CA1067076A - Pyrimidone derivatives - Google Patents
Pyrimidone derivativesInfo
- Publication number
- CA1067076A CA1067076A CA262,162A CA262162A CA1067076A CA 1067076 A CA1067076 A CA 1067076A CA 262162 A CA262162 A CA 262162A CA 1067076 A CA1067076 A CA 1067076A
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- CA
- Canada
- Prior art keywords
- methyl
- pyrimidone
- imidazolylmethylthio
- ethylamino
- methylthio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
-
- 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
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
There is disclosed the preparation of compounds of the formula wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl (preferably methyl), halogen (preferably chlorine or bromine), trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by lower alkyl {preferably methyl), lower alkoxy (preferably methoxy), halogen (preferably chlorine or bromine), amino or hydroxy, a 2-thiazolyl ring, a 3-isothiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5) thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl) ring; Z is sulphur or a methylene group; X is oxygen or sulphur; W is methylene, oxygen or sulphur; m and n are such that their sum is from 1 to 4 when W is oxygen or sulphur, or from O to 4 when W is methylene; A is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring substituted with one or more lower alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(loweralkyl)amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl group and when
There is disclosed the preparation of compounds of the formula wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl (preferably methyl), halogen (preferably chlorine or bromine), trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by lower alkyl {preferably methyl), lower alkoxy (preferably methoxy), halogen (preferably chlorine or bromine), amino or hydroxy, a 2-thiazolyl ring, a 3-isothiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5) thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl) ring; Z is sulphur or a methylene group; X is oxygen or sulphur; W is methylene, oxygen or sulphur; m and n are such that their sum is from 1 to 4 when W is oxygen or sulphur, or from O to 4 when W is methylene; A is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring substituted with one or more lower alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(loweralkyl)amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl group and when
Description
f o l This invention relates to pharmacologically active compounds, to method~ ior preparing these compounds, to pharmaceutical compositions containing these compounds and to methods of bloeking histamine H2-receptors by administering these eompounds. The eompounds oi' the invention can exist as aeld additlon salts but, ior eonvenienee, reierenee ~ill be made througbout this speeiiieation to the parent eompounds.
any physiologieally aetive 6ubstanee#-elieit thelr biological a¢tio'ns by lnteraction ~ith speeiiie sltes known as reeeptors.
Hlstamine i~ such a #ubsta~ee and hns a number oi biological actions. Those biological aetion8 oi histamine which are in-;hibited~by drugs eommonly ealled "antihi#tamines" oi whiehmepyramlné,~ diphenhydramlne~`and ehloropheniramine are ; ~ 5~ examples,1are mediat-d~through histamine Hl-rec-ptors (Ash and~Schild, Brit. J. Pharmac. Chemother~, 27, 427, (1966)), ;~ and drug8 with~thi8~àetlvity`are~hereinaiter reierred to ' a8 histamine ~ -antagonlsts. H~ever, other oi the biological aetlon8 oi~his'tamine are not inhlbited by histamlne ~ -antagoni8ts and actions~oi this type ~hieh are lnhlbited by 20 ~ a e opound deocribed~by Blaek et al. (Nature~ 385, (1972)) and~ealled buri~a~ide~are mediated through receptors ~hl¢h ar-~dbiined by~Black~et al. a8 hlstamlne~H2-receptors.
Thu~hi~ta~ln~ -r-eeptors~may~be deiined as those histamine reGept~ors~ ~hieh~are~not bloeked by me W ramine but are bloeked S~ br~hurlna~ide.~ Co~pounds ~hieh b}oek Sistamine H2-reeeptors are reierred to~is~hi8tamine H2-antagonists.
