CA2071497A1 - 2-substituted 4,5-diphenyl-imidazoles - Google Patents
2-substituted 4,5-diphenyl-imidazolesInfo
- Publication number
- CA2071497A1 CA2071497A1 CA002071497A CA2071497A CA2071497A1 CA 2071497 A1 CA2071497 A1 CA 2071497A1 CA 002071497 A CA002071497 A CA 002071497A CA 2071497 A CA2071497 A CA 2071497A CA 2071497 A1 CA2071497 A1 CA 2071497A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- formula
- symbols
- atom
- dpim
- 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.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Imidazole derivatives of the formula (I): [DPIM]-S-W-Y, wherein [DPIM] represents a group of formula (DPIM), wherein R and R1 represent hydrogen, halogen or alkyl, W represents straight chain alkylene of 1 to 6 carbon atoms optionally substituted by alkyl, Y
represents a group of formulas (II), (III), (IV), (V), (VI) and salts thereof, are inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase useful for the conditions such as atherosclerosis, hyperlipidaemia, cholesterol or ester storage disease and atheroma in vein grafts.
represents a group of formulas (II), (III), (IV), (V), (VI) and salts thereof, are inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase useful for the conditions such as atherosclerosis, hyperlipidaemia, cholesterol or ester storage disease and atheroma in vein grafts.
Description
WOQl/09030 PCT/EP90/02147 1- 207~97 ;-- j, - ..
2-substituted 4,5-diphenyl-imidazoles :
This invention relates to therapeutically useful imidazole derivatives, to processes ~or their production, to pharmaoeutical compositions containing them, and to their use in a method of treatment of the human or animal body.
The present invention provides compounds of the general formula:-[DPIM]-S-W-Y (I) wherein ~DPIM] is as hereinafter depic~ed, R and R1 are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from 1 to about 5 carbon atoms, W
represents a methylene group or a straight a~kylene chain containing from 2 to about 5 carbon atoms and is optionally substituted with one or more straight- or branched-chain alkyl groups containing from 1 to about 4 carbon a oms, Y represents a group of formula ~II), (III~, (IV), (V) or (VI) hereinafter depicted, wherein : .
the symbols R2 axe the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or differènt and each .
represents a hydrogen atom or a straight- or branched-~chain~alkyl qroup containing from 1 to about 4 carbon atoms, ~he s~mbols R each represent a hydrogen atom or -else together the two symbols R~ and the carbon atom to .. . ..
-- '.: .
' ~ .
W091/09030 PCT/EP90i~2147 which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, æ
represents an oxygen or sulphur atom or a group of formula [C(R3)2]~ or NR3, m represents zero or an irlteger from 1 to about 5, n represents zero or an integer from 1 to about 5, and p represents zero or i, such that m ~ n + p = about 3, 4 or 5, g represents 0, 1 or 2, and pharmaceutically acceptable acid addition salts thereof, for use in the preparation of a pharmaceutical composition for the treatment of.
conditions which can be ameliorated by the administration of an inhibitor of acyl coenzyme-A~
cholesterol-O-acyl transferase (ACAT; EC Z.3.1.26), such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
The invention also provides a method for the treatment of a human or animal patient suffering from, or subje~t to, conditions,whi~h can be ameliorated by :
the admlnlstration of an inhibitor of acyl coenzyme-A:-cholesterol-O-acyl transferase, such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein ~rafts,-which comprises administering to the patient an effective amount of a eompound of formula ~I), or a .. . . . . ... . .
pharmaceutically accept~ble acid additi~n salt thereof, as hereinbefore defined, to se~ure an improvement in the ~ondition of the patient.
-` 207149~
~, ` ,7 ' ` ( ;
This invention relates to therapeutically useful imidazole derivatives, to processes ~or their production, to pharmaoeutical compositions containing them, and to their use in a method of treatment of the human or animal body.
The present invention provides compounds of the general formula:-[DPIM]-S-W-Y (I) wherein ~DPIM] is as hereinafter depic~ed, R and R1 are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from 1 to about 5 carbon atoms, W
represents a methylene group or a straight a~kylene chain containing from 2 to about 5 carbon atoms and is optionally substituted with one or more straight- or branched-chain alkyl groups containing from 1 to about 4 carbon a oms, Y represents a group of formula ~II), (III~, (IV), (V) or (VI) hereinafter depicted, wherein : .
the symbols R2 axe the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or differènt and each .
represents a hydrogen atom or a straight- or branched-~chain~alkyl qroup containing from 1 to about 4 carbon atoms, ~he s~mbols R each represent a hydrogen atom or -else together the two symbols R~ and the carbon atom to .. . ..
-- '.: .
' ~ .
W091/09030 PCT/EP90i~2147 which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, æ
represents an oxygen or sulphur atom or a group of formula [C(R3)2]~ or NR3, m represents zero or an irlteger from 1 to about 5, n represents zero or an integer from 1 to about 5, and p represents zero or i, such that m ~ n + p = about 3, 4 or 5, g represents 0, 1 or 2, and pharmaceutically acceptable acid addition salts thereof, for use in the preparation of a pharmaceutical composition for the treatment of.
conditions which can be ameliorated by the administration of an inhibitor of acyl coenzyme-A~
cholesterol-O-acyl transferase (ACAT; EC Z.3.1.26), such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
The invention also provides a method for the treatment of a human or animal patient suffering from, or subje~t to, conditions,whi~h can be ameliorated by :
the admlnlstration of an inhibitor of acyl coenzyme-A:-cholesterol-O-acyl transferase, such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein ~rafts,-which comprises administering to the patient an effective amount of a eompound of formula ~I), or a .. . . . . ... . .
pharmaceutically accept~ble acid additi~n salt thereof, as hereinbefore defined, to se~ure an improvement in the ~ondition of the patient.
-` 207149~
~, ` ,7 ' ` ( ;
The invention also provides a compound of formula (I~, or a pharmaceutically acceptable acid addition salt thereof, as hereinbefore defined, for use in a new method of treatment, of the human or animal bo~y, by therapy, of conditions which can be ameliorated by the administration o~ an inhibitor of acyl coenzyme-A:cholesterol-O-acyl transferase, such as atherosclerosis, hyperlipidaemia, cholesterol ester istorage disease or atheroma in vein grafts. `.
The present invention also provides pharmaceutical formulations which contain at least one of the compounds of formula (I), or a pharmaceutically acceptable acid addition salt thereof, as hereinbefore defined, provided that when W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), as hereinafter depicted, wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C~R3)2]q~ wherein g represents O or 1, or NR3, or the symbols R4 and the carbon..atom to which they are both joined form a carbonyl group and Z represents a group of formula ~C(R3)2]g~ wherein q represents 0, R, Rl and R3 being as hereinbefore defined, in association with a.
pharmceutically acceptable carrier or coating.
' .
.
.- . . :
.,.. , .. ,,~'.,'~. 'i ,",., ~ ""; ,",,,,";"",~ "~, wos1/09030 PCT/EP90/02147 ~0.7~497 `
The present invcntion also provides new imidazole derivatives of general formula (I), and pharmaceutically a~ceptable acid addition salts thereof, as hereinbefore de~ined, subject ~o the proviso that when W represents a methylene group or a .: .
straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), as hereinafter depicted, wherein the symbols ~4 represent hydrogen atoms and Z represents an oxygen : :
atom or a group of formula lC(R3)2]q~ wherein g represents 0 or 1, or NR3, or the symbols ~4 and the carbon atom to which the~ are both joined form a carbonyl group and Z represents a group of formula ~ .
[C(R3)2]~, wherein g xepresents 0, R, Rl and R3 being as hereinbefore defined. ~ .
Compounds within the scope of general formula ~I), whe_ein R and Rl are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from : :
- ... .
l to 5 carbon atoms, W represents a methylene group or :: :
: a straight alkylene.chain containing from 2 to 4 carbon -::
., . . . .. i -........ , , . . , ... . . . . . . .. ~ .. . .. . .
, . . , . . ... . , .. . . ., . , , ~ , .
: , . .
- '.,;, :.
''' ' !
i ...'.';:' ~
WO91/09030 PC~/EP90/02147 ~ ~ ~07;1 ~ 9 7 .
atoms, Y represents a ~roup of formula (V~, as hereinafter depiGted, the symbols R3 are the same or dif~erent and each represents a hydrogen atom or a straight- or branched-chain alkyl ~roup containing from 1 to 4 carbon atoms, and wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of fonmula [C(R3)2]q~ whereln q represents 0 or 1, or NR3, or the symbols R4 and the carbon atom to which they are both joined form a ~arbonyl group and Z represents a ~roup of formula EC(R )2]q~ wherein ~ represents 0, and their pharmaceutically acceptable acid addition:salts, alone and in association with pharmaoeutically acceptable carrLers or coatings, have been disclosed in the specification of Japanese Patent O.P.I. No. 64-40467 (Application ~o. 62-196117).
However, in that specification, those compounds and their pharmaceu~ical compositions are described as having anti-ul~er and anti-inflammatory activity.
. .. . . . .. , . . ~
Nowhere in that specification is there any suggestion .. .
that the compounds and their pharmaceutical compositions could be useful as inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase or in the treatment of conditions such as atherosclerosis, - ; ~ . ...
~ hyperlipidaemia, cholesterol ester storage disease and .. - . -, ... ,~ , .. . .. , . , ~ .
atheroma in vein graf~s.
', ;:~
WO91/09030 PCT/~P9QtO2147 ;; 2~:71~97 Thus, the utilities disclosed in the present specification are entirely unexpected.
Especially important features of the present invention are, or involve, compounds of general formula (I) wherein at least one of the symb91s has a value selected from the following~
(i) R represents a hydrogen or chlorine atom or a methyl group;
(ii) Rl represents a hydrogen or chlorine atom or a methyl group;
(iii) W represents a methylene group or an alkylene chain of 2, 3 or 4 carbon atoms;
(iv) Y represents a phthalimido grou~ or an optionally substituted maleimido, pyrrolidinyl, piperidyl, perhydroazepinyl, piperazinyl, or morpholino -group; and/or (v) R3 represents a hydrogen atom or a methyl or ethyl group; ' '' the'other symbols bein~ as hereinbefore defin~d, and . , . , . .. . .i . .~ , . ,.... , . , : .
'thelr pharmaceutically acceptable acid addltion salts.
'' ''' Important compounds according to the present ~'' '' ~' invention inciudé''''' ~' ' ''~'''~~~ ' ' '' ' 'iA- ' N-[2-('4,5-diphenylimidazol-2-yi ~ ethyl]~
'~'~-'' ~''`'~''''m'or'pholinë''"' ''`~'''~=~~~~ ~~ ''~~~'`~~~`~ ~ -~.~ ...... . . ................ . .... .. , .
'`'' '''''''' -'lAA ''N-t2-(4,50diphenylimida'zol-2-ylthio)ethyl]-morpholine hydrochloride ~ I
1 :' WO91/09030 pcT/Epso/o2l47 2 ~ 7 1 ~ 9 7 - 7 - .
lB N-~3-(4,5-diphenylimidazol-2-ylthio)propyl]-morpholine lBA N-13-(4,5-diphenylimidazol-2-ylthio)propyl]-morpholine dihydrochloride lC N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-piperidine lCA N-[2-(4,5-diphen~limidazol-2-ylthio)ethyl]-piperidine dihydrochloride lD N-[3-~4,5-diphenylimidazol-2-ylthio)propyl]-N'-methylpipera~ine lE N-t2-(4,5-diphenylimidazol-2-ylthio)ethyl~-pyrrolidine-2-one .
lF N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-- pyrrolidine lG N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-piperidine lGA N-~3-(4,5-diphenylimidazol-~-ylthio)propyl3-piperidine dihydrochloride lH N-t2-[4,5-diphenyllmidazol-2-ylthio)ethyl]- ~- .
- pexh~droazepine ~ ~
:~ ~ lH~ N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl3-erhydroazepine~dihydrochloride -lI cis- and~trans-2,6-dimethyl-N-[4-(4,5-diphenyl-r ~ imidazol-2.-ylthio)butyl]morph~Iine~
A cis- and.5E3~-2,6-dimethyl-N-[4-[4,5-diphenyl-imidaz~l-2-ylthio)butyl]morpholine Wosl/09030 PCT/EP90/02147 - ` 20.~ 8 -dihydrochloride 2A N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-phthalimide . ~ :
2B N-~3~(4,5-diphenylimidazol-2-ylthio)propyl]-phthalimide ~ .
2C N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]-phthalimide 2D N-[3-(4,5-diphenylimidazol-2-ylthioJpropyl]-morpholine-3,5-dione ;
2E 3~5-dimethyl-N-~3-(4,5-diphenylimidazol-2-yl-thio)propyl]piperidine-2,6-dione . :
2F N-[2-(4,~-diphenylimidazol-2-ylthio)ethyl]-maleimide 2G N-~3-(4,5-diphenylimidazol-2-ylthio)propyl~-4-methylmaleimide 2H N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- .
pyrrolidine-2,5-dione ~ :
2I N-t3-(4,5-diphenylimidazol-2-ylthio)propyl]--- pyrrolidine-2,~-dione :`.
2J N-r3 (4,5-diphenylimidazol-2-ylthio)propyl~
. piperidine-2,6-dione .
2K 4,4-dimethyl-N-[2-~4,~5-diphenylimidazol-2-yl- .
-, ~3 ~ thio ) ethyl ]pip2ridine-2, 6-dione ~
2L 4,4-dimethyl-N-[3-t4,5-diphenylimidazol-2-yl-thio)propyl~piperidine-2,6-dione -.
~; ~ ' .. '".
''' `; 2~71497 _ 9 _ i . ;'T ~
2M N-[3-(4,5-diphenylimidazol-2-ylthio~propyl]-4-methylpiperidine-2,6-dio~e 2N N-~3-(4,5-diphen~limidazol-2-ylthio)propyl~-4-ethyl-4-methylpiperidine-2,6-dione ~-~3-(4,5-diphenylimidazol~2-ylthio)propyl]-thiomorpholine-3,5-dione 2P 4,4-dimethyl-N-[3-t4,5-di-p-tolylimidazol-2-yl-thio1propyl]piperidine-2,6-dione 2Q N-[3-(4,5-di-p-~olylimidazol-2-ylthio)propyl]-morpholine-3,5-dione 2R N-[3-(4,5-di-2-chlorophenylimidazol-2-ylthio)-propyl]-4,4-dimethylpiperidine-2,6-dlone 2S N-~4-(4,5-diphenylimidazol-2-ylthio)butyl]~
morpholine-2,6-dione 2T 3,3-dimethyl-N-~3-(4,5-diphenylimidazol-2-yl-thio)propyl]piperidine-2,6-dione 3A [3-R,5]-3-~(4,5-diphenylimidazol-2-ylthio1-methyl]-l-methylpiperidine 3AA [3-R,5]-3-~(4,5-diphenylimid~zol-2-ylthio)-methyl]-l-methylpiperidine hydrochloride 3B [5-R,S]-5-[(4,5-diphenylimidazol-2-ylthio)-methyl-2-pyrrolidinone - ~
3C r 6-R,S~-6-[(4,5-diphenylimidazol-2-ylthio)-. methyl]-2-piperidin~ne - -- 3D t6-R~S]-4~4-dimethYl-6-~(4~5-diphenylimidazol-2-ylthio~methyl~-2-piperidinone .
W091~09~30 PCT/EP90/02147 `~ 2~
3E [4-R,5]-4-[2-(4,5~diphenylimidazol-2-ylthio)-ethyl]-l-methylpiperidine 3F ~2-R,S]-2-[S4,5-diphenylimidazol-2-ylthio)-methyl]-1-methylpiperidine 4A N-~3-(4,5-diphenylimidazol-2-ylthio)propyl]-5-hydroxypyrrolidin-2-one `
4B N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-5-hydroxymorpholin-3-one The codes lA to 4B are allocated to compounds for easy reference later in the specification.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the following in vivo and in vitro tests which are believed to correlate to pharmacological activity in humans and other mammals.
In assays performed in vitro, microsomes, prepared from the livers of rats fed a diet supplemented with 0.5%w/w cholesterol and 0.25%w/w -cholic acid for 7 days, were incubated with radiolabelled oleoyl-CoA in the presence of compounds according to the invention at a concentration of 0.5, 1 or lO~g/ml. The de~ree of`ACAT inhibition produced is~shown~in~Table I. ~~ ` - , In in ~ivo tests, using rats fed on a similar diet to that above and ~urther ~suppIemented by 0.03%
w/w of test compound, the compounds according to the :: -., .; . . , ' ' , . ; . , . . ` , .
invention inhibited increases in ~lasma cholesterol concentrations, measured after 3 days, relatlve to :
control animals fed on the cholesterol supplemented diet without the drug, by amounts as sho~,~n, for example, in Table I~.
., ~ . . . . i, , . .. . , ... : ;... : . - ~ .
WO 91/09030 PCr/EP90/02147 ~ `"` 2071~97 ---Table I
Compound Concentration % Inhibition llg/ml lA 10 74 lAA 10 90 '' lB 10 91 lC 10 go -lD 10 88 lE 10 86 lF 10 72 .
lGA 10 66 .:
lHA 10 77 ~
2A 1 6 8 ;.:
2B 1 86 . :
~' 2C 1 86 -: 2G 1 90 `
: . . .
contd. ;.
~; , . . .
.. .
wo ~1/09030 pcr~Ep9o/o2l47 ;2 0~ 7 1 4 9 7 Table I ( cont~) Compound Corlcentration % Inhibition lls/ml 2~ 1 ~6 2M l 83 2N 0.5 87 2P 0.5 88 2Q 0. 5 75 2R 0.5 70 2S 0. 5 78 2T o.5 9O
3D ~ 1 82 3E 0.5 70 3F ~ 0.5 84 ., . . . . , .. :
.
