrystallized from ethyl acetate to give 2 ( 2 cyclopentyl 2,2 diphenylethyl) 1 azabicyclol 2 2 21 octane maleate ( 1:1) This compound melts at from 196 to 198 C.
Example 12
To a solution of 2 91 parts of 2 ( 2,2 diphenylethyl) 1 35 azabicyclol 2 2 2 loctane in 40 parts, by volume, of hexane was added, under a nitrogen atmosphere, 5 1 parts, by volume, of a 2 17 M solution of nbutyl lithium in hexane and 1 15 parts of TMEDA This solution was then stirred at reflux, under a nitrogen atmosphere, for 1 hour The resulting deep red solution was cooled to room temperature and then placed in an ice-water bath which resulted in the 40 formation of a red gummy precipitate To this mixture was added 1 93 parts of 3bromocyclohexene This mixture was stirred for 25 minutes in a cooling bath After the 25 minute period, the cooling bath was removed and the mixture was allowed to stir for an additional 10 minutes The mixture was washed with five portions of water and then extracted with dilute hydrochloric acid which resulted in the 45 formation of an emulsion The emulsion was made basic with aqueous sodium hydroxide and the organic layer was dried over sodium sulphate and stripped in vacuo to give a gum This gum was taken up in ether and the ethereal extracts were extracted with dilute hydrochloric acid The acidic extracts were then basified with aqueous sodium hydroxide which resulted in the formation of an oil This oil was 50 extracted with ether These ethereal extracts were washed with water, dried over sodium sulphate and stripped in vacuo to give a gum which contains 2 l 2 ( 2 cyclohexenyl) 2,2 diphenylethyll 1 azabicyclol 2 2 2 loctane.
Example 13
Substantial repetition of the procedure detailed in Example 11 using an 5 equivalent quantity of cyclohexylbromide for the bromocyclopentane of Example 11 afforded 2 ( 2 cyclohexyl 2,2 diphenylethyl) I azabicyclol 2 2 2 loctane Treatment of this material with maleic acid again following the procedure detailed in Example 11 afforded 2 ( 2 cyclohexyl 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane maleate ( 1:1) melting at from 134 5 to 60 1360 C.
1,569,249 1,569,249 10 Example 14
Repetition of the procedure detailed in Examples 1, 2 and 3 using an equivalent quantity of bis( 4-chlorophenyl)acetaldehyde lprepared according to the procedure detailed in J Med Chem, 11 ( 2) 380-382 ( 1968)l in place of the diphenylacetaldehyde afforded 2 l 2,2 bis( 4 chlorophenyl)ethyll I 5 azabicyclol 2 2 2 l octane.
Example 15
Substitution of an equivalent quantity of 2 l 2,2 bis( 4 chlorophenyl)ethyll I azabicyclol 2 2 2 loctane in the procedure of Example 4 afforded 2 l 2,2 bis( 4 chlorophenyl) hexyll 1 azabicyclol 2 2 2 loctane 10 Substitution of an equivalent quantity of 2 l 2,2 bis( 4 chlorophenyl)ethyll 1 azabicyclol 2 2 2 loctane in the procedure of Example 5 afforded 2 l 2,2 bis( 4 chlorophenyl) 4 pentenyll 1 azabicyclol 2 2 2 l octane.
Example 16 15
Repetition of the procedures of Examples 1, 2 and 3 using an equivalent quantity of bis( 4 methylphenyl) acetaldehyde lprepared according to the procedure detailed in U S S R 173,783, CA 64:2005 al in place of the diphenylacetaldehyde afforded 2 l 2,2 bis( 4 methylphenyl)ethyll 1 azabicyclol 2 2 2 loctane 20 Example 17
Substitution of an equivalent quantity of 2 l 2,2 bis( 4methylphenyl)ethyll 1 azabicyclol 2 2 2 loctane for the 2 ( 2,2diphenylethyl) I azabicyclol 2 2 2 loctane of Example 11 and repetition of the procedure which is described in Example 11 afforded 2 l 2 cyclopentyl 2,2 25 bis( 4 methylphenyl)ethyll 1 azabicyclol 2 2 2 loctane.