Bloekade~oi hi~taeine~H2-reeeptor8 i~ o~ utility in inhibiting ;the biologieal;-etlons oi hi~stamlne ~hieh are'not inhibited 30~ by~hl8tamine ~ -antagoni8t8. Hi8tamlne H2-antagonist8 are therefore useful, ior example,'as inhibitors oi gastric acid seeretion, as anti-ini'lammatory agents and as agents which act on the cardiovascular srstem, ior example as inhibitors o$ the eiiects oi histamine on blood pressure. In the treatment oi certain conditions, ior example, inilammation : and in inhibiting the actions oi histamine on blood pressure, i :-:
:; :
, .
`` 1067076 1 a combination of histamine Hl- and H2-antagonists is ; useful. The compounds of this invention have both histamine Hl-antagonigt and histamine H2-antagonist activity, and are useful in the treatment o$ conditions wherein histamine H2-S antagonistg are use$ul and conditions wherein a ccmbination of histamine Hl- and H2-antagonigts are use$ul.
":
Throughout this specification by the term "lower alkyl" we mean an alkyl group containing $rom 1 to 4 carbon at~ms.
~:
' 10 In British Patent Speci$ication No. 1419994 we described and claimed, inter alia, ccmpounds of Formula 1 and tautomers ~ ;- thereof as histamine H2-antagonists.
: ~ yl N
: 11 R-NH ~-~N ~ ~ X
H
; FORMULA 1 In Formula 1, R repregents a group of the st~ucture sh~wn . . .
in Formula 2:
Het-CH2z(cH2)n FOR~ULA 2 where~n ~et is a nitrogen-conta~n~ng heterocyclic ring such ag lmidazole, pyridine, thiazole, isothiazole-or thiadiazole, which ring is optionally gubætituted by lower alkyl, amino, hydroxy or halogen; Z i~ sulphur or a methylene group; and n is 2 or 3; X is oxygen or sulphur;
and y2, which may be the same or di$ferent, are hydrogen, lower alkyl, aryl or aralkyl.
:
~e have now found that a particular group o$ compounds same o$ which $all within the above de$inition o$ compounds o$
Formula 1 posgess certain advantages over the general group 1 oi compounds oi' Formula 1. This partlcular group of compounds are more potent as histamine H2-antagonists than the sald general group of compounds of Formula 1, and this i particular group oi' compounds have histamine Hl-antagonist activity as well as histamine H2-antagonist activity.
The particular group of compounds selected because of the Z ~ above-mentioned advantages is represented by Formula 3:
~ (CH2)mW (CH2) nA
! ~ : Het -cH2zcH2cH2-NH ~ N ~ X
~ FOR~ULA 3 : ~:
wh-rein Het' 18 a 2- or 4-imidazolyl ring optionally.
: substituted by lower alkyl (pre~erably methyl), halogen ~ (preierably chlorine or bromine), tri~luoromethyl or j~ : hydroxy ethyl, a 2-pyridyl ring optionally substituted by lo~er alkyl (preferably methyl), lo~er alkoxy (pre~erably ; . 20: methoxy), halogen (preferably chlorine or bromine), amino or hydroxy, a 2-thiazolyl ring, a 3-lsothiazolyl ring optlonally substituted by.chlorine or bromine, a 3-(1,2,5)7 thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amlno-1,3,4-thiadiazolyl)ring; Z i8 ;5~ sulphur~or a methylene group; X is oxygen or sulphur-; W is : thylene, oxygen or sulphur; m and n are such that their sum ia~`~rom 1 to 4 when ~ is oxygen or sulphur, or i'rom 0 : : to~4 when W is methylene; A is a 1- or 2-naphthyl ring, a
any physiologieally aetive 6ubstanee#-elieit thelr biological a¢tio'ns by lnteraction ~ith speeiiie sltes known as reeeptors.