- ~ Table.. II ~
~ = .
- . Compound .. . - ~ -. ~ % Inhibition 3AA ~ 88 -, ' WO 91/09030 PCI~/EP90/02147 207i~97 Compounds of formula (I) can be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or des~ribed in the literature. -Thus, according to a feature of the present invention, compounds of for~ula tI), as hereinbefore defined, are prepared by the rea~tion of a salt of the general formula:-[DPIM]-S M (VII) -wherein ~DPIM] is as hereinbefore defined and N is an alkali metal, preferably a sodium or potassium, atom, with a ~ompound of the general formula:-X-W-Y (VIII) or an acid addition salt thereof, wherein X is a group displaceable by a thiolate salt, such as a halogen, e.g. a chlorine, atom or an alkyl- or aryl-sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluene-sulphonyloxy) and W and Y are as hereinbefore defined.
The reaction is carried out in an inert organic .
solvent, such as dimethylformamide or tetrahydrofuran, at from room temperature to 100C, optionally in the presence of a proton acceptor, which may be organic, such as an-amine (e.g. triethylamine), or i~organic, . such as a carbonate of an alkali metal (e.g. potassium -carbonate).
WO 91/09030 PCI`/EP90/02147 2~71497 According to a further feature of the present invention, compounds of general formula (I) wherein Y
represents a group of formula (II), lIII) or (IV), the other symbols being as herei~before defined, are prepared by the reaction of a compound of the general formula:-. ., 1 DPIM ] S-W-NH ( IX ) wherein the symbols are as hereinbefore defined, with a comp~und of the ~eneral formula (X), (XI) or (XII), hereinafter depicted, wherein ~, R2 and R3 are as hereinbefore defined. The reaction is generally carried out in an inert organic solvent, f~r example xylene, and optionally in the presence of an acidic catalyst, suoh as 4-toluenesulphonic acid, at the reflux temperature, with azeotropic removal of water.
According to a further feature of the present invention, compounds of formula ~I), wherein Y
represents a group of formula (V3 and the other symbols are as hereinbefore defined, are ~repared from the correspanding compounds of formula (I) wherein Y
represents a group of formula (IV) and the other sym~ols are as hereinbefore defined, by reduction with a metal hydride reducin~ agent, such as lithium aluminium hydride, in an inert solvent, such as an ether, e.g. diethyl ether or tetrahydrofuran, at O~C
~o room temperature.
' : ' ;
' . ':
:: .. . . : .. .. ;, . . .- , , ~ . .
WO91/09030 PCTtEP90/02147 20``7~7 --.. ~ ` . . ` ... ... .
- 1~
Acoording to a further feature of the present invention, compounds of formula (IJ, wherein Y
represents a group of formula (V) in which the symbols R represent hydro~en atoms and the other symbols are as hexeinbefore defined, are prepared by reduction of the corresponding compounds of formula (I) wherein Y
represents a group of formula (Y) in which the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group and the other symbols are as hereinbefore defined, in conditions similar to those :
described hereinbefore for the reduction of compounds ~ :
of formula I wherein Y represents a group of formula . . .
(IV) to corres~onding compounds wherein Y represents a ~-~
group of formula (V).
According to a further feature of the present invention, compounds of the general formula:-~ DPIM]-S-Wl-CH2-Y (XIV) within formula (I ), wherein Wl represents a methylene group or a straight alkylene chain containing from 2 to :~ .
, - - . :
.
: ......... ' `'`'~`' '''''~ .
.
. --4 carbon atomsr op~ionally substituted with one or more straight- or branched-chain alkyl groups containiny from 1 to 4 ~arbon atoms, the other ~ymbols bein~ as hereinbefore defined, are prepared by reduction of compounds of the general ~ormula:-[D~IM]-S-Wl-~O-Y ~XV) wherein the symbols are as hereinbefore defined, in conditions similar to those described hereinbefore for ~
the reduction of compounds of formula (I) wherein Y . :
represents a ~roup of formula (IV) to corresponding compounds wherein Y represent~ a group of formula (V). ~
The starting materials and intermediates can be ~ .
prepared by the application or adaptation of known methods.
Thus, compounds of formula (VII) can be prepared by the reaction of a bai~e such as ~odium hydride with compounds of the general formula:-[DPIM~-SH (XVI) wherein ~DPIM] is as hereinbefore defined. This reaction is ~onveniently carried out ~n situ.
Compounds o~ formula lIX) can be prepared by the reaction of a compound of formula-(VII), as hereinbefore defined, with a compound of the general :: :
.. . . . .
formula:~
- - : X-W-N~2 - - (XIII) .
- .
WO91/090~0 PCT/~P9o/02147 Z~7149 ~ - 18 -or a salt thereof, wherein X and W are as hereinbefore defined, under conditions similar to those described above for the reaction of a compound of formula (VII) with a compound of formula (VIII).
Compounds of formula (IX) can also be prepared by the reaction of compounds of formula (I), wherein Y ;
represents a phthalimido group, with hydrazine, in a solvent such as eth~nol at temperatures up to reflux.
C~mpounds of formula (XY) can be prepared by the reaction of compounds of formula (~II) with compounds of the general formula:-X-Wl_co-y (XVII) wherein the symbols are as hereinbefore defined, under conditions similar to those described above ~or the .
reaction of a compound of formula (VII) with a compound of formula (vIII).
By the term "pharmaceutically acceptable acid addition salts" as used in this specification is meant .
acid addition salts the anions of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmaceutical properties of the parent compounds of general formula (I).~.are not vitiated-by side-effects ascribable to those anions.
suitable acid.addition salts for use in phar~aceuticals may be selected from salts derived from ,, . . ~, . , ,: I . , , ' WO91/09030 PC~tEP9OtO2~47 ,, ,` ` 20ql497 inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates, , tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-~-hydroxynaphthoates, gentisates and di-~-toluoyltartra~es.
According to a fur~her feature of the invention, acid addition salts of compounds of formula (I) are prepared by reaction of the parent compounds of formula (I) with the appropriate acid, by the application or adaptation of known methods.
As well as being useful in themselves as active compounds, salts of compounds of ~ormula (I) ar~ useful for the purposes of purification of the parent compounds of formula (I), for example by exploitation of the solubility differences between the salts and the parent compounds, by techniques well known to those :~
skilled in the ar~.
: The parent compounds of formula (I) can be regenerated from their salts by the application or adaptation of known methods.
For example, parent compounds of general formula ~I~ can be reg~nerated from ~heir acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
..
. :. : . . - .. :, ., ;: , , : ~. . ~ : -.
WO91/09030 pcT/Epso/o2147 `` ;2~t71497 -`
. .... : .
~ 20 -In this specification reference to compounds of formula ~I) is intended to include reference to their pharmaceutically acceptable acid addition salts, where the context so permit~.
Compounds of formula (I) can be purified by ~he usual physical means, ~or example by crystallisation or chromatography.
The following Examples illustrate the preparation of compounds according to the invention and the Reference Examples illustrate the preparation of intermediates.
N.M.R. spectra were recorded at 200MHz or 400MXz. Chemical shi~ts are expressed in ppm relative to tetra~ethylsilane. Abbreviations have the following significances:-s = singlet, d = doublet, t ~ triplet, q = guartet, quin = quintet, m = multiplet, dd = doublet of doublets, dt - doublet of triplets, br = broad signal.
Infra-red spectra were recorded in potassium bromide discs. The positions of the major absorption peaks are given.
., . :
.
~: . , I ' WO 91/09030 PCI'/EP90/02147 o 21 ~ . ,` `. ~071~g7 --~ (D~) ~' ~L
)~R2 (II) r ~Z -:
(III) 0 1~3 3 ~Ly .
(n) Ir /\ 3 o ~3 . ~ :
(V) R ~ R3 `; ;` ` 2~7i"497 . :
-- 22 -- ~
~{C'R~ 'T~
~r( )2]n ;' ~ ' : . -~,~1~ (X) ' O
o~ (XI) ' ~ .
: .
0 R3 ~3 2 (XII ) :: : , ; O -~
; ~ .
: : :
WOsl/09030 PCT/EP90/02147 .~ ~07~4~7 Com~ounds lA, lB, lC and lD
Sodium hydride (1.2g, 40mmol of an 80%
dispersion in oil) was added to a stirred suspension of.
4,5-diphenylimidazol-2-thiol (5.04~, 20mmol) in dry tetrahydrofuran t180ml) at ambient temperature. After stirring for 0.Shr, N-~2-chloroethyl)morpholine hydrochloride ~3.72~, 20mmol) was added followed by triethyl~mine (3ml). The mixture was heated under reflux for 48hr, then poured into water (300ml) and extracted with ether (2 x 200ml). The ethereal solution was then extracted with aqueous 2N
hydrochloric acid (200ml). The acidic aqueous solution was then basified (NaOH) and extracted with ether (2 x 150 ml). This ethereal solution was dried ~MgSO4), :
evaporated, and the residue recrystallised from toluene to give N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- .
morpholine (4.9g), as a colourless solid, m.p. ;
- 129-132~C;
EElemental analysis:- C, 68.9; H, 6.3; N, 11.
. Calculated for C21H23N3OS:- C, 69.0; H, 6.3;
- N, 11.5%;
-- ~ . N.M.R.(CDCl3 &.D2O): 2.55 ~(4H, br t, J=4Hz), 2.86 (2H, t, J=6Hz), 3~11 (2H,-~, J=6Hz), 3.5 (4H, br - .t,:J=4Hz), 7.2-7.6 (10H, m)].~ . :
~.
.. . ~ . .. .... .. . . . . .. . .. . . .. .. . .
WO9l/09030 PcT/EP90/02l47 ~071~97 - 24 - ~
By proceeding in the s~me manner, but replacing ~he N-(2-~hloroethyl)morpholine by:
1) N-(3-chloropropyl)morpholine;
ii) N-(2-chloroethyl)piperidine; and iii) N-(3-chloropropyl)-N'-methylpiper~2ine there were prepared:
i) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl~-morpholine, m.p. 135-1379C;
ii) N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-piperidine, m.p. 143-145C; and iii) N-(4,~-diphenylimidazol-2-ylthio)propyl]-N'-methylpiperazine, m.p. 175-178C.
Compound lAA
Acetyl chloride (2Oml) was added dropwise to cold (10C) ethanol (90ml) with stirring, main~aining the temperature below 30C. After stirring for 0.5hr, a solution of N-[2-(4,5-diphenylimidazol-2-yl~hio)-ethyl~morpholine (1.5g, 4.1mmol) in ethanol (lOml) was added and stirring continued for 0.5hr. The mixture was then evaporated and the residue recrystallised from ethanol to give N-[2-(4~5-diphenylimidazol-2-ylthio)-ethyl]morpholine dihydrochloride (1-46g~, as a colourless~solid, m.p. 247C; ~ ~ 3 [Elemental analysis:- C, 55.1;-H, 5.95;
Clt 15.3; N, 8.9~;
..
.,. . .. . . . . . .. , . . ., .. , .;.. . . . ~ .. . , . , , ~ .. , . , . ;; ,, , .. ~ , , i WO91~OgO30 pcT/Epso/o2l47 207..~497 .
Calculated for C21H23N3S.2HCl.H20:- C, 55.3;
H, 5.96; Cl, 15.5; N, 9.2~
N.M.R. (CD3SOCD3 & D2O) 3.23-3.95 (12H, m), 7.3~-7.56 (lOH, m)].
ompound lE
Sodium hydride ~ 0.48g, 16mmol of an 80%
dispersion in oil) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (3.78g, 15mmol) in dry tetrahydrofuran at ambient temperature. After stirring ~:
for 0.5hr, N-(2-tosyloxyethyl)pyrrolidin-2-one (5.66g, 20mmol) was added and stirring continued for 3hr. The ~ :
mixture was then poured into water (500ml) and extracted with ether (2 x 200ml). The ethereal solution was dried (~gS04), evaporated, and purified by flash chromatography (19:1 dichloromethane / methanol as eluent). The product was crystallised from 1:1 ethyl ~
ace~ate / petroleum ether ~60-80C) to give N-[2-(4,5~ :
diphenylimidazol-2-ylthio)ethyl]pyrrolidin-2-one .
(4.2g), as a colourless solid, m.p. 128-130 C; :~
~Elemental analysis:- C, 69.4; H, 5.75; N, 11.7%
. .
.
C21~21N3S:-~C~ 69-4; H 5 82 - - N, 11.6~; ., : .~ ..... ; -, . .
,~ f~
,. ~,, , . ~ ,, ,, . , . . ,:, . . . ` - , : ,, ', , ' .: ', ' , '. . ':; ', . ' ' ' ` '., ' ' :, ` ' ' ~ ' . '. . ' .. : ' . - ' . ` :':" ': .': -WO 91/09030 PCI'/EP90/02147 ~Q~4~7 2 ~
.
N.M.R. (CDCl3): 2.14 (2H, q, J=7Hz), 2.58 (2H, t, J=7HzJ, 2.96 (2H, t, J=6Hz), 3.46 (2H, t, J=7Hz), 3.64 (2H, t, J=6Hz), 7.1-7.45 (6H, m), 7.46-7.74 (4~, m~, 12.3 (lH, br s)].
ComPound lF
A solution of N-[2-(4,5-diphenylimidazol-2-yl-thio)ethyl]pyrrolidin-2-one (3.2g, 9mmol ) in dry tetrahydrofuran (20ml) was added to a stirred suspension of lithium aluminium hydride (1.07g, 28mmol) in diethyl ether (300ml) at ambient temperature under an argon atmosphere. Stirring was continued for 0.5hr, then ethyl acetate (50ml) was added slowly with ice cooling followed by water (300ml) and stirring then continued for 0.5hr. The organic layer was separated, dried (MgS04), and evaporated to a gum which was purified by flash chromatography (9:1 dichloromethane / methanol as eluent). The product was dissolved in ethyl acetate (5ml) and petroleum ether (60-80~C; 50ml) was added to give N-~2-(4,5-diphenylimidazol-2-ylthio)-ethylJpyrrolidine (1.9g), as a colourless crystalline solid, m.p. 102-103C; - - -tElemental a~alysis:- C, 72.3; H, 6.4; N, 12.1% -21H23N3S: C, 72.2; H, 6.6;
~, 12.0%
... .. . .; . .. .. . . . . .
rl 2 0 7 1 4 9 7 N.M.R. (CDC13 & D20~: 1.53-1.64 (4H, m), 2.6-2.68 (4H, m), ~03-3.1 (4H, m)~ 7.2-7.33 (6H, m), 7.41-7.~5 (4H, m)~
S
Compounds lG and lGA
Potassium tert.-bu~oxide (4.44g, 39.6mmol) was added to a stirxed suspension of 4,5-diphenylimidazol-2-thiol (lOg, 39.Smmol) at ambient temperature to give a yellow solution. Af~er stirring for O.Shr, N-(3-chloropropyl)piperidine hydrochloride (11.77g, 59.4mmol) was added. The mixture was stirred for 18hr and evaporated, and the residue mixed with ethyl acetate (200ml) and washed with water (250ml), saturated a~ueous sodium bicarbonate solution (200ml) and water (200ml). The organic phase was dried (MgS04) and evaporated and the orange residue was crystallised from agueous ethancl to give N-[3-(4,5-diphenyl-imidazol-2-ylthio)propyl~piperidine (3.98g), as a colourless solid~ m.p. 118-120~C.
Acetyl chloride 125ml) was added dropwise to cold ~<10C) ethanol (70ml) with stirring, maintaining :-.
the temperature below 10C. After stirring for O.Shr, a solutio~ of ~-t3,.(4,5-diPhen~limidazol-2-ylthio)-propyl]piperidine-(3.98g) in;etha~ol (lOml) was àdded . .- .. . ... . .
Wo91/09030 PCT/EP~0/02147 `: 2071~7 -`
and stirring continued for 0.5hr. The mixture was then evaporated and the residue crystallised ~rom ethanol /
ether to give N-r3-(4,5-diphenylimidazol-2-ylthio)-propyl~piperidine dihydroc~.loride (2.62g~ as a colourless solld, m.p. 180-185C;
~ Elemental ana~ysis:- C, 59.3; H, 6.5; Cl, 14.8;
N, 9.1; S, 6.6%
Calcul~ted for C23H27N3s.2Hcl~H2o - C, 59.0;
H, 6.67; Cl, 15.1; N, 8.97; S, 6.84%]
Co~ nds lH and lHA
Potassium tert.-butoxide (4.44g, 39.6mmol) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (lOg, 39.6mmol) at ambient temperature to give a yellow solution. Af~er stirring for 0.5hr, 2-(hexa-methyleneimino)ethyl chloride monohydrochloride (11.9g, 60mmol) was added. The mixture was stirred for 18hr filtered, and the solid washed with small portions of dimethylformamide until the washings-were colourless.
The insoluble material was shaken with a ~ixture of ethyl acetate (50Oml) and a~ueous potassium carbonate solution 110%, 250ml) until complete solution occurred.
.. .. ~ ~ .
The organic;phase;was-washed-with water (2xiOOmlj, dried (MgS04) and~evaporated to give-N-~2-(4,5-diphenylimidazol-2-ylthio~ethyl]perhydroazepine ~10.8g~, as a colourless solid.
....
.: .: . ... . .. .
WO9l/09030 PCr/EP90/02147 .~ 207~97 Acetyl chloride (25ml~ was added dropwise to cold (<lO~C) methanol (150ml) with stirring, :
maintaining the temperature ~elow 10C. After stirring for O.Shr, a ~olution of N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]perhydroazepine (10.8g) in methanol (lOOml) was added and stirring continued for 5min.