Example 18
To a solution of 1 6 parts of 2 ( 2,2 diphenylethyl) I azabicyclol 2 2 2 loctane in 20 parts, by volume, of cyclohexane were added under a nitrogen atmosphere 2 8 parts, by volume, of a 2 17 M solution of n-butyl lithium in 30 hexane and 0 83 parts, by volume, of N,N,N’,N’-tetramethylethylenediamine.
Heating this mixture under reflux, with stirring, for one hour under a nitrogen atmosphere resulted in the formation of a deep red solution Cooling of this solution in an ice-bath resulted in the formation of a solid To this mixture was added, dropwise, cyclopropylmethyl bromide The resulting mixture was stirred at 35 ambient temperature overnight and was then diluted with 30 parts, by volume, of cyclohexane, washed with seven portions of water and dried over sodium sulphate.
The solution was stripped in vacuo to give a tan oil The tan oil was chromatographed using neutral silica gel as the column adsorbent and a solvent mixture of benzene-ethanol-ammonium hydroxide ( 96:4:1/4) as the eluant The 40 desired fractions were combined and stripped in vacuo to give a white solid This solid was then dissolved in ethyl ether and treated with an excess of 7 N HC/iso Pr OH which caused the formation of a gummy precipitate The mixture was stripped in vacuo to give a mixture of solid and gum This mixture was then triturated with 10 parts of ether until all the gum solidified The resulting solid was 45 filtered off, washed with ether and air-dried The solid was then recrystallized from ethyl acetate to give 2 ( 3 cyclopropyl 2,2 diphenylpropyl) I azabicyclol 2 2 2 loctane hydrochloride melting at from 224 to 226 C.
Example 19
Substitution of an equivalent quantity of n-propyl bromide for n-butyl iodide 50 used in Example 4 afforded, by the procedure detailed therein, 2 ( 2,2diphenylpentyl) 1 azabicyclol 2 2 2 loctane, which is identical to the compound obtained in Example 6.
Example 20
Substitution of an equivalent quantity of isopropyl bromide for iodomethane 55 used in Example 7 afforded, by the procedure detailed therein, crude 2 ( 3 methyl 2,2 diphenylbutyl) I azabicyclol 2 2 2 loctane and 2 ( 3 methyl 2,2 diphenylbutyl) I azabicyclol 2 2 2 loctane hydrochloride.
Example 21
Substitution of an equivalent quantity of ethyl bromide for iodomethane called for in Example 7 afforded, by the procedure detailed therein, crude 2 ( 2, 2 diphenylbutyl) I azabicyclol 2 2 2 loctane and 2 ( 2,2 diphenylbutyl) 1 ‘ azabicyclol 2 2 2 loctane hydrochloride 5 Example 22
Pharmaceutical and veterinary compositions were prepared in the following manner with amounts indicating the relative amounts per tablet, capsule, suppository or parenteral product.
Tablet 10 mgs of 2 ( 2,2 diphenyl 4 pentenyl) 1 azabicyclol 2 2 2 loctane was dissolved in isopropyl alcohol and distributed on 82 2 mgs of lactose The mixture is air-dried and passed through a 40 mesh screen 24 mgs of corn starch and 3 2 mgs of polyvinylpyrrolidone were added to the drug substance-lactose mixture, mixed thoroughly and passed through a 40 mesh screen The mixture was then 15 granulated with isopropyl alcohol, spread on trays and dried at 49 C for 16 hours.
The dried granulation was then screened The granules were mixed thoroughly with 0.6 mgs of magnesium stearate and the mixture compressed into tablets of the appropriate size There was thus obtained a tablet having a concentration of active ingredient of 10 mgs 20 Capsule mgs of 2 ( 2,2 diphenyl 4 pentenyl) 1 azabicyclol 2 2 2 l 1 octane was mixed thoroughly with 113 75 mgs of corn starch and 113 75 mgs of lactose, screened through a 40 mesh screen and remixed 12 5 mgs of talc were added and the mixture was thoroughly mixed and filled into the appropriate hard gelatin 25 capsule by hand or machine using 250 mgs fill per capsule There was thus obtained a capsule having a concentration of active ingredient of 10 mgs.