Hlstamine i~ such a #ubsta~ee and hns a number oi biological actions. Those biological aetion8 oi histamine which are in-;hibited~by drugs eommonly ealled "antihi#tamines" oi whiehmepyramlné,~ diphenhydramlne~`and ehloropheniramine are ; ~ 5~ examples,1are mediat-d~through histamine Hl-rec-ptors (Ash and~Schild, Brit. J. Pharmac. Chemother~, 27, 427, (1966)), ;~ and drug8 with~thi8~àetlvity`are~hereinaiter reierred to ' a8 histamine ~ -antagonlsts. H~ever, other oi the biological aetlon8 oi~his'tamine are not inhlbited by histamlne ~ -antagoni8ts and actions~oi this type ~hieh are lnhlbited by 20 ~ a e opound deocribed~by Blaek et al. (Nature~ 385, (1972)) and~ealled buri~a~ide~are mediated through receptors ~hl¢h ar-~dbiined by~Black~et al. a8 hlstamlne~H2-receptors.
Thu~hi~ta~ln~ -r-eeptors~may~be deiined as those histamine reGept~ors~ ~hieh~are~not bloeked by me W ramine but are bloeked S~ br~hurlna~ide.~ Co~pounds ~hieh b}oek Sistamine H2-reeeptors are reierred to~is~hi8tamine H2-antagonists.
Bloekade~oi hi~taeine~H2-reeeptor8 i~ o~ utility in inhibiting ;the biologieal;-etlons oi hi~stamlne ~hieh are'not inhibited 30~ by~hl8tamine ~ -antagoni8t8. Hi8tamlne H2-antagonist8 are therefore useful, ior example,'as inhibitors oi gastric acid seeretion, as anti-ini'lammatory agents and as agents which act on the cardiovascular srstem, ior example as inhibitors o$ the eiiects oi histamine on blood pressure. In the treatment oi certain conditions, ior example, inilammation : and in inhibiting the actions oi histamine on blood pressure, i :-:
:; :
, .
`` 1067076 1 a combination of histamine Hl- and H2-antagonists is ; useful. The compounds of this invention have both histamine Hl-antagonigt and histamine H2-antagonist activity, and are useful in the treatment o$ conditions wherein histamine H2-S antagonistg are use$ul and conditions wherein a ccmbination of histamine Hl- and H2-antagonigts are use$ul.
":
Throughout this specification by the term "lower alkyl" we mean an alkyl group containing $rom 1 to 4 carbon at~ms.
~:
' 10 In British Patent Speci$ication No. 1419994 we described and claimed, inter alia, ccmpounds of Formula 1 and tautomers ~ ;- thereof as histamine H2-antagonists.
: ~ yl N
: 11 R-NH ~-~N ~ ~ X
H
; FORMULA 1 In Formula 1, R repregents a group of the st~ucture sh~wn . . .
in Formula 2:
Het-CH2z(cH2)n FOR~ULA 2 where~n ~et is a nitrogen-conta~n~ng heterocyclic ring such ag lmidazole, pyridine, thiazole, isothiazole-or thiadiazole, which ring is optionally gubætituted by lower alkyl, amino, hydroxy or halogen; Z i~ sulphur or a methylene group; and n is 2 or 3; X is oxygen or sulphur;
and y2, which may be the same or di$ferent, are hydrogen, lower alkyl, aryl or aralkyl.
:
~e have now found that a particular group o$ compounds same o$ which $all within the above de$inition o$ compounds o$
Formula 1 posgess certain advantages over the general group 1 oi compounds oi' Formula 1. This partlcular group of compounds are more potent as histamine H2-antagonists than the sald general group of compounds of Formula 1, and this i particular group oi' compounds have histamine Hl-antagonist activity as well as histamine H2-antagonist activity.
The particular group of compounds selected because of the Z ~ above-mentioned advantages is represented by Formula 3:
~ (CH2)mW (CH2) nA
! ~ : Het -cH2zcH2cH2-NH ~ N ~ X
~ FOR~ULA 3 : ~:
wh-rein Het' 18 a 2- or 4-imidazolyl ring optionally.