Decolourising charcoal (lg) was added, stirring conti~ued for 15min and the mixture was filtered. The filtrate was evaporated to low volume and ether added to give N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- :
perhydroazepine dihydrochloride (ll.Sg), as a colourless solid, m.p. 225-230~C; : .
tElemental analysis:- C, 59.8; H, 6.7; Cl, 15.4; ~:-N, 9.2; S, 7.4% :.
Calculated for C23H2~N3S.2HCl.~H20:- C, 60.1;
H, 6.58; Cl, 15.4; N, 9.15; S, 6.98%]
Compounds_2A, 2B and 2C
i) Sodium hydride (0.6g, 20mmol of an 80%
dispersion in oil) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (4.45g, 17.7mmol) in dry :
tetrahydrofuran (130ml~ at ambient temperature. After stirring . f or O.5hr, N-(2-bromoethyl~phthalimide (5.08g, . ~ ~ .. .
20mmol) was added and the solution heated under reflux for 6hr. The mixture was then poured into water ~500ml) and extracted with ethyl acetate (2 x 200ml). -:
: . .
:.
2071~97 The extract was dried (MgS04) and evaForated to a gum which was crystallised from toluene to give N-~2-(4,5-diphenyllmidazol-2-yl hio)ethyl~phthalimide ~5.05g), as a very pale cream solid, m.p. 165-166C;
~Elemental analysis:- C, 70.8; H, 4.5; N, 9.8%;
Calculated ~or C25H1gN3O2S:~ C, 70.6; ~, 4.5;
N, 9.9%
N.M.R. (CDC13 & D2O): 3.22 (2H, t, J=5Hz), 3.98 (2H, ~, J=5Hz), 7.23-7.45 (6H, m), 7.54 (2H, d, J-7Hz), 7.62 (2H, d, J=7Hz), 7.73-7.78 (2H, m) 7.86-7.92 ~2~, m)]. : :
By proceeding in a similar manner, but replacing the N-(2-bromoethyl)phthalimide by N-(3-bromopropyl)-phthalimide and N-(4-bromobutyl)phthalimide there were prepared: :
- ii) N-[3-(4,5-diphenylimidazol-2-ylthio)-propyl]phthalimide, a colourless solid, m.p. 188-190C;
~ Elemental analysis:- C, 70.7; H, 4.7; N, 9~2%
26 21 3O2S: C, 71.0~; H, 4.8;
N, 9.6% ..
.
N.M.X. (CDC13 & D2OJ: 2.03 (2H, guin, J=7Hz), : 3.05 (2H, t, J=7Hz), 3.96 (2H, t, J=7Hz), 7.2-7.4 (6H, m), 7.42-?.62 (4H, m), 7.:7~-(2H, dd, J-6 and 3Hz), 7.82 12H! dd, J=6 and 3HzJ~; and -~
iii) N-~4-(4,~-diphenylimidazol-2-yithio)butyl]-phthalimide, a colourlsss solid, m.p. 170-171C;
W091/09030 PCT/EP90/02147 ~ ~
2~71~97 [Elemental analysis:- C, 71.7; H, 5.0; N, 9.3;
S, 7.4%
27 23N32S: C, 71.5; H, S.1;
N, 9.3; S, 7.1% i-~
N.M.R. (CDC?3 & D2O): 1.62-1.93 (4R, m~, 3.15 (2~, t, J=6Hz), 3.74 (2H, t, J=6Hz), 7.2-7.39 (6H, mJ, 7.4-7.6 (4H, m), 7.62-7.78 (4H, m~].
EXA~MPLE B
C~ , .:
Diglycolic anhydride (8.34g, 32.3mmol) was added~.
to boiling xylene (500ml) with stirring.
2-(3-Aminopropylthio)-4,5-diphenylimidazole (5.0g, ~:.
16.2mmol) was then added in lg portions at 45 minute intervals with vigorous stirring to the boiling mixture, removing any water formed azeotropically.
After the final addition, heating under reflux was ~on~inued for l.Shr and the mixture was allowed to cool and decanted. The solution was evaporated and the :
residue puxified by flash chromatography on silica gel ~39:1 dichloromethane / methanol as eluent). The .
product was recrystallised from acetonitrile to give N-~3-(4,5-diphenylimidaæol-2-ylthio)propyl3morpholine-3,5-dione (3~7g), a~ a colourless solid, m.p. :
16~-166~C;
~ . .. ..
WOgl/09030 PCT/EP90/02147 ~: ~d~ -~
~ Elemental analysis :- C, 64.6; H, 5.1; N, 10.2;
S, 8.0%
CalCulated for C22H21N33S:- C~ 64-9; H 5 2;
N, 10.3; S, 7.9~ ;
N.M.R. (CDCl3 & D2O): l.9B (2H, guin, J=7Hz), 3.09 (2H, t, J=7Hz), 4.02 (2H, t, J=7H2), 4.34 (4H, s), 7.2-7.37 (6H, m), 7.45-7.57 (4H, m)].
m~ounds ?E to 2T
2,4-Dimethylglutari~ anhydride (7.3~g, 51.7mmol) was added to boiling xylene (500ml) with stirring.
2-(3-Aminopropylthio)-4,5-diphenylimidazole (4.0g, 12.9mmol) was added in lg portions at 1 hour intervals, with vigoxous stirring, to the boiling mixture removing any water formed azeotropically. Reflux was continued $or 2hr and then toluenesulphonic acid monohydrate (0.4g, 2.1mmol) was added and reflux continued for 8hr.
The mix~ure was allowed to cool and decanted and the solu~ion was then evaporated. The ref~ulting residue was purified by flash ~hromatography on silica gel , .. .. .
.
.. ~ , . . . .. ; . .
. . . ~ , . .
' .
,.~ ~,-, .
WO91/09030 PCT/EP90tO2147 2 ~ 7 1 4 9 ~
(97:3 dichloromethane / methanol as eluent). The product was recrystallised from acetonitrile to give 3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio)-propyl]piperidine-2,6-dione (3.23g~, as a colourless solid, m.p. 132-134DC;
~Elemental analysis :- C, 69.0; H, 6.2; N, 9.8;
S, 7.4% :~ :
Calculated for C25~27N325 - C~ 69.3; H~ 6-3;
N, 9.7; S, 7.4%
N.M.R. (CDC13 & D2O): 1.27 ~6H, d, J=7Hz), 1.49 (lH, q, J=12Hz), 1.73-2.04 14~, m), 2.02 (lH, dt, J-4 and 12Hz), 2.53-2.82 (2H, m), 2.93 (2~, t, J=~Hz), 4.13 ~2H, t, J=7Hz), 7.22-7.34 (6H, m), 7.48-7.62 (4H, m)].
The N.M.R. spectrum indicated that this was a 9:1 mixture of syn and anti isomers.
By proceeding in a similar manner, but replacing the 2,4-dimethylglutaric anhydride by the appropriate anhydride and the 2-(3-aminopropylthio)-4,5-diphenyl-imidazole by the appropriate amine, there:were prepared:-ii) N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl]-maleimide, a yellow solid, m.p. 132-133C; ` -. _ . . .
~ Elemental analysis:- C, 67.Q; H, 4.5,-N, li.1%
. Calculated for C21Hl~N3O2S:- C, 67-2; H, 4-53;
N, 11.2%]; .
' . -` `- 2071497 N.M.R. (CDC13 & D20): 3.13 ~2H, t, J=6Hz), 3.82 ~ :
(2H, t, J=6Hz), 7.2-7.45 ~6H, m), 7.46-7.7 (4H, m)].
iii) N ~3-(4,5-diphenylimidazol-2-ylthio)- .
propyl]-4-methylmaleimide, a buff solid, m.p.
136-138C;
EElemental analysis:- C, 68.2; H, 5.15; N, 10.4;
S, 8.1%
23H21N3O2S: C, 68.5; H, 5.2;
N, 10.4; S, 7.94%];
N.M.R. (CDC13 & D2o~ 94 (2H, quin, J-7Hz), 2.06 (3H, d, J=4Hz), 3.02 (2H, t, J=7Hz), 3.78 (2H, t, J=7Hz), 6.32 (lH, d, J=4Hz), 7.22-7.38 (6H, m), 7.45-7.56 (4H, m)~;
iv) N-r2-(4,5-diphenylimidazol-2-ylthio)-e~hyl]pyrrolidine-2,5-dione, a colourless solid, m.p.
189-191C;
[Elemental analysis:- C, 66.8; H, 5.1; N, 11.1;
S, 8.5%
Calculated for C2lH1gN302S:~ C, 66.8; ~, 5.04;
N, 11.14; S, 8.5~
v) . N-~3-(4,5-diphenylimidazol-2-ylthio)- ~.
p~opylJpyrrolidine-2,5-dione, a colourless solid, m.p.
177-179C,~
Elementai-analysis:- C, 67.6; H, 5.4; N, 10.6 Calculated for C22H21N3o2s , 10.7~];
:
- -:
~ "
2~7~497 vi) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-piperidine 2,6-dione, a colourless solid, m.p. -154-155C;
[Elemental anal~sis:-C, 68.2; H, 5.8; ~, 10.4%
C23H23N3O2S: C, 68 .1; H, 5 . 7;
N, 10.36%~;
vii) 4,4-dimethyl-N-[2-(4,5-diphenylimidazol- .
2-ylthio)ethyl]piperidine-2,6-dione, a buff solid, m.p.
86-88C;
[Elemental analysis:- C, 68.2; ~, 6.27; N, 9.6; :
S, 7.5% ~`
24 25N325 C, 68.7; H, 6.0 N, 10.0; S, 7.6%];
viii) 4,4-dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]piperidine-2,6-dione, a colourless :
solid, m.p. 1~5-157C;
[Elemental analysis:- C, 69.0; H, 6.24; N, 9.6;
S, ~.4% :
Calculate~ for C25H27N32S:- C~ 69-26; H~ 6-2~;
N, 9.7; S, 7.4%];
ix) N-[3-(4,5-diphenylimidazol-2-ylthio)-propyl~-4-methylpiperidine-2,6-dione, a colourless solid! m.p. 1~0-162C;
[Elemental analysis:- C, 68.9; H, 6.03; N, 9.9%
Calculated for C2~H25N3O25:- C, 6d.7; H, 6.0;
N, 10.0% ];
. j , , ~ ", ' i ' . . . ; . . , ' ~ ' ' ' ~ ' . . , ' . .
WOgl/09030 PCT/EP90/02147 x) N-~3-(4,5-diphenylimidazol-2-ylthio)-propyl]-4-ethyl-4-methylpiperidine-2,6-dione, a buff solid, m.p. 134-136C;
[Elemental analysis:- C, 69.6; H, 6.5; N, 9.3;
S, 7.3%
Calculated for C26H29N302S:- C, 69.77; H, 6.53;
N, 9.4; S, 7.16%];
xi) N-r3-(4,5-diphenylimidazol-2-ylthio)propyl]-thiomorpholine-3,5-dione, a cream solid, m.p.
164-16~C.;
[Elemental analysi~:- C,62.3; H, 4.84; N, 9.8;
S, 15.0%
Calculated for C22H2lN3o2s2 :~ C, 62-4; H~ 5.0;
N, 9.9; S, 15.14%~;
xii) 4,4-dimethyl-N-~3-(4,5-di-p-tol~l-imidazol-2-ylthio)propyl]piperidine-2,6-dione, a cream ~.
solid, m.p. 175-177C;
[Elemental analysis:- C, 69.8; H, 6.65; N, 9.1;
S, 6.95% . .
r C27H3l~3o2s:- C, 7~.25; ~, 6.77; -N, 9.1; S, 6.95%];
xiii3 No[3-t4,5-di-p-tolylimidazol-2-ylthio)-propyl]morpholine-3,5-dione, a buff solid, m.p.
148-149C; ~ - ' . ~ . . I .
- ~
. . :.. :.. :.. . ... : . .. , ..... :........ . .. .... .... . . - .
W091/09030 PCT/EPso/02147 .
[Elemental analysis:- C, 66.4; H, 5.7; N, 9.5; :;
S, 7.4%; ~ :
~24H25~3035:- C, 66.18; H, 5.8;
N, 9.65; S, 7.36%];
xiv) N-[3-(4,5-di-2-chlorophenylimidazol-2-ylthio)propyl]-4,4-dimethylpiperidine-2,6-dione;
xv) N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]-morpholine-3,5-dione, a colourless solid, m.p.
153-155C; ~-:
[Elemental analysis:- C, 65.1; H, 5.45, N, 10.0;
S, 7.5~
Calculated for C~3H23N3035:- C, 65.5; H, 5.5;
N, 9.97; S, 7.61~]; and xvi) 3,3-dimethyl-N-t3-(4,5-diphenylimidazol- :
2-ylthio)propyl]piperidine-2,6-dione, a colourles~
solid, m.p. 168-170^C; ..
~Elemental analysis:- C, 69.3; H, 603; N, 9.7;
S, 7.~% . -Calculated for C25H27N32S - C, 69 26; ~ 6 28; ~
N, 9.69; S, 7.496]. ~:
EXAMPLE 10 . .- .......................... ;
ComDounds 3A and 3AA
i) A suspension of 4,5-diphenylimidazole-.2-thiol 15.04g 20mmol) in anhydrous THF (180ml) was treated with sodium hydride (80% dispersion in oil, 1.2g,. ~-~ ' ~, .. , ,~, , .
wosl/09030 PCT/EP90/02147 .. .
40mmol) and the mixture stirred at room temperature for30min. A mixture of (~)-3-~hloromethyl-1-methyl-piperidine hydrochloride (3.68~, 20mm~1) and sodium hydride (80% dispersion in oil, 0.6g, 20mmo1) in anhydrous T~F (20ml) was also stirred at room temperature for 30min. The two mixtures were mixed together, triethylamine (3.0ml~ was added, and the whole mixture stirred at reflux overnight. After cooling to room temperature the reaction mixture was poured onto iced water (300ml) and extracted with ether (3x200ml). The ~ombined ethereal extracts were extracted with 2M hydrochloric acid (3xlOOml). The acidic solution was basified with 50% sodium hydroxide solutio~ with ice cooling and the product extracted into ether (3xlOOml). The combined extracts were dried (MgS04) and evaporated to give a whi~e solid (2.0g).
Crystallisation from toluene gave [3-R,S]-3-[~4,5-diphenylimidazol-2-ylthio)methyl~-1-methyl-piperidine (1.5~), as a white crystalline solid, mp 167-169C;
~Found:-C, 72.6; H~ 6.9; N, 11.5; S, 8.$.%
CalCulated for C22H25N3S - C~ 72-7; H- 6-9;- ¦
N,~11.6;~ S,- 8.8%~
~ N M R (CDC13) 1.92~(3H-j s), 1.40-2.70, (9H, -m~,-3.20 (2H, m), 7.20-7.50 (lOH, m) IR (RBr): 696, 765, 1445, 1494, 2926 and ~, , . .
` . 1 ' WO91/09030 PCT~EPgo/02147 . ~.
. . . ;.
- 39 - 20 71 ~ 9 7 -3433 cm 1~.
ii~ A solution of [3-R,S]-3-~(4,5-diphenyl-imidazol-2-ylthio)methyl]-1-methylpiperidine (4.1g, 11.3mmol) in ethanol (30ml) was ~dded with stirring and ice cooling to a solution of hydrogen chloride in ethanol [prepared by adding acetyl chloride (40ml) dropwise to cold (10C) ethanol (180ml) with stirring, maintainin~ the temperature below 30C]. The mixture was allowed to warm to room temperature and s~irred ~or 2hr. Ether (200ml) was added and the white precipitate .
was collected by filtration and wash~d thoroughly with fresh ether to give [3-R,S]-3-[(4,5-diphenyl-imidaæol-2-ylthio)methyl]-1-methylpiperidine hydrochloride ~4.6g), as a white powder, mp 175-177C;
[Found:- C, 59.7; H, 6.5; N, 9.0; Cl, 14.3;
S, 6 ~ 8 % - .
Calculated ~or c22H2sN35 l 8Hcl H2O - C~ 59-2;
H, 6.5; N, 9.4; Cl, 14.3; S, 7.2%~. -~ - EXAMPLE 11 Compounds 3R, 3C and 3D
i) A mixture of 5-iodomethyl-2-pyrrolidinone (1.83g, 8.1mmol), 4,5-diphenylimidazole-2-thiol (1.83g, 7 . 3mmol ) and anhydrous potassium carbonate ( O . 70g, ~ -~ . .. . .
5.1mmol) in DMF (35ml) was stirred at room temperature overnight. The mixture was evaporated to low bulk and the residue suspended`in watèr (70ml). The product was .
:~ ' .
WO91/09030 PCT/EPgo/02l47 ,. 2071~97 .:
. .
collected b~ ~iltration, dried, and cr~6talli~ed from ethanol / ether to give rs-R~s~-s-r(4~s-dip~e~vl-imldazol-2-ylthio~methylJ-2-p~rrolldinone (O.g~g) as a whi~e crystalline solld, mp 218C;
~Fo~nd:- C, 68.6~ H, 5.5; N, 12.0J S, 9.1%
20H19~30S:- C, 68.7) ~, g,5;
N, 12.0~ S, 9.2~ :
N.M.R. (CDCl3): 1.85 & 2.35 (4H, 2m), 3.00 ~ .