In the preparation of tablets and capsules from the compounds corresponding to above general formula (I) and pharmaceutically or veterinarily acceptable acid addition salts thereof, a variety of excipients diluents or carriers may be used 30 These are summarized as follows: sugars, such as lactose, sucrose, mannitol or sorbitol; starches, such as corn starch, tapioca starch or potato starch; cellulose derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose or methyl cellulose; gelatin; calcium phosphates, such as dicalcium phosphate or tricalcium phosphate; sodium sulphate; calcium sulphate; polyvinylpyrrolidone; polyvinyl 35 alcohol; stearic acid, alkaline earth metal stearates, such as magnesium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil or corn oil; surfactants (non-ionic, cationic or anionic); ethylene glycol polymers; beta-cyclodextrin; fatty alcohols, hydrolyzed cereal solids; as well as other nontoxic compatible fillers, binders, disintegrants, and lubricants commonly used in 40 pharmaceutical or veterinary formulations.
Parenteral Products I mg of 2 ( 2,2 diphenyl 4 pentenyl) 1 azabicyclol 2 2 2 loctane was dissolved in 0 5 ml of ethanol and 5 0 ml of sesame oil, filtered and filled into an ampoule and sealed The ampoule was then sterilized by an appropriate procedure 45 There was thus obtained an ampoule having a concentration of active ingredient, 1 mg/5 ml.
In the preparation of parenteral products from the compounds corresponding to above general formula (I) and the pharmaceutically or veterinarily acceptable salts thereof a variety of vehicles and solubilizers may be used Examples of these 50 are summarized as follows: vegetable oils, such as peanut, corn, cottonseed or sesame oil, benzyl alcohol, saline, phosphate buffer, water, ethylene glycol polymers, urea, dimethylacetamide, “Triton”, (Registered Trade Mark), dioxolanes, ethyl carbonate, ethyl lactate, glycerol formal, isopropyl myristate, ‘5 surfactants (non-ionic, cationic or anionic), polyhydricalcohols and ethanol 55 Suppository 990 mgs of cocoa butter were melted, preferably on a water or steam bath to avoid local overheating; then 10 mgs of 2 ( 2,2 diphenyl 4 pentenyl) I azabicyclol 2 2 2 loctane was either emulsified or suspended in the melt Finally, the 1,569,249 -mass was poured into cooled metal moulds, which were chrome plated, and the suppository was readily solidified The total weight of the suppository is 1000 mg.
In the preparation of suppositories from the compounds according to lhe present invention a variety of vehicles and bases for suppository application may be used Examples of these are summarized as follows: triglycerides of oleic, palmitric 5 and stearic acids (cocoa butter), partially hydrogenated cottonseed oil, branchea saturated fatty alcohols, such as Suppository base G, hydrogenated coconut oil triglycerides of Cz-C 1 t fatty acids, water-dispersible vehicles, such as the polyethylene glycols, glycerin, gelatin, polyoxyl 40 stearates and polyethylene 4 sorbitan mono-stearates, also materials which may raise the melting point of the 10 suppository base, such as beeswax and spermaceti.