: substituted by lower alkyl (pre~erably methyl), halogen ~ (preierably chlorine or bromine), tri~luoromethyl or j~ : hydroxy ethyl, a 2-pyridyl ring optionally substituted by lo~er alkyl (preferably methyl), lo~er alkoxy (pre~erably ; . 20: methoxy), halogen (preferably chlorine or bromine), amino or hydroxy, a 2-thiazolyl ring, a 3-lsothiazolyl ring optlonally substituted by.chlorine or bromine, a 3-(1,2,5)7 thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amlno-1,3,4-thiadiazolyl)ring; Z i8 ;5~ sulphur~or a methylene group; X is oxygen or sulphur-; W is : thylene, oxygen or sulphur; m and n are such that their sum ia~`~rom 1 to 4 when ~ is oxygen or sulphur, or i'rom 0 : : to~4 when W is methylene; A is a 1- or 2-naphthyl ring, a
2,3-dihydro-1,4-benzodloxinyl or a l,3-benzodioxolyl ring, a phenyl ring substituted with one or more lower alkyl, iower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, ~ trii'luoromethyl, di(loweralkyl)amino, phenoxy, halophenoxy, ,~ : alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl groups and when -(CH2)m~(CH2)n- is not a methylene group, A may also . 35 be phe~yl; and Y3 is hydrogen or lower alkyl.
:~
::
1067~76 1 PreferablY Het' iB a 2-thiazolyl, 5-methyl-4-imidazolyl, S-bromo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl,
:~
::
1067~76 1 PreferablY Het' iB a 2-thiazolyl, 5-methyl-4-imidazolyl, S-bromo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl,
3-methoxy-2-pyridyl or 3-hydroxy-2-pyridyl ring.
Preferably Z is sulphur.
Pre~erably X is oxygen.
Preferably Y3 is hydrogen.
Preferably A is a phenyl group substituted by one or more lower alkoxy groups, or is a 2,3-dihydro-1,4-benzodioxinyl or 1,3-benzodioxolyl ring, as compounds of Formula 3 wherein A has these meanings have ~avourable solubility properties when compared to the general group of compounds of $ormula 3.
A preferred group of compounds is that wherein m and n are O and W is methylene. Another preferred group of compounds l ~ 15 is that wherein m is 0 n is 1 and W is oxygen.
;. Some ~pecl~lc pre~erred compounds hich fall within the particular group of compounds of Formula 3 are:-2-[2-(S-methyl-4-imidazolylmethylthio)ethylamino]-S-(g-- 20 chlorobenzyl)-4-pyrimidone 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-
Preferably Z is sulphur.
Pre~erably X is oxygen.
Preferably Y3 is hydrogen.
Preferably A is a phenyl group substituted by one or more lower alkoxy groups, or is a 2,3-dihydro-1,4-benzodioxinyl or 1,3-benzodioxolyl ring, as compounds of Formula 3 wherein A has these meanings have ~avourable solubility properties when compared to the general group of compounds of $ormula 3.
A preferred group of compounds is that wherein m and n are O and W is methylene. Another preferred group of compounds l ~ 15 is that wherein m is 0 n is 1 and W is oxygen.
;. Some ~pecl~lc pre~erred compounds hich fall within the particular group of compounds of Formula 3 are:-2-[2-(S-methyl-4-imidazolylmethylthio)ethylamino]-S-(g-- 20 chlorobenzyl)-4-pyrimidone 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-
4-pyrimidone 2-12-(3-brall,o-2-pyridylmethylthio)ethylamino]-5-(4-chloro-- benzyl)-4-pyrimidone 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-6-methyl-4-pyrimidone :~ 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-chlorobenzyl)-4-pyrimidone 2-[2-(S-methyl-4-imidazolylmethylthio)ethylaminol-5-(3,4-dichlorobenzyl)-4-pyrimidone ; 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyr~midone 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4--~ methylbenzyl)-4-pyrimidone 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-phenylethyl)-4-pyrimidone 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(2-phenylethyl)-6-methyl-4-pyrimidone _5 ~ .