3.27 (2H, 2dd, J=14Hz and 4HzJ, 3.91 ~lH, m), 7.2-7.7 tlO~, m) I~ (KBr): 69B, 762 and 1680 cm ~ i) By proceeding in the Eame mann~r, but replacing the S-lodomethyl-2-p~rrolidin~ne by 6-lodo~ethyl-~-piperidinone 3nd puri~ylng t~e crude prod~ct ~ flash chromatography (10% ethanol in ethyl acetate) followed by crystallis~tion ~ro~ ethanol /
et~er, there was prepared ~6-R,S]-6-~(4,~-dlphenyl-~midaziol-2-ylthio)methyl]-2-piperldinone, as a ~hite ~ .
~olid, mp 209-~10C:
[Founds- C, 69.4; H, 5.8~ N, ll.~t S, 8.~.%
- ~iouiated ~or~c2l.
~, 11.6, S, 8.8%
. .. . .... . . ~ . - - ; .. . . . ,. j N.M.R. (CD3SOCD3)- 1.4-2.0 ~ 2.05-2.10 (6H, 2 3.24 (2H, m), 3.63 (1~, m), 7.20-7.55 (10~, m,) IR (KBr~: 697, 7~3 and 1634 cm 1~.
.
, . .
WO91/09030 PCT/EPsO/02147 . ~ .
- 2071~97 iii) By proceeding in the same mannex, but replacing the 5-iodomethyl-2-pyrrolidinone by 4,4-dimethyl-5-iodomethyl-2-piperidinone and purifying the crude product by flash ~hromatography tethyl acetate), there was prepared r6-R,S]-4,4-dimethyl-6-[(4,5-~iphenylimidazol-2~ylthio)methyl]-2-piperidinone as a white solid, mp 148-150C;
tFound:- c, 70.3; ~, 6.6; N, 10.4.%
Calculated for C23~25N~os - C, 70.6; H, 6.4;
N, 10.7%.
~.M.R. (CD3SOCD3): 0.94 ~ 0.98 (6H, 2s), 1.2-1.8 (2H, m), 1.96 (2H, m), 3.26 (2H, m), 3.73 (lH, m), 7.20-7.58 (lOH, m) IR (RBr): 695, 763, 1488 and 1636 cm 1].
The iodomethyllactam starting materials were prepared by the method of S. Knapp et al, -J. org. Chem., 1988, 53, 4006.
Com~ounds 3E and 3F - .
. i) A suspension of 4,5-diphenylimidazole-2-thiol (8g, 31,7mmol) in anhydrous THF (250ml) was-treated ... . , . ~ . i ..with.;sodium hydride 580%:in oil;.0,97g, 32.7mmol) and .the.~mixture.stirredjat room temperature for 30min`. A
.mixture of (~)-4-~l2-(~-toluenesulPhonYloxy)ethyl]-l-methylpiperidine t9.4g, 31.6mmol) in anhydrous THF
t20ml) was added and the mixture stirred at room .' .
.;" 2'b7l~g7 temperature for 18hr, followed by refluxing for 24hr.
After ~ooling to room temperature, the reaction mixture was poured into i~ed water (500ml) and extracted with ether (4xlOOml). The combined ethereal extracts were extracted with hydrochloric acid (2M, 4xlOOml~. The a~idi~ solution was basified with 50% sodium hydroxide solution with ice cooling and the product extracted into ether (3x500ml). The combined extra~ts were dried (MgS04) and evaporated and the residual solid (5.4g) was purified by flash chromatography on silica gel (9:1 dichloromethane J methanol as eluent) to give [4-R,S]- ..
4-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-1-methyl-piperidine (2.28g), as a colourless solid, m.p.
74-76C;
[Found:- C, 73.3; H, 7.4; N, 10.8; S, 8.6%
Calcula~ed for C23H27N35:- C~ 73 16; H 7 2;
N, 11.3; S, 8.5%J.
ii) By proceeding.-in a similar manner, but ; ' repla~ing the (l)-4-[2-(p-toluenesulphonyloxy)ethyl]-l~methylpiperidine by (~ 2-(p-toluenesulphonyloxy)-methyl-1-methylpiperidine and purifying the crude product by crystallisation from toluene followed by .
conversion to the hydrochloride s'alt~''and':'s'ubséquént .
regeneration:of.-the.~ree base, there was prëpared' .
- 12-R,]-2-[~4,5-diphenylimidazol-2-ylthio~methyl~- :
, - :.: . ~ ' I
. .
-1-methylpiperidine, as a colourless solid, m.p.
62-64C;
[Found:- C, 71.4; H, 6.9; N, 11.2; S~ 8.2%
Calculated for C2~H25N3S-~H2O:- C, 71-7;
H, 6.98; N, 11.42; S, 8.71%].
Com~ound lI
By proceeding in a manner similar to that described in Example 4, but replacing the N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl~pyrrolidin-2-one, used as a starting material, by a mixture of cis- and trans-2,6-dimeth~l-N-~4-(4,5-diphenylimidazol-2-yl-thio)butan-1-oyl]morpholine, carrying out the reaction for 4 hours, followed by the addition of water and then aqueous sodium hydroxide solution for the work-up, there was prepared a mixture of cis- and trans-2,6-dimethyl-N-[4-(4,5-diphenylimidazol 2-ylthio)butyl]-morpholine, m.p. 50-60C (slowly melts). [Elemental analysis:- C,70.0;~,7.4;N,9.8;S,7.6;H20,1.4%;
calculated for C25H31N35 -5~2 -C,69.73;H,7.49;N,9.76;S,7.44;H2o,2.09%].: :
~ ; - EXAMPLE 14 Compounds 18A, lCA ~nd lIA - -By proceeding in a manner similar to that des~ribed in Example 2, but staxting with:-i) N-~3-(4,5-diphenylimidazol-2-ylthio)propyl]-""~ ,"" ~-"~ ,;; "
, ~; 20714~7 44 morpholine;
ii) N-[2-(4,5-diphenylimidazol-2 ylthio)ethyl]-piperidine; ~nd iii) a mixturP of cis- and trans-2,6-dimethyl-N-~4-(4,5-diphenylimidazol-2-ylthio)butyl)-morpholine;
there were prepared:-i~ N-~3-(4,5-di~henylimidazol-2-ylthio)pro~yl]-morpholine dihydrochloride, m.p. 173-175C ~Elemental analysis:- C,54.7;H,6.02;Cl,14.9;N,9.1;S,6.41;H2O,6.4%;
calculated for C22H25N3Os:2~ .75H20 Cl,15.09;N,8.7;S,6.64;H2O,6.52%~;
ii) N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl~-piperidine dihydrohloride, m.p. 237-240C [Elemental analysis:- C,60.06;H,6.4;Cl,16.0;N,9.6;S,7.3%;
calculated for C22H~5N3S:2HCl:- C,60.54;H,6.24;
Cl,16.25;N,9.63;S,7.35%]; and iii) a mixture of cis- and trans-2,6-dimethyl-N- r 4-(4,5-diphenylimidazol-2-ylthi~)butyl]morpholine ;
dihydrochloride, m.p. 208-210C [Elemental analysis:-C,60,6;~,6.9;Cl,13.9;N,8.5;S,6.47i~; cal~ulated for ~ :
C252H31~5N305:2HCl:~ C,60.?2;H,6.73;Cl,14.34;N,8.5; . ' S,6.48%~. . ~ ....... .. . .~ i.:
. ~ ., . . ~ .. . .
... . ., .. - - :~:
. . .; ~ ~;
, ,:
! ~
j~ , ~ , , , , . : , . ~ , . : :
WO91/09030 pcT/Epso/o2l47 ,. . ' ~ 45 ~ ~ 2~71`-49~7 8~ ::
Com~ounds 4A and 4~
~ y proceeding in a manner similar to that described in Example 4 but starting with:-i) N-[3-(~,5~diphenylimidazol-2-ylthio)propyl]-pyrrolidin-2,5-dione; and ii) N-t3-(4,5-diphenylimidazol-2-ylthio)propyl]-morpholin-3,5-dione;
there were prepared:-i) N-[3-(4,5-diphenylimidazol-2-yl~hio)propyl]-5-hydroxypyrrolidin-2-one, m.p. 185-187C; and ii) N-t3-(4,5-diphenylimidazol-2-ylthio)propyl]-5-hydroxymorpholin-3-one; m.p. 105C (shrinks at 87C).
. . .: . .
.
~:
; , , . ,. , ........... .: -2071.49.~ 6 -i) Sodium hydride (1.4g, 46mmol of an 80~
dispersion in oil) wa~ added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (5.04g, 20mmol) in dry THF
(150ml) at ambient temperature. After stirring for 0.25hr, 3-bromopropylamine hydrobromide (4.38g, 20mmol) was added. The mixture was then heated under reflux for lhr then poured into water (lOOOml) and extracted with ethyl acetate (2 x 500ml). The combined extract w~s dried (~gSO4) and evaporatPd. The residue was triturated with ethyl acetate / ether (1:1; 70ml) and the solid collected to give 2-(3-aminopropylthio)-4,5-diphenylimidazole (4.8g). An analytical sample was prepared by recrys~allisation from toluene to give ;
colourless crystals, m.p 162-163C;
[Elemental analysis:- C, 70.1; H, 6.3; N, 13.5%
Calculated for C18H19N3S - C~ 69.9; H~ 6-2;
N, 13.6%
N.M.R (CDCl3 & D2O): 1.88 (2H, quin, J=7Hz~, :
2.93 (2H, t, J-7Hz), 3.2 ~2H, t, J-7~z), 7.2-7.32 (6H, m), 7.47-7.53 (4H, m)].
ii) By proceeding in a similar manner, but ~ i replacing the 3-bromopropylamine hyc~obromide by j~
2-bromoethylamine hydrobromide there was prepared 2-(2-aminoethylthio)-4,5-diphenylimidazole, ~ :
m.p.152-154C;
wosl/09030 PCT/~P90/02147 ``: 2~1497 ~ Elemental analysis:- C, 68.6; ~, 5.8; N, 14~1;
S, 10. 5%
17 17N3S C, 69.1; H, 5.8;
N, 14.2; S, 10.85%
N.M.R. (CDC13 & D2O): 3.1 (4H, br s), 7.16-7.36 (6H, m), 7.42-7.56 (4~, m)3.
N r 4-(4,5-Diphenylimidazol-2-ylthio)butyl~-phthalimide (10.2g, 22.5mmol) [prepared as in Example l(iii)~ was heated under reflux in a mixture o~ ethanol (25Qml~ and hydrazine hydrate (1.25g, 25mmol) for 22hr.
An aqueous solution of hydrochloric acid (2N; 50ml) was then added and boiling continued for 0.5hr. The mixtl~re was then chilled (10C) and the solid filtered and discarded. The filtrate was evaporated and the residue dissolved in water (250ml) and filtered. The filtrate was then basified (~pHlO) with a~ueous sodium hydroxide solution (2N) and the mixture extracted with ethyl acetate (3 x 200ml~. The combined extraot was dried (MgSO4), evaporated and recrystallised from ace oni~rile to give 2-(4-aminobutylthio)-4,5-diphenyl-imidazole (4.5g), as colourless ~rystals, m.p.
138-139C;
[Elemèntal analysis :- C,70.7; H,6.6; N,13.0;
Calculated for C1gH21N3S :- C, 70.6; H, 6.5;
N, 13.0%~.
-: ~ ' ' ' , .;. ~ ' ~ ' Wosl/09030 PCT/EP90/02147 :2~7~97 By proceeding in a manner similar to that described in Example 1, but using a mixture of cis- and trans-N-( 4-chlorobutanoyl) 2,6-dimethylmorpholine as a starting material, there was prepared a nixture o~ cis- and trans-2,6-dimethyl-N-t4-(4,5-diphenylimidazol-2-yl-thio)butan-1-oyl]morpholine, m.p.147-149c.
.. ~ . .. . , ~ .
-: ~. .. ,. . ~
' ~ ' ~ '' , .... . , '. ' ' , ~ . .
WO91/09030 pcT/Epso/o2147 ..20~1497 In clinical practice compounds of the pre~ent invention may be administered parenterally, rectally or orally.
Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of the a~tive compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
The compositions may also ~omprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
Liquid compositions for oral administration -include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the a~t such as water and liguid paraffin. Besides inert diluents such composi~ions may comprise adjuvants, such as wettin~
and-suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention ~or oral administration also ~include capsules of absorbable-material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients. ~ ~ ~
, .
1.~
. ' ' ' , ' ' ~ ' , ,: ., . .
wog1/oso30 PC~/EP90/02147 `2071497 Compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic~ and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glyool, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, ~or example, by filtration through a bacteria-retaining filter, by incorporation in the -~
compositions o~ sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Solid compositions ~or rectal administration include suppositories formulated in accordance with known methods and containing at least one compo~1nd of formula (I1.
The percen'age of active ingredient in the compositions cf the invention may be varied, it being necessary that it should constitute a proportion such . . .
that a suitable dosage shall be obtained. Obviously, several unit dosage ~orms may be administered at about the same time. The dose employed will be determined WO91/09030 PCT/EP90!02147 . .
~. ~';;i ~ / .
- 51 - ` 20~1497 by the physician, and depends upon the desired therapeutic ef~ect, the route of administration and the duration of the treatment, and the condition of the ¦
patient. In the adult, the doses are generally from about O S to about 70 preferably about 1 to about 10 mg/kg body weight per day by oral administration.
The following Composition Examples illustrate pharmaceutical compositions according to the present invention.
No. 2 size gelatin capsules each containing:-;~ N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl]-morpholine 20 mg lactose 100 mg ~; starch 60 mg dextrin- 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
WO 91/09030 PCr/EP90/02147 NQ. 2 size gelatin capsules each containing:-3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-yl- :
thio)propyl]piperidine-2,6-dione 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg .
were prepared in accordance with the usual procedure.
COMPOSITION EXAMRLE 3 :
No. 2 size gelatin capsules each containing:-[3-R,SJ-3-[(4,5-diphenylimidazol-2-ylthio)-methyl]-1-methylpiperidine 20 m~
lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate .1 mg :
were prepared in accordance with the usual procedure. -,:
.
'' . ,,.'.~,.. ,"
. ., i ., .
~. :
The present invention also provides pharmaceutical formulations which contain at least one of the compounds of formula (I), or a pharmaceutically acceptable acid addition salt thereof, as hereinbefore defined, provided that when W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), as hereinafter depicted, wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C~R3)2]q~ wherein g represents O or 1, or NR3, or the symbols R4 and the carbon..atom to which they are both joined form a carbonyl group and Z represents a group of formula ~C(R3)2]g~ wherein q represents 0, R, Rl and R3 being as hereinbefore defined, in association with a.
pharmceutically acceptable carrier or coating.
' .
.
.- . . :
.,.. , .. ,,~'.,'~. 'i ,",., ~ ""; ,",,,,";"",~ "~, wos1/09030 PCT/EP90/02147 ~0.7~497 `
The present invcntion also provides new imidazole derivatives of general formula (I), and pharmaceutically a~ceptable acid addition salts thereof, as hereinbefore de~ined, subject ~o the proviso that when W represents a methylene group or a .: .
straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), as hereinafter depicted, wherein the symbols ~4 represent hydrogen atoms and Z represents an oxygen : :
atom or a group of formula lC(R3)2]q~ wherein g represents 0 or 1, or NR3, or the symbols ~4 and the carbon atom to which the~ are both joined form a carbonyl group and Z represents a group of formula ~ .
[C(R3)2]~, wherein g xepresents 0, R, Rl and R3 being as hereinbefore defined. ~ .
Compounds within the scope of general formula ~I), whe_ein R and Rl are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from : :
- ... .
l to 5 carbon atoms, W represents a methylene group or :: :
: a straight alkylene.chain containing from 2 to 4 carbon -::
., . . . .. i -........ , , . . , ... . . . . . . .. ~ .. . .. . .
, . . , . . ... . , .. . . ., . , , ~ , .
: , . .
- '.,;, :.
''' ' !
i ...'.';:' ~
WO91/09030 PC~/EP90/02147 ~ ~ ~07;1 ~ 9 7 .
atoms, Y represents a ~roup of formula (V~, as hereinafter depiGted, the symbols R3 are the same or dif~erent and each represents a hydrogen atom or a straight- or branched-chain alkyl ~roup containing from 1 to 4 carbon atoms, and wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of fonmula [C(R3)2]q~ whereln q represents 0 or 1, or NR3, or the symbols R4 and the carbon atom to which they are both joined form a ~arbonyl group and Z represents a ~roup of formula EC(R )2]q~ wherein ~ represents 0, and their pharmaceutically acceptable acid addition:salts, alone and in association with pharmaoeutically acceptable carrLers or coatings, have been disclosed in the specification of Japanese Patent O.P.I. No. 64-40467 (Application ~o. 62-196117).
However, in that specification, those compounds and their pharmaceu~ical compositions are described as having anti-ul~er and anti-inflammatory activity.
. .. . . . .. , . . ~
Nowhere in that specification is there any suggestion .. .
that the compounds and their pharmaceutical compositions could be useful as inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase or in the treatment of conditions such as atherosclerosis, - ; ~ . ...
~ hyperlipidaemia, cholesterol ester storage disease and .. - . -, ... ,~ , .. . .. , . , ~ .
atheroma in vein graf~s.
', ;:~
WO91/09030 PCT/~P9QtO2147 ;; 2~:71~97 Thus, the utilities disclosed in the present specification are entirely unexpected.
Especially important features of the present invention are, or involve, compounds of general formula (I) wherein at least one of the symb91s has a value selected from the following~
(i) R represents a hydrogen or chlorine atom or a methyl group;
(ii) Rl represents a hydrogen or chlorine atom or a methyl group;
(iii) W represents a methylene group or an alkylene chain of 2, 3 or 4 carbon atoms;
(iv) Y represents a phthalimido grou~ or an optionally substituted maleimido, pyrrolidinyl, piperidyl, perhydroazepinyl, piperazinyl, or morpholino -group; and/or (v) R3 represents a hydrogen atom or a methyl or ethyl group; ' '' the'other symbols bein~ as hereinbefore defin~d, and . , . , . .. . .i . .~ , . ,.... , . , : .