It will be understood that any of the compounds corresponding to above general formula (I) or pharmaceutically or veterinarily acceptable salts thereof or mixtures thereof, may be used in the compositions according to the present invention 15

Claims (1)

WHAT WE CLAIM IS:-
1 A compound corresponding to the following general formula (I):
Ru II 0 (CH 2)n-C-Rl C R (I) R wherein R and R’, which may be the same or different, each represents a phenyl, a pyridyl, a monosubstituted halophenyl or a mono-substituted alkylphenyl group in 20 which the alkyl radical has from 1 to 4 carbon atoms; R” represents an alkyl radical having from 1 to 8 carbon atoms, an alkenyl radical having from 3 to 6 carbon atoms, a cycloalkyl radical having from 3 to 6 carbon atoms, a cycloalkyl alkyl radical in which the cycloalkyl moiety has from 3 to 6 carbon atoms and the alkyl moiety has from I to 3 carbon atoms or a cycloalkenyl radical having from 4 to 7 25 carbon atoms; and N represents an integer of from I to 3; and acid addition salts thereof.
2 2 ( 2,2 diphenyloctyl) 1 azabicyclol 2 2 2 loctane and acid addition salts thereof.
3 2 ( 2,2 diphenylheptyl) 1 azabicyclol 2 2 2 loctane and acid addition 30 salts thereof.
4 2 ( 2,2 diphenylhexyl) 1 azabicyclol 2 2 2 loctane and acid addition salts thereof.
2 ( 2,2 diphenylpropyl) I azabicyclol 2 2 2 loctane and acid addition salts thereof 35 6 2 ( 2,2 diphenylpentyl) 1 azabicyclol 2 2 2 loctane and acid addition salts thereof.
7 2 ( 2,2 diphenyl 4 pentenyl) 1 azabicyclol 2 2 2 loctane and acid addition salts thereof.
8 2 ( 5 methyl 2,2 diphenylhex 4 enyl) 1 azabicyclol 2 2 2 loctane 40 and acid addition salts thereof.
9 2 ( 2 cyclopentyl 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane and acid addition salts thereof.
2 ( 2 cyclohexyl 2,2 diphenylethyl) 1 azabicyclol 2 2 2 loctane and acid addition salts thereof 45 11 2 ( 3 cyclopropyl 2,2 diphenylpropyl 1 azabicyclol 2 2 2 loctane and acid addition salts thereof.
12 2 l 2 ( 2 cyclohexenyl) 2,2 diphenylethyll 1 azabicyclol 2 2 2 loctane and acid addition salts thereof.
13 2 ( 3 methyl 2,2 diphenylbutyl) 1 azabicyclol 2 2 2 loctane and 50 acid addition salts thereof.
14 2 ( 2,2 diphenylbutyl) 1 azabicyclol 2 2 2 loctane and acid addition salts thereof.
A process for the preparation of a compound corresponding to general formula (I) as defined in claim 1 and acid addition salts thereof which comprises 55 treating a compound corresponding to the following general formula (VI):
1,569,249 (dl) ((CH 2)n-CH-R'(V) R wherein R, R’ and N are as defined in claim 1 with a strong base, optionally in the presence of N,N,N’,N’-tetramethylethylenediamine, and then with a compound corresponding to the following general formula (VII):
REX (VII) wherein R’ is as defined in claim 1; and X represents a chlorine, a bromine or an iodine atom.
16 A process as claimed in claim 15 in which the strong base is n-butyl lithium.
17 A process for the preparation of 2 ( 2,2 diphenyl 4 pentenyl) 1 azabicyclol 2 2 2 loctane which comprises reacting 2 ( 2,2 diphenylethyl) 1 10 azabicyclol 2 2 2 loctane with n-butyl lithium in the presence of N,N,N’ N’tetramethylethylenediamine and then with 3-bromopropene.