~' 1 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-~ benzyloxy-4-pyrimidone :~ 2-12-(5-methyl-4-imidazolylmethylthio)ethylaminol-5-(3-' methoxybenzyl)-4-pyrimidone 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-, chlorobenzyl)-4-pyrimidone , 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenyl-~; butyl)-4-pyrimidone ~, 2-[2-(5-methyl-4-lmidazolylmethylthio)ethylamino]-5-(S-(1,3-benzodioxolyl)m,et~yl)-4-pyrimidone 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-ethox~-benzyl)-4-pyrimidone ,2-[2~-(5 _ethg,1-4-imidazolylmethylthio)ethyla ino]-5-(3-benzyloxybenzyl)-4-pyrimidone ' 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-naphthylmethyl)-4-pyrimidone.
The compound~ of Formula 3 are shown and described as 4-one and 4-thione derivatives and these derivatives exist in~equilibrium ~ith the corresponding 6-one and 6-t~ione , 20~ ~ tautomers. These compound# al80 exi#t to a les~er extent a~ the~mercapto and hydro~y tautomers and the p~rimidine ring may~also esist in the i'ollowing tautomeric forms:
N ~ ~ ~
Het' m q al#0 exist in #everal tautomeric forms,and it ill be understood tha~ all these tautomeri¢ forms are ~w1thin the ~ope of the present lnvention.
The compounds oi' thi~ invention may be prepared by treating an amine oi' Formula 4:
~-CH2ZCH2CH2NH2 Formula 4 106'70'76 1 wherein Het' and Z are as de~ined in Formula 3, with a compound of Formula 5: 3 Y
~ (CH2)mW(cH2)n ~
Q N X
.
. Formula 5 , .
wherein X, Y3, m, W,. n and A are as deiined in Formula 3 and Q iB loweralkylthio, benzylthio, halogen, or other ,~
reactive grouping which is conveniently displaced with aD amine. Preierably thi;s reaction is carried out in the ; absence o~ a solvent ~at about:l50C or in the presence .:
~ 15;;~ oi a solvent, SUch as re~iluxing pyridine.
I ~ ~ The intermediates o~ Formula 5 wherein W is methylene, Y3 20~ hgdrogen and Q is loweralkylthio (shown as Formula.8) may be prepared according to Scheme 1:-: Scheme 1 (wh-r-in A is as:del'ined in Formula 3 and a is 0 to 4 and Alk:i~ lo~er alkyl) CH2(CH2)aA
( ~ )ao~2cH2Qo2Et 1) Na, HC02Et ~ > S N
.- ,,~ - :, ormula ~ 2) thiourea : Formula 7 alkyl halide or sulphate HN ~ CH2(CH2)aA
- ~::: AlkS'~N ~ ~0 i ~
Formula 8 7-.
~' .
: :
`` 1067076 l The esters of Formula 6 wherein a is O may be prepared by eonden~ing a sub8tituted benzaldehyde ~ith malonie aeid, and hydrogenating and esteriiying the produet ~he intermediates oi' Formula 5 wherein ~ is methylene, Y3 is loweralkyl and~Q is loweralkylthio (shown a- Formula 9) may be prepared according to Scheme 2 -;~ ~
Scheme 2 (wh-rein A i8 as de~inea in Formula 3, i8 0 to 4, Hal is chlorlne or bromine, and Alk i8 lower alkyl) Y3-cccH2co2Et NaOEt, Hal~H2(CH2)aA Y3-CoCHCo2Et lS;~ ~ thiourea 3 ~ y3 I alkyl halide or H ~ CH2(CH2)aA gulphate H ~ CH2(CH2)aA
; Alk ~ N ~ O H
For~ul- 9~
The ~1nbermed1-t-s~o~ Formula S wherein Q i8 halogen (~hown-as For~ula~ may be prepared according to Scheme 3 -Sohem- 3 (~herein A and Y3 are as ~e$ined in i'~rmula 3, a is O to 4- and Hal;ls ehlorine or bromine : ' ~:
-' :~:
.:
~067076 CH2(CH2)aA
Y COCHC02Et sodium salt \guanidine Formula 10 ~CH2 (CH2) aA
: . H2N 1 N ~ 0 1) HCl, NaNOa.