'thelr pharmaceutically acceptable acid addltion salts.
'' ''' Important compounds according to the present ~'' '' ~' invention inciudé''''' ~' ' ''~'''~~~ ' ' '' ' 'iA- ' N-[2-('4,5-diphenylimidazol-2-yi ~ ethyl]~
'~'~-'' ~''`'~''''m'or'pholinë''"' ''`~'''~=~~~~ ~~ ''~~~'`~~~`~ ~ -~.~ ...... . . ................ . .... .. , .
'`'' '''''''' -'lAA ''N-t2-(4,50diphenylimida'zol-2-ylthio)ethyl]-morpholine hydrochloride ~ I
1 :' WO91/09030 pcT/Epso/o2l47 2 ~ 7 1 ~ 9 7 - 7 - .
lB N-~3-(4,5-diphenylimidazol-2-ylthio)propyl]-morpholine lBA N-13-(4,5-diphenylimidazol-2-ylthio)propyl]-morpholine dihydrochloride lC N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-piperidine lCA N-[2-(4,5-diphen~limidazol-2-ylthio)ethyl]-piperidine dihydrochloride lD N-[3-~4,5-diphenylimidazol-2-ylthio)propyl]-N'-methylpipera~ine lE N-t2-(4,5-diphenylimidazol-2-ylthio)ethyl~-pyrrolidine-2-one .
lF N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-- pyrrolidine lG N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-piperidine lGA N-~3-(4,5-diphenylimidazol-~-ylthio)propyl3-piperidine dihydrochloride lH N-t2-[4,5-diphenyllmidazol-2-ylthio)ethyl]- ~- .
- pexh~droazepine ~ ~
:~ ~ lH~ N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl3-erhydroazepine~dihydrochloride -lI cis- and~trans-2,6-dimethyl-N-[4-(4,5-diphenyl-r ~ imidazol-2.-ylthio)butyl]morph~Iine~
A cis- and.5E3~-2,6-dimethyl-N-[4-[4,5-diphenyl-imidaz~l-2-ylthio)butyl]morpholine Wosl/09030 PCT/EP90/02147 - ` 20.~ 8 -dihydrochloride 2A N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-phthalimide . ~ :
2B N-~3~(4,5-diphenylimidazol-2-ylthio)propyl]-phthalimide ~ .
2C N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]-phthalimide 2D N-[3-(4,5-diphenylimidazol-2-ylthioJpropyl]-morpholine-3,5-dione ;
2E 3~5-dimethyl-N-~3-(4,5-diphenylimidazol-2-yl-thio)propyl]piperidine-2,6-dione . :
2F N-[2-(4,~-diphenylimidazol-2-ylthio)ethyl]-maleimide 2G N-~3-(4,5-diphenylimidazol-2-ylthio)propyl~-4-methylmaleimide 2H N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- .
pyrrolidine-2,5-dione ~ :
2I N-t3-(4,5-diphenylimidazol-2-ylthio)propyl]--- pyrrolidine-2,~-dione :`.
2J N-r3 (4,5-diphenylimidazol-2-ylthio)propyl~
. piperidine-2,6-dione .
2K 4,4-dimethyl-N-[2-~4,~5-diphenylimidazol-2-yl- .
-, ~3 ~ thio ) ethyl ]pip2ridine-2, 6-dione ~
2L 4,4-dimethyl-N-[3-t4,5-diphenylimidazol-2-yl-thio)propyl~piperidine-2,6-dione -.
~; ~ ' .. '".
''' `; 2~71497 _ 9 _ i . ;'T ~
2M N-[3-(4,5-diphenylimidazol-2-ylthio~propyl]-4-methylpiperidine-2,6-dio~e 2N N-~3-(4,5-diphen~limidazol-2-ylthio)propyl~-4-ethyl-4-methylpiperidine-2,6-dione ~-~3-(4,5-diphenylimidazol~2-ylthio)propyl]-thiomorpholine-3,5-dione 2P 4,4-dimethyl-N-[3-t4,5-di-p-tolylimidazol-2-yl-thio1propyl]piperidine-2,6-dione 2Q N-[3-(4,5-di-p-~olylimidazol-2-ylthio)propyl]-morpholine-3,5-dione 2R N-[3-(4,5-di-2-chlorophenylimidazol-2-ylthio)-propyl]-4,4-dimethylpiperidine-2,6-dlone 2S N-~4-(4,5-diphenylimidazol-2-ylthio)butyl]~
morpholine-2,6-dione 2T 3,3-dimethyl-N-~3-(4,5-diphenylimidazol-2-yl-thio)propyl]piperidine-2,6-dione 3A [3-R,5]-3-~(4,5-diphenylimidazol-2-ylthio1-methyl]-l-methylpiperidine 3AA [3-R,5]-3-~(4,5-diphenylimid~zol-2-ylthio)-methyl]-l-methylpiperidine hydrochloride 3B [5-R,S]-5-[(4,5-diphenylimidazol-2-ylthio)-methyl-2-pyrrolidinone - ~
3C r 6-R,S~-6-[(4,5-diphenylimidazol-2-ylthio)-. methyl]-2-piperidin~ne - -- 3D t6-R~S]-4~4-dimethYl-6-~(4~5-diphenylimidazol-2-ylthio~methyl~-2-piperidinone .
W091~09~30 PCT/EP90/02147 `~ 2~
3E [4-R,5]-4-[2-(4,5~diphenylimidazol-2-ylthio)-ethyl]-l-methylpiperidine 3F ~2-R,S]-2-[S4,5-diphenylimidazol-2-ylthio)-methyl]-1-methylpiperidine 4A N-~3-(4,5-diphenylimidazol-2-ylthio)propyl]-5-hydroxypyrrolidin-2-one `
4B N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-5-hydroxymorpholin-3-one The codes lA to 4B are allocated to compounds for easy reference later in the specification.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the following in vivo and in vitro tests which are believed to correlate to pharmacological activity in humans and other mammals.
In assays performed in vitro, microsomes, prepared from the livers of rats fed a diet supplemented with 0.5%w/w cholesterol and 0.25%w/w -cholic acid for 7 days, were incubated with radiolabelled oleoyl-CoA in the presence of compounds according to the invention at a concentration of 0.5, 1 or lO~g/ml. The de~ree of`ACAT inhibition produced is~shown~in~Table I. ~~ ` - , In in ~ivo tests, using rats fed on a similar diet to that above and ~urther ~suppIemented by 0.03%
w/w of test compound, the compounds according to the :: -., .; . . , ' ' , . ; . , . . ` , .
invention inhibited increases in ~lasma cholesterol concentrations, measured after 3 days, relatlve to :
control animals fed on the cholesterol supplemented diet without the drug, by amounts as sho~,~n, for example, in Table I~.
., ~ . . . . i, , . .. . , ... : ;... : . - ~ .
WO 91/09030 PCr/EP90/02147 ~ `"` 2071~97 ---Table I
Compound Concentration % Inhibition llg/ml lA 10 74 lAA 10 90 '' lB 10 91 lC 10 go -lD 10 88 lE 10 86 lF 10 72 .
lGA 10 66 .:
lHA 10 77 ~
2A 1 6 8 ;.:
2B 1 86 . :
~' 2C 1 86 -: 2G 1 90 `
: . . .
contd. ;.
~; , . . .
.. .
wo ~1/09030 pcr~Ep9o/o2l47 ;2 0~ 7 1 4 9 7 Table I ( cont~) Compound Corlcentration % Inhibition lls/ml 2~ 1 ~6 2M l 83 2N 0.5 87 2P 0.5 88 2Q 0. 5 75 2R 0.5 70 2S 0. 5 78 2T o.5 9O
3D ~ 1 82 3E 0.5 70 3F ~ 0.5 84 ., . . . . , .. :
.
- ~ Table.. II ~
~ = .
- . Compound .. . - ~ -. ~ % Inhibition 3AA ~ 88 -, ' WO 91/09030 PCI~/EP90/02147 207i~97 Compounds of formula (I) can be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or des~ribed in the literature. -Thus, according to a feature of the present invention, compounds of for~ula tI), as hereinbefore defined, are prepared by the rea~tion of a salt of the general formula:-[DPIM]-S M (VII) -wherein ~DPIM] is as hereinbefore defined and N is an alkali metal, preferably a sodium or potassium, atom, with a ~ompound of the general formula:-X-W-Y (VIII) or an acid addition salt thereof, wherein X is a group displaceable by a thiolate salt, such as a halogen, e.g. a chlorine, atom or an alkyl- or aryl-sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluene-sulphonyloxy) and W and Y are as hereinbefore defined.
The reaction is carried out in an inert organic .
solvent, such as dimethylformamide or tetrahydrofuran, at from room temperature to 100C, optionally in the presence of a proton acceptor, which may be organic, such as an-amine (e.g. triethylamine), or i~organic, . such as a carbonate of an alkali metal (e.g. potassium -carbonate).
WO 91/09030 PCI`/EP90/02147 2~71497 According to a further feature of the present invention, compounds of general formula (I) wherein Y
represents a group of formula (II), lIII) or (IV), the other symbols being as herei~before defined, are prepared by the reaction of a compound of the general formula:-. ., 1 DPIM ] S-W-NH ( IX ) wherein the symbols are as hereinbefore defined, with a comp~und of the ~eneral formula (X), (XI) or (XII), hereinafter depicted, wherein ~, R2 and R3 are as hereinbefore defined. The reaction is generally carried out in an inert organic solvent, f~r example xylene, and optionally in the presence of an acidic catalyst, suoh as 4-toluenesulphonic acid, at the reflux temperature, with azeotropic removal of water.
According to a further feature of the present invention, compounds of formula ~I), wherein Y
represents a group of formula (V3 and the other symbols are as hereinbefore defined, are ~repared from the correspanding compounds of formula (I) wherein Y
represents a group of formula (IV) and the other sym~ols are as hereinbefore defined, by reduction with a metal hydride reducin~ agent, such as lithium aluminium hydride, in an inert solvent, such as an ether, e.g. diethyl ether or tetrahydrofuran, at O~C
~o room temperature.
' : ' ;
' . ':
:: .. . . : .. .. ;, . . .- , , ~ . .
WO91/09030 PCTtEP90/02147 20``7~7 --.. ~ ` . . ` ... ... .
- 1~
Acoording to a further feature of the present invention, compounds of formula (IJ, wherein Y
represents a group of formula (V) in which the symbols R represent hydro~en atoms and the other symbols are as hexeinbefore defined, are prepared by reduction of the corresponding compounds of formula (I) wherein Y
represents a group of formula (Y) in which the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group and the other symbols are as hereinbefore defined, in conditions similar to those :
described hereinbefore for the reduction of compounds ~ :
of formula I wherein Y represents a group of formula . . .
(IV) to corres~onding compounds wherein Y represents a ~-~
group of formula (V).
According to a further feature of the present invention, compounds of the general formula:-~ DPIM]-S-Wl-CH2-Y (XIV) within formula (I ), wherein Wl represents a methylene group or a straight alkylene chain containing from 2 to :~ .
, - - . :
.
: ......... ' `'`'~`' '''''~ .
.
. --4 carbon atomsr op~ionally substituted with one or more straight- or branched-chain alkyl groups containiny from 1 to 4 ~arbon atoms, the other ~ymbols bein~ as hereinbefore defined, are prepared by reduction of compounds of the general ~ormula:-[D~IM]-S-Wl-~O-Y ~XV) wherein the symbols are as hereinbefore defined, in conditions similar to those described hereinbefore for ~
the reduction of compounds of formula (I) wherein Y . :
represents a ~roup of formula (IV) to corresponding compounds wherein Y represent~ a group of formula (V). ~
The starting materials and intermediates can be ~ .
prepared by the application or adaptation of known methods.
Thus, compounds of formula (VII) can be prepared by the reaction of a bai~e such as ~odium hydride with compounds of the general formula:-[DPIM~-SH (XVI) wherein ~DPIM] is as hereinbefore defined. This reaction is ~onveniently carried out ~n situ.
Compounds o~ formula lIX) can be prepared by the reaction of a compound of formula-(VII), as hereinbefore defined, with a compound of the general :: :
.. . . . .
formula:~
- - : X-W-N~2 - - (XIII) .
- .
WO91/090~0 PCT/~P9o/02147 Z~7149 ~ - 18 -or a salt thereof, wherein X and W are as hereinbefore defined, under conditions similar to those described above for the reaction of a compound of formula (VII) with a compound of formula (VIII).
Compounds of formula (IX) can also be prepared by the reaction of compounds of formula (I), wherein Y ;
represents a phthalimido group, with hydrazine, in a solvent such as eth~nol at temperatures up to reflux.
C~mpounds of formula (XY) can be prepared by the reaction of compounds of formula (~II) with compounds of the general formula:-X-Wl_co-y (XVII) wherein the symbols are as hereinbefore defined, under conditions similar to those described above ~or the .
reaction of a compound of formula (VII) with a compound of formula (vIII).
By the term "pharmaceutically acceptable acid addition salts" as used in this specification is meant .
acid addition salts the anions of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmaceutical properties of the parent compounds of general formula (I).~.are not vitiated-by side-effects ascribable to those anions.
suitable acid.addition salts for use in phar~aceuticals may be selected from salts derived from ,, . . ~, . , ,: I . , , ' WO91/09030 PC~tEP9OtO2~47 ,, ,` ` 20ql497 inorganic acids, for example hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates, , tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-~-hydroxynaphthoates, gentisates and di-~-toluoyltartra~es.
According to a fur~her feature of the invention, acid addition salts of compounds of formula (I) are prepared by reaction of the parent compounds of formula (I) with the appropriate acid, by the application or adaptation of known methods.
As well as being useful in themselves as active compounds, salts of compounds of ~ormula (I) ar~ useful for the purposes of purification of the parent compounds of formula (I), for example by exploitation of the solubility differences between the salts and the parent compounds, by techniques well known to those :~
skilled in the ar~.
: The parent compounds of formula (I) can be regenerated from their salts by the application or adaptation of known methods.
For example, parent compounds of general formula ~I~ can be reg~nerated from ~heir acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
..
. :. : . . - .. :, ., ;: , , : ~. . ~ : -.
WO91/09030 pcT/Epso/o2147 `` ;2~t71497 -`
. .... : .
~ 20 -In this specification reference to compounds of formula ~I) is intended to include reference to their pharmaceutically acceptable acid addition salts, where the context so permit~.
Compounds of formula (I) can be purified by ~he usual physical means, ~or example by crystallisation or chromatography.
The following Examples illustrate the preparation of compounds according to the invention and the Reference Examples illustrate the preparation of intermediates.
N.M.R. spectra were recorded at 200MHz or 400MXz. Chemical shi~ts are expressed in ppm relative to tetra~ethylsilane. Abbreviations have the following significances:-s = singlet, d = doublet, t ~ triplet, q = guartet, quin = quintet, m = multiplet, dd = doublet of doublets, dt - doublet of triplets, br = broad signal.
Infra-red spectra were recorded in potassium bromide discs. The positions of the major absorption peaks are given.
., . :
.
~: . , I ' WO 91/09030 PCI'/EP90/02147 o 21 ~ . ,` `. ~071~g7 --~ (D~) ~' ~L
)~R2 (II) r ~Z -:
(III) 0 1~3 3 ~Ly .
(n) Ir /\ 3 o ~3 . ~ :
(V) R ~ R3 `; ;` ` 2~7i"497 . :
-- 22 -- ~
~{C'R~ 'T~
~r( )2]n ;' ~ ' : . -~,~1~ (X) ' O
o~ (XI) ' ~ .
: .
0 R3 ~3 2 (XII ) :: : , ; O -~
; ~ .
: : :
WOsl/09030 PCT/EP90/02147 .~ ~07~4~7 Com~ounds lA, lB, lC and lD
Sodium hydride (1.2g, 40mmol of an 80%
dispersion in oil) was added to a stirred suspension of.
4,5-diphenylimidazol-2-thiol (5.04~, 20mmol) in dry tetrahydrofuran t180ml) at ambient temperature. After stirring for 0.Shr, N-~2-chloroethyl)morpholine hydrochloride ~3.72~, 20mmol) was added followed by triethyl~mine (3ml). The mixture was heated under reflux for 48hr, then poured into water (300ml) and extracted with ether (2 x 200ml). The ethereal solution was then extracted with aqueous 2N
hydrochloric acid (200ml). The acidic aqueous solution was then basified (NaOH) and extracted with ether (2 x 150 ml). This ethereal solution was dried ~MgSO4), :
evaporated, and the residue recrystallised from toluene to give N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- .
morpholine (4.9g), as a colourless solid, m.p. ;
- 129-132~C;
EElemental analysis:- C, 68.9; H, 6.3; N, 11.
. Calculated for C21H23N3OS:- C, 69.0; H, 6.3;
- N, 11.5%;
-- ~ . N.M.R.(CDCl3 &.D2O): 2.55 ~(4H, br t, J=4Hz), 2.86 (2H, t, J=6Hz), 3~11 (2H,-~, J=6Hz), 3.5 (4H, br - .t,:J=4Hz), 7.2-7.6 (10H, m)].~ . :
~.
.. . ~ . .. .... .. . . . . .. . .. . . .. .. . .