18 A process as claimed in claim 15 or claim 16 in which the compound corresponding to general formula (VI) is prepared by heating a compound corresponding to the following general formula (V): 15 <)9 (CH 2)n-CH RI ( 7) R wherein R, R' and N are as defined in claim 1; with hydrazine monohydrate in the presence of potassium hydroxide. 19 A process as claimed in claim 15 substantially as herein described. 20 A process as claimed in claim 15 substantially as herein described with 20 reference to any one of the Examples. 21 A compound corresponding to general formula (I) as defined in claim 1 when prepared by a process as claimed in any of claims 15 to 20. 22 A pharmaceutical or veterinary composition which comprises a compound corresponding to general formula (I) as defined in claim 1 or a pharmaceutically or 25 veterinarily acceptable acid addition salt thereof and a pharmaceutically or veterinarily acceptable carrier or diluent. 23 A composition as claimed in claim 22 in unit dose form. 24 A composition as claimed in claim 23 comprising 10 mg of active ingredient 30 A composition as claimed in any of claims 22 to 24 in a form suitable for oral or parenteral administration. 26 A composition as claimed in claim 22 substantially as herein described. 27 A composition as claimed in claim 22 substantially as herein described with reference to Example 22 35 28 A process for the preparation of a composition as claimed in claim 22 which comprises admixing a compound corresponding to general formula (I) as defined in claim 1 or a pharmaceutically or veterinarily acceptable acid addition salt thereof with a pharmaceutically or veterinarily acceptable carrier or diluent. 1,569,249 14 1,569,249 14 29 A process as claimed in claim 28 substantially as herein described. A process as claimed in claim 28 substantially as herein described with reference to Example 22. 31 A composition as claimed in claim 22 when prepared by a process as claimed in any of claims 28 to 30 5 ELKINGTON & FIFE, Chartered Patent Agents, High Holborn House, 52/54 High Holborn, London, WCIV 65 H. Agents for the Applicants. Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa 1980 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY from which copies may be obtained. GB14965/78A 1977-04-18 1978-04-17 2-(2,2-diarylalkyl)1-azabicyclo(2.2.2)octane and compounds Expired GB1569249A (en) Applications Claiming Priority (1) Application Number Priority Date Filing Date Title US05/788,189 US4125531A (en) 1977-04-18 1977-04-18 2-Substituted-1-azabicyclo[2.2.2]octanes Publications (1) Publication Number Publication Date GB1569249A true GB1569249A (en) 1980-06-11 Family ID=25143721 Family Applications (1) Application Number Title Priority Date Filing Date GB14965/78A Expired GB1569249A (en) 1977-04-18 1978-04-17 2-(2,2-diarylalkyl)1-azabicyclo(2.2.2)octane and compounds Country Status (19) Country Link US (1) US4125531A (en) JP (1) JPS53132596A (en) AT (1) AT357553B (en) AU (1) AU3516178A (en) BE (1) BE866031A (en) DE (1) DE2816633A1 (en) DK (1) DK166978A (en) ES (1) ES468874A1 (en) FI (1) FI781161A (en) FR (1) FR2387980A1 (en) GB (1) GB1569249A (en) IE (1) IE46737B1 (en) IL (1) IL54519A0 (en) NL (1) NL7804145A (en) NO (1) NO781333L (en) NZ (1) NZ186991A (en) PT (1) PT67910B (en) SE (1) SE7804307L (en) ZA (1) ZA782212B (en) Families Citing this family (20) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US4203990A (en) * 1979-04-30 1980-05-20 G. D. Searle & Co. Anti-diarrheal 2-substituted quinuclidines 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 US4599344A (en) * 1984-10-31 1986-07-08 Schering A.G. Quinuclidines and quinuclidinium salts as antiarrhythmic agents EP0412798A3 (en) * 1989-08-08 1992-07-01 Merck Sharp & Dohme Ltd. Substituted pyridines, their preparation, formulations and use in dementia EP0499313B1 (en) * 1991-02-11 1997-06-11 MERCK SHARP & DOHME LTD. Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy US5962477A (en) * 1994-04-12 1999-10-05 Adolor Corporation Screening methods for cytokine inhibitors US6190691B1 (en) 1994-04-12 2001-02-20 Adolor Corporation Methods for treating inflammatory conditions US6573282B1 (en) 1995-09-12 2003-06-03 Adolor Corporation Peripherally active anti-hyperalgesic opiates US5849761A (en) 1995-09-12 1998-12-15 Regents Of The University Of California Peripherally active anti-hyperalgesic opiates US6353004B1 (en) 1997-07-14 2002-03-05 Adolor Coporation Peripherally acting anti-pruritic opiates US5849762A (en) * 1997-07-14 1998-12-15 Adolor Corporation Peripherally acting anti-pruritic opiates DK2368554T3 (en) 2003-04-08 2015-01-26 Progenics Pharm Inc A pharmaceutical composition comprising methylnaltrexone AR057035A1 (en) 2005-05-25 2007-11-14 Progenics Pharm Inc SYNTHESIS OF (R) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES AR057325A1 (en) 2005-05-25 2007-11-28 Progenics Pharm Inc SYNTHESIS OF (S) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES ES2570374T3 (en) 2007-03-29 2016-05-18 Progenics Pharm Inc Peripheral opioid receptor antagonists and uses thereof PT2565195E (en) 2007-03-29 2015-07-28 Wyeth Llc Peripheral opioid receptor and antagonists and uses thereof EP3263571B2 (en) 2007-03-29 2023-08-23 Progenics Pharmaceuticals, Inc. Crystal form of (r)-n-methylnaltrexone bromide and uses thereof EP2240489A1 (en) 2008-02-06 2010-10-20 Progenics Pharmaceuticals, Inc. Preparation and use of (r),(r)-2,2'-bis-methylnaltrexone CA2676881C (en) 2008-09-30 2017-04-25 Wyeth Peripheral opioid receptor antagonists and uses thereof CN110372571B (en) 2018-04-12 2022-11-15 中国科学院大连化学物理研究所 2- (2, 2-diarylethyl) -cyclic amine derivative or salt, synthesis and application thereof, and composition Family Cites Families (3) * Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title US3506672A (en) * 1968-03-29 1970-04-14 Aldrich Chem Co Inc 2-(4,4'-dihalo)-benzhydryl-3-quinuclidinols SU495310A1 (en) * 1974-03-05 1975-12-15 Всесоюзный Научно-Исследовательский Химико-Фармацевтический Институт Им.С.Орджоникидзе Hinuclidyl-3-diaral (heteryl) carbinols exhibiting antihistamine, antiserotonin and antiallergic activity and a method for their preparation US4013667A (en) * 1976-03-08 1977-03-22 G. D. Searle & Co. 2,2-Diaryl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionamides and intermediates thereto 1977 1977-04-18 US US05/788,189 patent/US4125531A/en not_active Expired - Lifetime 1978 1978-04-17 NZ NZ186991A patent/NZ186991A/en unknown 1978-04-17 ES ES468874A patent/ES468874A1/en not_active Expired 1978-04-17 AU AU35161/78A patent/AU3516178A/en active Pending 1978-04-17 SE SE7804307A patent/SE7804307L/en unknown 1978-04-17 DK DK166978A patent/DK166978A/en not_active IP Right Cessation 1978-04-17 PT PT67910A patent/PT67910B/en unknown 1978-04-17 NO NO781333A patent/NO781333L/en unknown 1978-04-17 FI FI781161A patent/FI781161A/en not_active Application Discontinuation 1978-04-17 AT AT266178A patent/AT357553B/en not_active IP Right Cessation 1978-04-17 BE BE186827A patent/BE866031A/en unknown 1978-04-17 DE DE19782816633 patent/DE2816633A1/en not_active Withdrawn 1978-04-17 IL IL54519A patent/IL54519A0/en unknown 1978-04-17 IE IE745/78A patent/IE46737B1/en