WO9l/09030 PcT/EP90/02l47 ~071~97 - 24 - ~
By proceeding in the s~me manner, but replacing ~he N-(2-~hloroethyl)morpholine by:
1) N-(3-chloropropyl)morpholine;
ii) N-(2-chloroethyl)piperidine; and iii) N-(3-chloropropyl)-N'-methylpiper~2ine there were prepared:
i) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl~-morpholine, m.p. 135-1379C;
ii) N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-piperidine, m.p. 143-145C; and iii) N-(4,~-diphenylimidazol-2-ylthio)propyl]-N'-methylpiperazine, m.p. 175-178C.
Compound lAA
Acetyl chloride (2Oml) was added dropwise to cold (10C) ethanol (90ml) with stirring, main~aining the temperature below 30C. After stirring for 0.5hr, a solution of N-[2-(4,5-diphenylimidazol-2-yl~hio)-ethyl~morpholine (1.5g, 4.1mmol) in ethanol (lOml) was added and stirring continued for 0.5hr. The mixture was then evaporated and the residue recrystallised from ethanol to give N-[2-(4~5-diphenylimidazol-2-ylthio)-ethyl]morpholine dihydrochloride (1-46g~, as a colourless~solid, m.p. 247C; ~ ~ 3 [Elemental analysis:- C, 55.1;-H, 5.95;
Clt 15.3; N, 8.9~;
..
.,. . .. . . . . . .. , . . ., .. , .;.. . . . ~ .. . , . , , ~ .. , . , . ;; ,, , .. ~ , , i WO91~OgO30 pcT/Epso/o2l47 207..~497 .
Calculated for C21H23N3S.2HCl.H20:- C, 55.3;
H, 5.96; Cl, 15.5; N, 9.2~
N.M.R. (CD3SOCD3 & D2O) 3.23-3.95 (12H, m), 7.3~-7.56 (lOH, m)].
ompound lE
Sodium hydride ~ 0.48g, 16mmol of an 80%
dispersion in oil) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (3.78g, 15mmol) in dry tetrahydrofuran at ambient temperature. After stirring ~:
for 0.5hr, N-(2-tosyloxyethyl)pyrrolidin-2-one (5.66g, 20mmol) was added and stirring continued for 3hr. The ~ :
mixture was then poured into water (500ml) and extracted with ether (2 x 200ml). The ethereal solution was dried (~gS04), evaporated, and purified by flash chromatography (19:1 dichloromethane / methanol as eluent). The product was crystallised from 1:1 ethyl ~
ace~ate / petroleum ether ~60-80C) to give N-[2-(4,5~ :
diphenylimidazol-2-ylthio)ethyl]pyrrolidin-2-one .
(4.2g), as a colourless solid, m.p. 128-130 C; :~
~Elemental analysis:- C, 69.4; H, 5.75; N, 11.7%
. .
.
C21~21N3S:-~C~ 69-4; H 5 82 - - N, 11.6~; ., : .~ ..... ; -, . .
,~ f~
,. ~,, , . ~ ,, ,, . , . . ,:, . . . ` - , : ,, ', , ' .: ', ' , '. . ':; ', . ' ' ' ` '., ' ' :, ` ' ' ~ ' . '. . ' .. : ' . - ' . ` :':" ': .': -WO 91/09030 PCI'/EP90/02147 ~Q~4~7 2 ~
.
N.M.R. (CDCl3): 2.14 (2H, q, J=7Hz), 2.58 (2H, t, J=7HzJ, 2.96 (2H, t, J=6Hz), 3.46 (2H, t, J=7Hz), 3.64 (2H, t, J=6Hz), 7.1-7.45 (6H, m), 7.46-7.74 (4~, m~, 12.3 (lH, br s)].
ComPound lF
A solution of N-[2-(4,5-diphenylimidazol-2-yl-thio)ethyl]pyrrolidin-2-one (3.2g, 9mmol ) in dry tetrahydrofuran (20ml) was added to a stirred suspension of lithium aluminium hydride (1.07g, 28mmol) in diethyl ether (300ml) at ambient temperature under an argon atmosphere. Stirring was continued for 0.5hr, then ethyl acetate (50ml) was added slowly with ice cooling followed by water (300ml) and stirring then continued for 0.5hr. The organic layer was separated, dried (MgS04), and evaporated to a gum which was purified by flash chromatography (9:1 dichloromethane / methanol as eluent). The product was dissolved in ethyl acetate (5ml) and petroleum ether (60-80~C; 50ml) was added to give N-~2-(4,5-diphenylimidazol-2-ylthio)-ethylJpyrrolidine (1.9g), as a colourless crystalline solid, m.p. 102-103C; - - -tElemental a~alysis:- C, 72.3; H, 6.4; N, 12.1% -21H23N3S: C, 72.2; H, 6.6;
~, 12.0%
... .. . .; . .. .. . . . . .
rl 2 0 7 1 4 9 7 N.M.R. (CDC13 & D20~: 1.53-1.64 (4H, m), 2.6-2.68 (4H, m), ~03-3.1 (4H, m)~ 7.2-7.33 (6H, m), 7.41-7.~5 (4H, m)~
S
Compounds lG and lGA
Potassium tert.-bu~oxide (4.44g, 39.6mmol) was added to a stirxed suspension of 4,5-diphenylimidazol-2-thiol (lOg, 39.Smmol) at ambient temperature to give a yellow solution. Af~er stirring for O.Shr, N-(3-chloropropyl)piperidine hydrochloride (11.77g, 59.4mmol) was added. The mixture was stirred for 18hr and evaporated, and the residue mixed with ethyl acetate (200ml) and washed with water (250ml), saturated a~ueous sodium bicarbonate solution (200ml) and water (200ml). The organic phase was dried (MgS04) and evaporated and the orange residue was crystallised from agueous ethancl to give N-[3-(4,5-diphenyl-imidazol-2-ylthio)propyl~piperidine (3.98g), as a colourless solid~ m.p. 118-120~C.
Acetyl chloride 125ml) was added dropwise to cold ~<10C) ethanol (70ml) with stirring, maintaining :-.
the temperature below 10C. After stirring for O.Shr, a solutio~ of ~-t3,.(4,5-diPhen~limidazol-2-ylthio)-propyl]piperidine-(3.98g) in;etha~ol (lOml) was àdded . .- .. . ... . .
Wo91/09030 PCT/EP~0/02147 `: 2071~7 -`
and stirring continued for 0.5hr. The mixture was then evaporated and the residue crystallised ~rom ethanol /
ether to give N-r3-(4,5-diphenylimidazol-2-ylthio)-propyl~piperidine dihydroc~.loride (2.62g~ as a colourless solld, m.p. 180-185C;
~ Elemental ana~ysis:- C, 59.3; H, 6.5; Cl, 14.8;
N, 9.1; S, 6.6%
Calcul~ted for C23H27N3s.2Hcl~H2o - C, 59.0;
H, 6.67; Cl, 15.1; N, 8.97; S, 6.84%]
Co~ nds lH and lHA
Potassium tert.-butoxide (4.44g, 39.6mmol) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (lOg, 39.6mmol) at ambient temperature to give a yellow solution. Af~er stirring for 0.5hr, 2-(hexa-methyleneimino)ethyl chloride monohydrochloride (11.9g, 60mmol) was added. The mixture was stirred for 18hr filtered, and the solid washed with small portions of dimethylformamide until the washings-were colourless.
The insoluble material was shaken with a ~ixture of ethyl acetate (50Oml) and a~ueous potassium carbonate solution 110%, 250ml) until complete solution occurred.
.. .. ~ ~ .
The organic;phase;was-washed-with water (2xiOOmlj, dried (MgS04) and~evaporated to give-N-~2-(4,5-diphenylimidazol-2-ylthio~ethyl]perhydroazepine ~10.8g~, as a colourless solid.
....
.: .: . ... . .. .
WO9l/09030 PCr/EP90/02147 .~ 207~97 Acetyl chloride (25ml~ was added dropwise to cold (<lO~C) methanol (150ml) with stirring, :
maintaining the temperature ~elow 10C. After stirring for O.Shr, a ~olution of N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]perhydroazepine (10.8g) in methanol (lOOml) was added and stirring continued for 5min.
Decolourising charcoal (lg) was added, stirring conti~ued for 15min and the mixture was filtered. The filtrate was evaporated to low volume and ether added to give N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- :
perhydroazepine dihydrochloride (ll.Sg), as a colourless solid, m.p. 225-230~C; : .
tElemental analysis:- C, 59.8; H, 6.7; Cl, 15.4; ~:-N, 9.2; S, 7.4% :.
Calculated for C23H2~N3S.2HCl.~H20:- C, 60.1;
H, 6.58; Cl, 15.4; N, 9.15; S, 6.98%]
Compounds_2A, 2B and 2C
i) Sodium hydride (0.6g, 20mmol of an 80%
dispersion in oil) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (4.45g, 17.7mmol) in dry :
tetrahydrofuran (130ml~ at ambient temperature. After stirring . f or O.5hr, N-(2-bromoethyl~phthalimide (5.08g, . ~ ~ .. .
20mmol) was added and the solution heated under reflux for 6hr. The mixture was then poured into water ~500ml) and extracted with ethyl acetate (2 x 200ml). -:
: . .
:.
2071~97 The extract was dried (MgS04) and evaForated to a gum which was crystallised from toluene to give N-~2-(4,5-diphenyllmidazol-2-yl hio)ethyl~phthalimide ~5.05g), as a very pale cream solid, m.p. 165-166C;
~Elemental analysis:- C, 70.8; H, 4.5; N, 9.8%;
Calculated ~or C25H1gN3O2S:~ C, 70.6; ~, 4.5;
N, 9.9%
N.M.R. (CDC13 & D2O): 3.22 (2H, t, J=5Hz), 3.98 (2H, ~, J=5Hz), 7.23-7.45 (6H, m), 7.54 (2H, d, J-7Hz), 7.62 (2H, d, J=7Hz), 7.73-7.78 (2H, m) 7.86-7.92 ~2~, m)]. : :
By proceeding in a similar manner, but replacing the N-(2-bromoethyl)phthalimide by N-(3-bromopropyl)-phthalimide and N-(4-bromobutyl)phthalimide there were prepared: :
- ii) N-[3-(4,5-diphenylimidazol-2-ylthio)-propyl]phthalimide, a colourless solid, m.p. 188-190C;
~ Elemental analysis:- C, 70.7; H, 4.7; N, 9~2%
26 21 3O2S: C, 71.0~; H, 4.8;
N, 9.6% ..
.
N.M.X. (CDC13 & D2OJ: 2.03 (2H, guin, J=7Hz), : 3.05 (2H, t, J=7Hz), 3.96 (2H, t, J=7Hz), 7.2-7.4 (6H, m), 7.42-?.62 (4H, m), 7.:7~-(2H, dd, J-6 and 3Hz), 7.82 12H! dd, J=6 and 3HzJ~; and -~
iii) N-~4-(4,~-diphenylimidazol-2-yithio)butyl]-phthalimide, a colourlsss solid, m.p. 170-171C;
W091/09030 PCT/EP90/02147 ~ ~
2~71~97 [Elemental analysis:- C, 71.7; H, 5.0; N, 9.3;
S, 7.4%
27 23N32S: C, 71.5; H, S.1;
N, 9.3; S, 7.1% i-~
N.M.R. (CDC?3 & D2O): 1.62-1.93 (4R, m~, 3.15 (2~, t, J=6Hz), 3.74 (2H, t, J=6Hz), 7.2-7.39 (6H, mJ, 7.4-7.6 (4H, m), 7.62-7.78 (4H, m~].
EXA~MPLE B
C~ , .:
Diglycolic anhydride (8.34g, 32.3mmol) was added~.
to boiling xylene (500ml) with stirring.
2-(3-Aminopropylthio)-4,5-diphenylimidazole (5.0g, ~:.
16.2mmol) was then added in lg portions at 45 minute intervals with vigorous stirring to the boiling mixture, removing any water formed azeotropically.
After the final addition, heating under reflux was ~on~inued for l.Shr and the mixture was allowed to cool and decanted. The solution was evaporated and the :
residue puxified by flash chromatography on silica gel ~39:1 dichloromethane / methanol as eluent). The .
product was recrystallised from acetonitrile to give N-~3-(4,5-diphenylimidaæol-2-ylthio)propyl3morpholine-3,5-dione (3~7g), a~ a colourless solid, m.p. :
16~-166~C;
~ . .. ..
WOgl/09030 PCT/EP90/02147 ~: ~d~ -~
~ Elemental analysis :- C, 64.6; H, 5.1; N, 10.2;
S, 8.0%
CalCulated for C22H21N33S:- C~ 64-9; H 5 2;
N, 10.3; S, 7.9~ ;
N.M.R. (CDCl3 & D2O): l.9B (2H, guin, J=7Hz), 3.09 (2H, t, J=7Hz), 4.02 (2H, t, J=7H2), 4.34 (4H, s), 7.2-7.37 (6H, m), 7.45-7.57 (4H, m)].
m~ounds ?E to 2T
2,4-Dimethylglutari~ anhydride (7.3~g, 51.7mmol) was added to boiling xylene (500ml) with stirring.
2-(3-Aminopropylthio)-4,5-diphenylimidazole (4.0g, 12.9mmol) was added in lg portions at 1 hour intervals, with vigoxous stirring, to the boiling mixture removing any water formed azeotropically. Reflux was continued $or 2hr and then toluenesulphonic acid monohydrate (0.4g, 2.1mmol) was added and reflux continued for 8hr.
The mix~ure was allowed to cool and decanted and the solu~ion was then evaporated. The ref~ulting residue was purified by flash ~hromatography on silica gel , .. .. .
.
.. ~ , . . . .. ; . .
. . . ~ , . .
' .
,.~ ~,-, .
WO91/09030 PCT/EP90tO2147 2 ~ 7 1 4 9 ~
(97:3 dichloromethane / methanol as eluent). The product was recrystallised from acetonitrile to give 3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio)-propyl]piperidine-2,6-dione (3.23g~, as a colourless solid, m.p. 132-134DC;
~Elemental analysis :- C, 69.0; H, 6.2; N, 9.8;
S, 7.4% :~ :
Calculated for C25~27N325 - C~ 69.3; H~ 6-3;
N, 9.7; S, 7.4%
N.M.R. (CDC13 & D2O): 1.27 ~6H, d, J=7Hz), 1.49 (lH, q, J=12Hz), 1.73-2.04 14~, m), 2.02 (lH, dt, J-4 and 12Hz), 2.53-2.82 (2H, m), 2.93 (2~, t, J=~Hz), 4.13 ~2H, t, J=7Hz), 7.22-7.34 (6H, m), 7.48-7.62 (4H, m)].
The N.M.R. spectrum indicated that this was a 9:1 mixture of syn and anti isomers.
By proceeding in a similar manner, but replacing the 2,4-dimethylglutaric anhydride by the appropriate anhydride and the 2-(3-aminopropylthio)-4,5-diphenyl-imidazole by the appropriate amine, there:were prepared:-ii) N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl]-maleimide, a yellow solid, m.p. 132-133C; ` -. _ . . .
~ Elemental analysis:- C, 67.Q; H, 4.5,-N, li.1%
. Calculated for C21Hl~N3O2S:- C, 67-2; H, 4-53;
N, 11.2%]; .
' . -` `- 2071497 N.M.R. (CDC13 & D20): 3.13 ~2H, t, J=6Hz), 3.82 ~ :
(2H, t, J=6Hz), 7.2-7.45 ~6H, m), 7.46-7.7 (4H, m)].
iii) N ~3-(4,5-diphenylimidazol-2-ylthio)- .
propyl]-4-methylmaleimide, a buff solid, m.p.
136-138C;
EElemental analysis:- C, 68.2; H, 5.15; N, 10.4;
S, 8.1%
23H21N3O2S: C, 68.5; H, 5.2;
N, 10.4; S, 7.94%];
N.M.R. (CDC13 & D2o~ 94 (2H, quin, J-7Hz), 2.06 (3H, d, J=4Hz), 3.02 (2H, t, J=7Hz), 3.78 (2H, t, J=7Hz), 6.32 (lH, d, J=4Hz), 7.22-7.38 (6H, m), 7.45-7.56 (4H, m)~;
iv) N-r2-(4,5-diphenylimidazol-2-ylthio)-e~hyl]pyrrolidine-2,5-dione, a colourless solid, m.p.
189-191C;
[Elemental analysis:- C, 66.8; H, 5.1; N, 11.1;
S, 8.5%
Calculated for C2lH1gN302S:~ C, 66.8; ~, 5.04;
N, 11.14; S, 8.5~
v) . N-~3-(4,5-diphenylimidazol-2-ylthio)- ~.
p~opylJpyrrolidine-2,5-dione, a colourless solid, m.p.
177-179C,~
Elementai-analysis:- C, 67.6; H, 5.4; N, 10.6 Calculated for C22H21N3o2s , 10.7~];
:
- -:
~ "
2~7~497 vi) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-piperidine 2,6-dione, a colourless solid, m.p. -154-155C;
[Elemental anal~sis:-C, 68.2; H, 5.8; ~, 10.4%
C23H23N3O2S: C, 68 .1; H, 5 . 7;
N, 10.36%~;
vii) 4,4-dimethyl-N-[2-(4,5-diphenylimidazol- .
2-ylthio)ethyl]piperidine-2,6-dione, a buff solid, m.p.
86-88C;
[Elemental analysis:- C, 68.2; ~, 6.27; N, 9.6; :
S, 7.5% ~`
24 25N325 C, 68.7; H, 6.0 N, 10.0; S, 7.6%];
viii) 4,4-dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]piperidine-2,6-dione, a colourless :
solid, m.p. 1~5-157C;
[Elemental analysis:- C, 69.0; H, 6.24; N, 9.6;
S, ~.4% :
Calculate~ for C25H27N32S:- C~ 69-26; H~ 6-2~;
N, 9.7; S, 7.4%];
ix) N-[3-(4,5-diphenylimidazol-2-ylthio)-propyl~-4-methylpiperidine-2,6-dione, a colourless solid! m.p. 1~0-162C;
[Elemental analysis:- C, 68.9; H, 6.03; N, 9.9%
Calculated for C2~H25N3O25:- C, 6d.7; H, 6.0;
N, 10.0% ];
. j , , ~ ", ' i ' . . . ; . . , ' ~ ' ' ' ~ ' . . , ' . .
WOgl/09030 PCT/EP90/02147 x) N-~3-(4,5-diphenylimidazol-2-ylthio)-propyl]-4-ethyl-4-methylpiperidine-2,6-dione, a buff solid, m.p. 134-136C;
[Elemental analysis:- C, 69.6; H, 6.5; N, 9.3;
S, 7.3%
Calculated for C26H29N302S:- C, 69.77; H, 6.53;
N, 9.4; S, 7.16%];
xi) N-r3-(4,5-diphenylimidazol-2-ylthio)propyl]-thiomorpholine-3,5-dione, a cream solid, m.p.
164-16~C.;
[Elemental analysi~:- C,62.3; H, 4.84; N, 9.8;
S, 15.0%
Calculated for C22H2lN3o2s2 :~ C, 62-4; H~ 5.0;
N, 9.9; S, 15.14%~;
xii) 4,4-dimethyl-N-~3-(4,5-di-p-tol~l-imidazol-2-ylthio)propyl]piperidine-2,6-dione, a cream ~.
solid, m.p. 175-177C;
[Elemental analysis:- C, 69.8; H, 6.65; N, 9.1;
S, 6.95% . .
r C27H3l~3o2s:- C, 7~.25; ~, 6.77; -N, 9.1; S, 6.95%];
xiii3 No[3-t4,5-di-p-tolylimidazol-2-ylthio)-propyl]morpholine-3,5-dione, a buff solid, m.p.
148-149C; ~ - ' . ~ . . I .
- ~
. . :.. :.. :.. . ... : . .. , ..... :........ . .. .... .... . . - .
W091/09030 PCT/EPso/02147 .
[Elemental analysis:- C, 66.4; H, 5.7; N, 9.5; :;
S, 7.4%; ~ :
~24H25~3035:- C, 66.18; H, 5.8;
N, 9.65; S, 7.36%];
xiv) N-[3-(4,5-di-2-chlorophenylimidazol-2-ylthio)propyl]-4,4-dimethylpiperidine-2,6-dione;
xv) N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]-morpholine-3,5-dione, a colourless solid, m.p.
153-155C; ~-:
[Elemental analysis:- C, 65.1; H, 5.45, N, 10.0;
S, 7.5~
Calculated for C~3H23N3035:- C, 65.5; H, 5.5;
N, 9.97; S, 7.61~]; and xvi) 3,3-dimethyl-N-t3-(4,5-diphenylimidazol- :
2-ylthio)propyl]piperidine-2,6-dione, a colourles~
solid, m.p. 168-170^C; ..
~Elemental analysis:- C, 69.3; H, 603; N, 9.7;
S, 7.~% . -Calculated for C25H27N32S - C, 69 26; ~ 6 28; ~
N, 9.69; S, 7.496]. ~:
EXAMPLE 10 . .- .......................... ;
ComDounds 3A and 3AA
i) A suspension of 4,5-diphenylimidazole-.2-thiol 15.04g 20mmol) in anhydrous THF (180ml) was treated with sodium hydride (80% dispersion in oil, 1.2g,. ~-~ ' ~, .. , ,~, , .
wosl/09030 PCT/EP90/02147 .. .
40mmol) and the mixture stirred at room temperature for30min. A mixture of (~)-3-~hloromethyl-1-methyl-piperidine hydrochloride (3.68~, 20mm~1) and sodium hydride (80% dispersion in oil, 0.6g, 20mmo1) in anhydrous T~F (20ml) was also stirred at room temperature for 30min. The two mixtures were mixed together, triethylamine (3.0ml~ was added, and the whole mixture stirred at reflux overnight. After cooling to room temperature the reaction mixture was poured onto iced water (300ml) and extracted with ether (3x200ml). The ~ombined ethereal extracts were extracted with 2M hydrochloric acid (3xlOOml). The acidic solution was basified with 50% sodium hydroxide solutio~ with ice cooling and the product extracted into ether (3xlOOml). The combined extracts were dried (MgS04) and evaporated to give a whi~e solid (2.0g).
Crystallisation from toluene gave [3-R,S]-3-[~4,5-diphenylimidazol-2-ylthio)methyl~-1-methyl-piperidine (1.5~), as a white crystalline solid, mp 167-169C;
~Found:-C, 72.6; H~ 6.9; N, 11.5; S, 8.$.%
CalCulated for C22H25N3S - C~ 72-7; H- 6-9;- ¦
N,~11.6;~ S,- 8.8%~
~ N M R (CDC13) 1.92~(3H-j s), 1.40-2.70, (9H, -m~,-3.20 (2H, m), 7.20-7.50 (lOH, m) IR (RBr): 696, 765, 1445, 1494, 2926 and ~, , . .
` . 1 ' WO91/09030 PCT~EPgo/02147 . ~.
. . . ;.
- 39 - 20 71 ~ 9 7 -3433 cm 1~.
ii~ A solution of [3-R,S]-3-~(4,5-diphenyl-imidazol-2-ylthio)methyl]-1-methylpiperidine (4.1g, 11.3mmol) in ethanol (30ml) was ~dded with stirring and ice cooling to a solution of hydrogen chloride in ethanol [prepared by adding acetyl chloride (40ml) dropwise to cold (10C) ethanol (180ml) with stirring, maintainin~ the temperature below 30C]. The mixture was allowed to warm to room temperature and s~irred ~or 2hr. Ether (200ml) was added and the white precipitate .
was collected by filtration and wash~d thoroughly with fresh ether to give [3-R,S]-3-[(4,5-diphenyl-imidaæol-2-ylthio)methyl]-1-methylpiperidine hydrochloride ~4.6g), as a white powder, mp 175-177C;
[Found:- C, 59.7; H, 6.5; N, 9.0; Cl, 14.3;
S, 6 ~ 8 % - .
Calculated ~or c22H2sN35 l 8Hcl H2O - C~ 59-2;
H, 6.5; N, 9.4; Cl, 14.3; S, 7.2%~. -~ - EXAMPLE 11 Compounds 3R, 3C and 3D
i) A mixture of 5-iodomethyl-2-pyrrolidinone (1.83g, 8.1mmol), 4,5-diphenylimidazole-2-thiol (1.83g, 7 . 3mmol ) and anhydrous potassium carbonate ( O . 70g, ~ -~ . .. . .
5.1mmol) in DMF (35ml) was stirred at room temperature overnight. The mixture was evaporated to low bulk and the residue suspended`in watèr (70ml). The product was .
:~ ' .
WO91/09030 PCT/EPgo/02l47 ,. 2071~97 .:
. .
collected b~ ~iltration, dried, and cr~6talli~ed from ethanol / ether to give rs-R~s~-s-r(4~s-dip~e~vl-imldazol-2-ylthio~methylJ-2-p~rrolldinone (O.g~g) as a whi~e crystalline solld, mp 218C;
~Fo~nd:- C, 68.6~ H, 5.5; N, 12.0J S, 9.1%
20H19~30S:- C, 68.7) ~, g,5;
N, 12.0~ S, 9.2~ :
N.M.R. (CDCl3): 1.85 & 2.35 (4H, 2m), 3.00 ~ .
3.27 (2H, 2dd, J=14Hz and 4HzJ, 3.91 ~lH, m), 7.2-7.7 tlO~, m) I~ (KBr): 69B, 762 and 1680 cm ~ i) By proceeding in the Eame mann~r, but replacing the S-lodomethyl-2-p~rrolidin~ne by 6-lodo~ethyl-~-piperidinone 3nd puri~ylng t~e crude prod~ct ~ flash chromatography (10% ethanol in ethyl acetate) followed by crystallis~tion ~ro~ ethanol /
et~er, there was prepared ~6-R,S]-6-~(4,~-dlphenyl-~midaziol-2-ylthio)methyl]-2-piperldinone, as a ~hite ~ .
~olid, mp 209-~10C:
[Founds- C, 69.4; H, 5.8~ N, ll.~t S, 8.~.%
- ~iouiated ~or~c2l.
~, 11.6, S, 8.8%
. .. . .... . . ~ . - - ; .. . . . ,. j N.M.R. (CD3SOCD3)- 1.4-2.0 ~ 2.05-2.10 (6H, 2 3.24 (2H, m), 3.63 (1~, m), 7.20-7.55 (10~, m,) IR (KBr~: 697, 7~3 and 1634 cm 1~.
.
, . .
WO91/09030 PCT/EPsO/02147 . ~ .
- 2071~97 iii) By proceeding in the same mannex, but replacing the 5-iodomethyl-2-pyrrolidinone by 4,4-dimethyl-5-iodomethyl-2-piperidinone and purifying the crude product by flash ~hromatography tethyl acetate), there was prepared r6-R,S]-4,4-dimethyl-6-[(4,5-~iphenylimidazol-2~ylthio)methyl]-2-piperidinone as a white solid, mp 148-150C;
tFound:- c, 70.3; ~, 6.6; N, 10.4.%
Calculated for C23~25N~os - C, 70.6; H, 6.4;
N, 10.7%.
~.M.R. (CD3SOCD3): 0.94 ~ 0.98 (6H, 2s), 1.2-1.8 (2H, m), 1.96 (2H, m), 3.26 (2H, m), 3.73 (lH, m), 7.20-7.58 (lOH, m) IR (RBr): 695, 763, 1488 and 1636 cm 1].
The iodomethyllactam starting materials were prepared by the method of S. Knapp et al, -J. org. Chem., 1988, 53, 4006.
Com~ounds 3E and 3F - .
. i) A suspension of 4,5-diphenylimidazole-2-thiol (8g, 31,7mmol) in anhydrous THF (250ml) was-treated ... . , . ~ . i ..with.;sodium hydride 580%:in oil;.0,97g, 32.7mmol) and .the.~mixture.stirredjat room temperature for 30min`. A
.mixture of (~)-4-~l2-(~-toluenesulPhonYloxy)ethyl]-l-methylpiperidine t9.4g, 31.6mmol) in anhydrous THF
t20ml) was added and the mixture stirred at room .' .
.;" 2'b7l~g7 temperature for 18hr, followed by refluxing for 24hr.
After ~ooling to room temperature, the reaction mixture was poured into i~ed water (500ml) and extracted with ether (4xlOOml). The combined ethereal extracts were extracted with hydrochloric acid (2M, 4xlOOml~. The a~idi~ solution was basified with 50% sodium hydroxide solution with ice cooling and the product extracted into ether (3x500ml). The combined extra~ts were dried (MgS04) and evaporated and the residual solid (5.4g) was purified by flash chromatography on silica gel (9:1 dichloromethane J methanol as eluent) to give [4-R,S]- ..
4-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-1-methyl-piperidine (2.28g), as a colourless solid, m.p.
74-76C;
[Found:- C, 73.3; H, 7.4; N, 10.8; S, 8.6%
Calcula~ed for C23H27N35:- C~ 73 16; H 7 2;
N, 11.3; S, 8.5%J.
ii) By proceeding.-in a similar manner, but ; ' repla~ing the (l)-4-[2-(p-toluenesulphonyloxy)ethyl]-l~methylpiperidine by (~ 2-(p-toluenesulphonyloxy)-methyl-1-methylpiperidine and purifying the crude product by crystallisation from toluene followed by .
conversion to the hydrochloride s'alt~''and':'s'ubséquént .
regeneration:of.-the.~ree base, there was prëpared' .
- 12-R,]-2-[~4,5-diphenylimidazol-2-ylthio~methyl~- :
, - :.: . ~ ' I
. .
-1-methylpiperidine, as a colourless solid, m.p.
62-64C;
[Found:- C, 71.4; H, 6.9; N, 11.2; S~ 8.2%
Calculated for C2~H25N3S-~H2O:- C, 71-7;
H, 6.98; N, 11.42; S, 8.71%].
Com~ound lI
By proceeding in a manner similar to that described in Example 4, but replacing the N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl~pyrrolidin-2-one, used as a starting material, by a mixture of cis- and trans-2,6-dimeth~l-N-~4-(4,5-diphenylimidazol-2-yl-thio)butan-1-oyl]morpholine, carrying out the reaction for 4 hours, followed by the addition of water and then aqueous sodium hydroxide solution for the work-up, there was prepared a mixture of cis- and trans-2,6-dimethyl-N-[4-(4,5-diphenylimidazol 2-ylthio)butyl]-morpholine, m.p. 50-60C (slowly melts). [Elemental analysis:- C,70.0;~,7.4;N,9.8;S,7.6;H20,1.4%;
calculated for C25H31N35 -5~2 -C,69.73;H,7.49;N,9.76;S,7.44;H2o,2.09%].: :
~ ; - EXAMPLE 14 Compounds 18A, lCA ~nd lIA - -By proceeding in a manner similar to that des~ribed in Example 2, but staxting with:-i) N-~3-(4,5-diphenylimidazol-2-ylthio)propyl]-""~ ,"" ~-"~ ,;; "
, ~; 20714~7 44 morpholine;
ii) N-[2-(4,5-diphenylimidazol-2 ylthio)ethyl]-piperidine; ~nd iii) a mixturP of cis- and trans-2,6-dimethyl-N-~4-(4,5-diphenylimidazol-2-ylthio)butyl)-morpholine;
there were prepared:-i~ N-~3-(4,5-di~henylimidazol-2-ylthio)pro~yl]-morpholine dihydrochloride, m.p. 173-175C ~Elemental analysis:- C,54.7;H,6.02;Cl,14.9;N,9.1;S,6.41;H2O,6.4%;
calculated for C22H25N3Os:2~ .75H20 Cl,15.09;N,8.7;S,6.64;H2O,6.52%~;
ii) N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl~-piperidine dihydrohloride, m.p. 237-240C [Elemental analysis:- C,60.06;H,6.4;Cl,16.0;N,9.6;S,7.3%;
calculated for C22H~5N3S:2HCl:- C,60.54;H,6.24;
Cl,16.25;N,9.63;S,7.35%]; and iii) a mixture of cis- and trans-2,6-dimethyl-N- r 4-(4,5-diphenylimidazol-2-ylthi~)butyl]morpholine ;
dihydrochloride, m.p. 208-210C [Elemental analysis:-C,60,6;~,6.9;Cl,13.9;N,8.5;S,6.47i~; cal~ulated for ~ :
C252H31~5N305:2HCl:~ C,60.?2;H,6.73;Cl,14.34;N,8.5; . ' S,6.48%~. . ~ ....... .. . .~ i.:
. ~ ., . . ~ .. . .
... . ., .. - - :~:
. . .; ~ ~;
, ,:
! ~
j~ , ~ , , , , . : , . ~ , . : :
WO91/09030 pcT/Epso/o2l47 ,. . ' ~ 45 ~ ~ 2~71`-49~7 8~ ::
Com~ounds 4A and 4~
~ y proceeding in a manner similar to that described in Example 4 but starting with:-i) N-[3-(~,5~diphenylimidazol-2-ylthio)propyl]-pyrrolidin-2,5-dione; and ii) N-t3-(4,5-diphenylimidazol-2-ylthio)propyl]-morpholin-3,5-dione;
there were prepared:-i) N-[3-(4,5-diphenylimidazol-2-yl~hio)propyl]-5-hydroxypyrrolidin-2-one, m.p. 185-187C; and ii) N-t3-(4,5-diphenylimidazol-2-ylthio)propyl]-5-hydroxymorpholin-3-one; m.p. 105C (shrinks at 87C).
. . .: . .
.
~:
; , , . ,. , ........... .: -2071.49.~ 6 -i) Sodium hydride (1.4g, 46mmol of an 80~
dispersion in oil) wa~ added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (5.04g, 20mmol) in dry THF
(150ml) at ambient temperature. After stirring for 0.25hr, 3-bromopropylamine hydrobromide (4.38g, 20mmol) was added. The mixture was then heated under reflux for lhr then poured into water (lOOOml) and extracted with ethyl acetate (2 x 500ml). The combined extract w~s dried (~gSO4) and evaporatPd. The residue was triturated with ethyl acetate / ether (1:1; 70ml) and the solid collected to give 2-(3-aminopropylthio)-4,5-diphenylimidazole (4.8g). An analytical sample was prepared by recrys~allisation from toluene to give ;
colourless crystals, m.p 162-163C;
[Elemental analysis:- C, 70.1; H, 6.3; N, 13.5%
Calculated for C18H19N3S - C~ 69.9; H~ 6-2;
N, 13.6%
N.M.R (CDCl3 & D2O): 1.88 (2H, quin, J=7Hz~, :
2.93 (2H, t, J-7Hz), 3.2 ~2H, t, J-7~z), 7.2-7.32 (6H, m), 7.47-7.53 (4H, m)].
ii) By proceeding in a similar manner, but ~ i replacing the 3-bromopropylamine hyc~obromide by j~
2-bromoethylamine hydrobromide there was prepared 2-(2-aminoethylthio)-4,5-diphenylimidazole, ~ :
m.p.152-154C;
wosl/09030 PCT/~P90/02147 ``: 2~1497 ~ Elemental analysis:- C, 68.6; ~, 5.8; N, 14~1;
S, 10. 5%
17 17N3S C, 69.1; H, 5.8;
N, 14.2; S, 10.85%
N.M.R. (CDC13 & D2O): 3.1 (4H, br s), 7.16-7.36 (6H, m), 7.42-7.56 (4~, m)3.