unknown 1978-04-17 GB GB14965/78A patent/GB1569249A/en not_active Expired 1978-04-18 NL NL7804145A patent/NL7804145A/en not_active Application Discontinuation 1978-04-18 FR FR7811370A patent/FR2387980A1/en not_active Withdrawn 1978-04-18 JP JP4578878A patent/JPS53132596A/en active Pending 1978-04-18 ZA ZA00782212A patent/ZA782212B/en unknown Also Published As Publication number Publication date ZA782212B (en) 1979-11-28 JPS53132596A (en) 1978-11-18 DK166978A (en) 1978-10-19 AT357553B (en) 1980-07-25 NL7804145A (en) 1978-10-20 ATA266178A (en) 1979-12-15 BE866031A (en) 1978-10-17 IL54519A0 (en) 1978-07-31 PT67910B (en) 1979-11-14 AU3516178A (en) 1979-10-25 DE2816633A1 (en) 1978-10-19 US4125531A (en) 1978-11-14 FI781161A (en) 1978-10-19 SE7804307L (en) 1978-10-19 IE780745L (en) 1978-10-18 NZ186991A (en) 1979-12-11 ES468874A1 (en) 1978-12-01 NO781333L (en) 1978-10-19 IE46737B1 (en) 1983-09-07 FR2387980A1 (en) 1978-11-17 PT67910A (en) 1978-05-01 Similar Documents Publication Publication Date Title GB1569249A (en) 1980-06-11 2-(2,2-diarylalkyl)1-azabicyclo(2.2.2)octane and compounds US4182767A (en) 1980-01-08 Antihyperglycemic N-alkyl-3,4,5-trihydroxy-2-piperidine methanol US4501893A (en) 1985-02-26 3-{6-[3-Pyrrolidino-1-(4-tolyl)prop-1-enyl]-2-pyridyl}acrylic acid and pharmaceutically acceptable salts thereof Sternbach et al. 1952 Antispasmodics. I. Bicyclic basic alcohols US3310553A (en) 1967-03-21 Alkylated thioxathenesulfonamides US4194045A (en) 1980-03-18 1-(3,3-Diaryl-3-oxadiazolalkyl)-4-phenyl-4-piperidinomethanols and related compounds GB1570271A (en) 1980-06-25 3,3,3-triarylalkyl-4-phenylalkyl-4-hydroxy piperidines and related compounds IE44639B1 (en) 1982-02-10 Oxadiazoloyl-substituted compounds having pharmacological activity CH648553A5 (en) 1985-03-29 NEW 3,4-DIHYDRO-5H-2,3-BENZODIAZEPINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. GB1581923A (en) 1980-12-31 J4-aminomethyl-1-(3,3,3 -triarylpropyl)-4-arylpiperidine and related compounds CA1072089A (en) 1980-02-19 1,1,1 triaryl alkylamines US4213984A (en) 1980-07-22 11-(Piperazino-acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-ones and salts thereof GB2049679A (en) 1980-12-31 2-substituted quinuclidines US3459767A (en) 1969-08-05 Aminomethylindoles US3316257A (en) 1967-04-25 Novel 5h-dihydrothiopyrano[4, 3-d] pyrimidines US4279914A (en) 1981-07-21 Thrombocyte aggregation inhibiting composition and methods US3396168A (en) 1968-08-06 Dibenzocycloheptane derivatives US3598829A (en) 1971-08-10 Certain isoxazolylpyridines and isothiazolylpyridines DE1568929A1 (en) 1970-04-30 Amino-substituted indanes and tetralins and processes for their preparation US3792050A (en) 1974-02-12 2-oxo-2h-pyrimido(2,1-a)isoquinoline US4013667A (en) 1977-03-22 2,2-Diaryl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionamides and intermediates thereto US3743735A (en) 1973-07-03 Pharmaceutical compositions containing tropanol esters of alpha-phenyl-alpha-cyclopentyl-acetic acid and methods of use US3576811A (en) 1971-04-27 1-alkyl-1-(beta-piperidino-ethyl)-1,2,3,4- tetrahydronaphthalen-2-ones HUT61760A (en) 1993-03-01 Process for producing bridged, bicyclic imides comprising 4-/4-(3-benzisothiazolyl)-1-piperazinyl/-butyl group and pharmaceutical compositions comprising such compounds KR830001667B1 (en) 1983-08-23 Process for preparing phenyl quinolizidines Legal Events Date Code Title Description 1980-08-28 PS Patent sealed [section 19, patents act 1949] 1982-11-17 PCNP Patent ceased through non-payment of renewal fee
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