N r 4-(4,5-Diphenylimidazol-2-ylthio)butyl~-phthalimide (10.2g, 22.5mmol) [prepared as in Example l(iii)~ was heated under reflux in a mixture o~ ethanol (25Qml~ and hydrazine hydrate (1.25g, 25mmol) for 22hr.
An aqueous solution of hydrochloric acid (2N; 50ml) was then added and boiling continued for 0.5hr. The mixtl~re was then chilled (10C) and the solid filtered and discarded. The filtrate was evaporated and the residue dissolved in water (250ml) and filtered. The filtrate was then basified (~pHlO) with a~ueous sodium hydroxide solution (2N) and the mixture extracted with ethyl acetate (3 x 200ml~. The combined extraot was dried (MgSO4), evaporated and recrystallised from ace oni~rile to give 2-(4-aminobutylthio)-4,5-diphenyl-imidazole (4.5g), as colourless ~rystals, m.p.
138-139C;
[Elemèntal analysis :- C,70.7; H,6.6; N,13.0;
Calculated for C1gH21N3S :- C, 70.6; H, 6.5;
N, 13.0%~.
-: ~ ' ' ' , .;. ~ ' ~ ' Wosl/09030 PCT/EP90/02147 :2~7~97 By proceeding in a manner similar to that described in Example 1, but using a mixture of cis- and trans-N-( 4-chlorobutanoyl) 2,6-dimethylmorpholine as a starting material, there was prepared a nixture o~ cis- and trans-2,6-dimethyl-N-t4-(4,5-diphenylimidazol-2-yl-thio)butan-1-oyl]morpholine, m.p.147-149c.
.. ~ . .. . , ~ .
-: ~. .. ,. . ~
' ~ ' ~ '' , .... . , '. ' ' , ~ . .
WO91/09030 pcT/Epso/o2147 ..20~1497 In clinical practice compounds of the pre~ent invention may be administered parenterally, rectally or orally.
Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of the a~tive compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
The compositions may also ~omprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
Liquid compositions for oral administration -include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the a~t such as water and liguid paraffin. Besides inert diluents such composi~ions may comprise adjuvants, such as wettin~
and-suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention ~or oral administration also ~include capsules of absorbable-material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients. ~ ~ ~
, .
1.~
. ' ' ' , ' ' ~ ' , ,: ., . .
wog1/oso30 PC~/EP90/02147 `2071497 Compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic~ and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glyool, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, ~or example, by filtration through a bacteria-retaining filter, by incorporation in the -~
compositions o~ sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Solid compositions ~or rectal administration include suppositories formulated in accordance with known methods and containing at least one compo~1nd of formula (I1.
The percen'age of active ingredient in the compositions cf the invention may be varied, it being necessary that it should constitute a proportion such . . .
that a suitable dosage shall be obtained. Obviously, several unit dosage ~orms may be administered at about the same time. The dose employed will be determined WO91/09030 PCT/EP90!02147 . .
~. ~';;i ~ / .
- 51 - ` 20~1497 by the physician, and depends upon the desired therapeutic ef~ect, the route of administration and the duration of the treatment, and the condition of the ¦
patient. In the adult, the doses are generally from about O S to about 70 preferably about 1 to about 10 mg/kg body weight per day by oral administration.
The following Composition Examples illustrate pharmaceutical compositions according to the present invention.
No. 2 size gelatin capsules each containing:-;~ N-~2-(4,5-diphenylimidazol-2-ylthio)ethyl]-morpholine 20 mg lactose 100 mg ~; starch 60 mg dextrin- 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
WO 91/09030 PCr/EP90/02147 NQ. 2 size gelatin capsules each containing:-3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-yl- :
thio)propyl]piperidine-2,6-dione 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg .
were prepared in accordance with the usual procedure.
COMPOSITION EXAMRLE 3 :
No. 2 size gelatin capsules each containing:-[3-R,SJ-3-[(4,5-diphenylimidazol-2-ylthio)-methyl]-1-methylpiperidine 20 m~
lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate .1 mg :
were prepared in accordance with the usual procedure. -,:
.
'' . ,,.'.~,.. ,"
. ., i ., .
~. :
Claims (11)
1. Compounds which are of the general formula :
[DPIM]-S-W-Y (I) wherein [DPIM] is of the general formula :
(DPIM) R and R1 are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from 1 to 5 carbon atoms, W
represents a methylene group or a straight alkylene chain containing from 2 to 5 carbon atoms and is optionally substituted with one or more straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, Y
represents a group of the formula :
(II) (III) (IV) (V) (VI) wherein the symbols R2 are the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, the symbols R4 each represent a hydrogen atom or else together the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, Z represent an oxygen or sulphur atom or a group of formula [C(R3)2]q or NR3, m represents zero or an integer from 1 to 5, n represents zero or an integer from 1 to 5, and p represents zero or 1, such that m + n + p = 3, 4 or 5, q represents 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof, for use in the preparation of a pharmaceutical composition for the treatment of conditions which can be ameliorated by the administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase.
[DPIM]-S-W-Y (I) wherein [DPIM] is of the general formula :
(DPIM) R and R1 are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from 1 to 5 carbon atoms, W
represents a methylene group or a straight alkylene chain containing from 2 to 5 carbon atoms and is optionally substituted with one or more straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, Y
represents a group of the formula :
(II) (III) (IV) (V) (VI) wherein the symbols R2 are the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, the symbols R4 each represent a hydrogen atom or else together the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, Z represent an oxygen or sulphur atom or a group of formula [C(R3)2]q or NR3, m represents zero or an integer from 1 to 5, n represents zero or an integer from 1 to 5, and p represents zero or 1, such that m + n + p = 3, 4 or 5, q represents 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof, for use in the preparation of a pharmaceutical composition for the treatment of conditions which can be ameliorated by the administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase.
2. A compound according to claim 1 for use in the preparation of a pharmaceutical composition for the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts.
3. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, provided that when W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), wherein the symbols R4 represent hydrogen atoms and Z
represents an oxygen atom or a group of formula [C(R3)2]q, wherein q represents 0 or 1, or NR3, or the symbols R4 and the carbon atom to which they are both joined form a carbonyl group and Z represents a group of formula [C(R3)2]q, wherein q represents 0, R, R1 and R3 being as hereinbefore defined, for use in a method of treatment of the human or animal body by therapy.
represents an oxygen atom or a group of formula [C(R3)2]q, wherein q represents 0 or 1, or NR3, or the symbols R4 and the carbon atom to which they are both joined form a carbonyl group and Z represents a group of formula [C(R3)2]q, wherein q represents 0, R, R1 and R3 being as hereinbefore defined, for use in a method of treatment of the human or animal body by therapy.
4. A compound according to claim 3 for use in a method of treatment of the human or animal body by therapy of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts.
5. An imidazole derivative of general formula (I), as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, subject to the proviso that when W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C(R3)2]q, wherein q represents 0 or 1, or NR3, or the symbols R4 and the carbon atom to which they are both joined form a carbonyl group and Z represents a group of formula [C(R3)2]q, wherein q represents O, R, R1 and R3 being as hereinbefore defined.
6. A compound according to claim 5 wherein at least one of the symbols has a value selected from the following :-(i) R represents a hydrogen or chlorine atom or a methyl group;
(ii) R1 represents a hydrogen or chlorine atom or a methyl group;
(iii) W represents a methylene group or an alkylene chain of 2, 3 or 4 carbon atoms;
(iv) Y represents a phthalimido group or an optionally substituted maleimido, pyrrolidinyl, piperidyl, perhydroazepinyl, piperazinyl or morpholino group; and/or (v) R3 represents a hydrogen atom or a methyl or ethyl group;
the other symbols being as hereinbefore defined, and their pharmaceutically acceptable acid addition salts.
(ii) R1 represents a hydrogen or chlorine atom or a methyl group;
(iii) W represents a methylene group or an alkylene chain of 2, 3 or 4 carbon atoms;
(iv) Y represents a phthalimido group or an optionally substituted maleimido, pyrrolidinyl, piperidyl, perhydroazepinyl, piperazinyl or morpholino group; and/or (v) R3 represents a hydrogen atom or a methyl or ethyl group;
the other symbols being as hereinbefore defined, and their pharmaceutically acceptable acid addition salts.
7. A process for the preparation of a compound of general formula (I) as defined in claim 5 which comprises:
(A) the reaction of a salt of the formula [DPIM]-S- M+ (VII) wherein [DPIM] is as defined in claim 1 and M is an alkali metal atom, with a compound of the general formula:-X-W-Y (VIII) or an acid addition salt thereof wherein X is a group displaceable by a thiolate salt and W and Y are as defined in claim 5;
(B) when Y represents a group of formula (II), (III) or (IV), the other symbols being as defined in claim 5, by the reaction of a compound of the formula :-[DPIM]-S-W-NH2 (IX) wherein the various symbols are as defined in claim 5, with a compound of the general formula :
(X) (XI) (XII) wherein Z, R2 and R3 are as defined in claim 5;
(C) when Y represents a group of formula (V) and the other symbols are as defined in claim 5, the reduction with a metal hydride reducing agent of a compound of formula (I) wherein Y represents a group of formula (IV) and the other symbols are as defined in claim 5;
(D) when Y represents a group of formula (V) in which the symbols R4 represent hydrogen atoms and the other symbols are as defined in claim 5, the reduction with a metal hydride reducing agent of a compound of formula (I) wherein Y represents a group of formula (V) in which the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group and the other symbols are as defined in claim 5;
(E) when the compound of formula (I) conforms to the formula:
[DPIM]-S-W1-CH2-Y (XIV) wherein W1 represents a methylene group or straight alkylene chain containing from 2 to 4 carbon atoms optionally substituted with one or more a straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, the other symbols being as defined in claim 5, the reduction with a metal hydride reducing agent of a compound of the formula :
[DPIM]-S-W1CO-Y (XV) wherein the various symbols are as defined in claim 5;
optionally followed by the conversion of a compound of general formula (I) into a pharmaceutically acceptable acid addition salt thereof.
(A) the reaction of a salt of the formula [DPIM]-S- M+ (VII) wherein [DPIM] is as defined in claim 1 and M is an alkali metal atom, with a compound of the general formula:-X-W-Y (VIII) or an acid addition salt thereof wherein X is a group displaceable by a thiolate salt and W and Y are as defined in claim 5;
(B) when Y represents a group of formula (II), (III) or (IV), the other symbols being as defined in claim 5, by the reaction of a compound of the formula :-[DPIM]-S-W-NH2 (IX) wherein the various symbols are as defined in claim 5, with a compound of the general formula :
(X) (XI) (XII) wherein Z, R2 and R3 are as defined in claim 5;
(C) when Y represents a group of formula (V) and the other symbols are as defined in claim 5, the reduction with a metal hydride reducing agent of a compound of formula (I) wherein Y represents a group of formula (IV) and the other symbols are as defined in claim 5;
(D) when Y represents a group of formula (V) in which the symbols R4 represent hydrogen atoms and the other symbols are as defined in claim 5, the reduction with a metal hydride reducing agent of a compound of formula (I) wherein Y represents a group of formula (V) in which the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group and the other symbols are as defined in claim 5;
(E) when the compound of formula (I) conforms to the formula:
[DPIM]-S-W1-CH2-Y (XIV) wherein W1 represents a methylene group or straight alkylene chain containing from 2 to 4 carbon atoms optionally substituted with one or more a straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, the other symbols being as defined in claim 5, the reduction with a metal hydride reducing agent of a compound of the formula :
[DPIM]-S-W1CO-Y (XV) wherein the various symbols are as defined in claim 5;
optionally followed by the conversion of a compound of general formula (I) into a pharmaceutically acceptable acid addition salt thereof.
8. A pharmaceutical composition which comprises an imidazole derivative of formula (I) as defined in claim 5, or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or coating.
9. A pharmaceutical composition useful in the treatment of a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A:
cholesterol-O-acyl transferase which comprises an amount effective to ameliorate said condition of a compound of general formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.
cholesterol-O-acyl transferase which comprises an amount effective to ameliorate said condition of a compound of general formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.
10. A method for the treatment of a human or animal host suffering from, or subject to, a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase which comprises the administration to said host of an amount effective to ameliorate said condition of an imidazole derivative of general formula (I) as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof.
11. An agent for use in the treatment of a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase which comprises an imidazole derivative of the general formula :
[DPIM]-S-W-Y (I) wherein [DPIM] is of the general formula :
(DPIM) R and R1 are the same or different and each represents a hydrogen or halogen atom or straight- or branched-chain alkyl group containing from 1 to 5 carbon atoms, W
represents a methylene group or a straight alkylene chain containing from 2 to 5 carbon atoms and is optionally substituted with one or more a straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, Y
represents a group of the formula:
(II) (III) (IV) (V) (VI) wherein the symbols R2 are the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, the symbols R4 each represent a hydrogen atom or else together the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, Z represents an oxygen or sulphur atom or a group of formula [C(R3)2]q or NR3, m represents zero or an integer from 1 to 5, n represents zero or an integer from 1 to 5, and p represents zero or 1, such that m + n + p = 3, 4 or 5, q represents 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof.
[DPIM]-S-W-Y (I) wherein [DPIM] is of the general formula :
(DPIM) R and R1 are the same or different and each represents a hydrogen or halogen atom or straight- or branched-chain alkyl group containing from 1 to 5 carbon atoms, W
represents a methylene group or a straight alkylene chain containing from 2 to 5 carbon atoms and is optionally substituted with one or more a straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, Y
represents a group of the formula:
(II) (III) (IV) (V) (VI) wherein the symbols R2 are the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, the symbols R4 each represent a hydrogen atom or else together the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, Z represents an oxygen or sulphur atom or a group of formula [C(R3)2]q or NR3, m represents zero or an integer from 1 to 5, n represents zero or an integer from 1 to 5, and p represents zero or 1, such that m + n + p = 3, 4 or 5, q represents 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB898928028A GB8928028D0 (en) | 1989-12-12 | 1989-12-12 | New use |
| GB8928028.3 | 1989-12-12 | ||
| GB9000698.2 | 1990-01-12 | ||
| GB909000698A GB9000698D0 (en) | 1990-01-12 | 1990-01-12 | New compositions of matter |
| GB909000697A GB9000697D0 (en) | 1990-01-12 | 1990-01-12 | New compositions of matter |
| GB9000697.4 | 1990-01-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2071497A1 true CA2071497A1 (en) | 1991-06-13 |
Family
ID=27264841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002071497A Abandoned CA2071497A1 (en) | 1989-12-12 | 1990-12-11 | 2-substituted 4,5-diphenyl-imidazoles |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0505481A1 (en) |
| JP (1) | JPH05502235A (en) |
| CA (1) | CA2071497A1 (en) |
| WO (1) | WO1991009030A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2933739B2 (en) * | 1990-04-09 | 1999-08-16 | 明治製菓株式会社 | Thiazole or imidazole derivatives and anti-ulcer agents |
| US5212318A (en) * | 1991-03-04 | 1993-05-18 | Eastman Kodak Company | Preparation of omega-substituted alkanamide |
| US5364875A (en) * | 1992-05-11 | 1994-11-15 | The Du Pont Merck Pharmaceutical Company | Imidazoles linked to bicyclic heterocyclic groups for the treatment of atherosclerosis |
| US5310748A (en) * | 1992-05-11 | 1994-05-10 | The Du Pont Merck Pharmaceutical Company | Imidazoles for the treatment of atherosclerosis |
| IT1265209B1 (en) * | 1993-11-22 | 1996-10-31 | Pierrel Spa | DIPHENYLIMIDAZOLES USEFUL IN THE TREATMENT OF DYSLIPIDEMIA, ARTERIOSCLEROSIS AND CORONARY DISEASES PROCEDURE FOR THEIR |
| WO1997018813A1 (en) * | 1995-11-22 | 1997-05-29 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| FR2751647B1 (en) * | 1996-07-25 | 1998-09-11 | Synthelabo | BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATIONS AND THEIR THERAPEUTIC APPLICATIONS |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3323870A1 (en) * | 1983-07-02 | 1985-01-03 | A. Nattermann & Cie GmbH, 5000 Köln | NEW IMIDAZOL-2-YLTHIOALKANIC ACIDS AND THEIR DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
| DK167187A (en) * | 1986-04-02 | 1987-10-03 | Otsuka Pharma Co Ltd | CARBOSTYRIC DERIVATIVES AND SALTS THEREOF, PROCEDURE FOR THE PREPARATION OF SUCH COMPOUNDS AND MEDICINAL CONTAINING THESE |
| JPS6440467A (en) * | 1987-08-04 | 1989-02-10 | Hisamitsu Pharmaceutical Co | Novel substituted diphenylimidazole derivative |
| US4900744A (en) * | 1988-09-14 | 1990-02-13 | E. I. Du Pont De Nemours And Company | Antihypercholesterolemic 4,5-diaryl-2-substituted thioimidazoles |
-
1990
- 1990-12-11 WO PCT/EP1990/002147 patent/WO1991009030A1/en not_active Application Discontinuation
- 1990-12-11 CA CA002071497A patent/CA2071497A1/en not_active Abandoned
- 1990-12-11 EP EP91902130A patent/EP0505481A1/en not_active Withdrawn
- 1990-12-11 JP JP91502395A patent/JPH05502235A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP0505481A1 (en) | 1992-09-30 |
| JPH05502235A (en) | 1993-04-22 |
| WO1991009030A1 (en) | 1991-06-27 |
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