2) CU2Hal2 .~ ~ ` y3 HN~2 (CH2) aA
Ha~N O
Formula 11 The campoundg oi iormula 10 wherein Y3 i~ hydrogen may : be prepared ~rom a compound oi Formula 6, sodium and ethyl iormate, and the compounds oi Formula 10 wherein Y3 is lower alkyl may be prepared as shown in Scheme 2.
~ ~ 25 ,~ The intermediates o$ Formula 5 wherein W is oxygen or sulphur may be prepared by the ~ollowing methods:-~ 30 :: (a) m is 0 A(CH2)nWCH2C02Et 1) HC02Et, Na ~ W(CH2)nA
2) thiourea AlkS ~ N 0 3) alkyl halide or W is oxygen or sulphate sulphur _9_ -~ 1067076 l (b) m is l These compounds may be prepared by the route:-~ CH20H l)SOCl2 or HBr ~ CH2W(CH2)nA
H2N O2)A(CH2)nO Na or H2 N
: H A(CH2)nS Na o W i8 oxygen or sulphur :~ . l) HClJNaN02 2) CU2 Hal2 ', ::
15~ `
:
HN ~ 2W(CH2)nA
Hal ~ N ~ O
; :. - 20: W i8 oxygen or sulphur , ~
~ : or alternatively, irom ethyl 4-benzyloxybutyrate, or a similar protected derivative o~ ethyl 4-hydroxybutyrate, by a proces~ analogous to that outlined in Scheme l, ~ollowed ~ucce~s1vely by deprotection,treatment with thionyl chloride, and treatment with the sodium derivative oi' A~CH2)nOH or ', `;, ~ A~ (Cll~) nSH .
::
1 (c) m is 2 to 4 :
O O
2 eth~l iormate,~odium CH2Jm (CH2 ` . l)thiourea :i~ 10 ; . 2)alkyl halide ~ . or-sulphate ~ , ~ (CH2)mW(CH2)nA HN ~ (CH )mOH
Alk N o 2)A(CH2) O~Na+ or Alk ~ N
is oxygen or sulphur n m is 2 to 4 A(CH2)nS Na ; 20 Compounds of Formula 3 wherein X is sulphur may be prepared by treating the compounds o~ Formula 3 wherein X is oxygen with phosphorus pentasulphide in a solvent such as ~yridine.
The amines o~ Formula 4 may be prepared by methods described in British Patent Speciiications 1305547 and 1338169, and ~ C~nad~an Patents 945,17I a~d 9.47,767.
: "
~:~ 30 C
`- 1067076 , The compounds of Formula 3 block histamipe H2-receptors, that is they inhibit the biological actions of histamine which are not inhibited by hi8tamine Hl-antagonists such as mepyramine but are inhibited by burimamide. For example, the compounds oi' this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 16 micro~oles per kilogram intravenously.
Many oi the compounds o~ the present invention produce at least 50% inhibition in this test at a dose of from 1 to 10 micromoles per kilogram. This procedure is re~erred to in the above-mentioned paper of Ash and Schild. The activlty of these compounds as histamine H2-antagonists is also demQnstrated by their ability to inhibit other actions of histamine ~hich, according to the above-mentioned paper of Ash & Schild, are not mediated by histamine Hl-receptors.
For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.
The compound~ oS thls lnventlon inhiblt the basal secretion of gastric 8cid and also that stimulated by pentagastrin or by ~ood.
In addition, the compounds of this invention show anti-inflammatory activlty in conventional tests such as the rat paw oedema test, where the oedema is induced by an lrrltant, the rat paw volume is reduced by subcutaneous inlec*lon of doses of about 500 micromoles/kg. of a compound oS Formula 3. In a con~entional te8t, such as the measure-ment o~ blood pressure ln the anae8thetised cat, the action o~ the compound8 o~ this lnventlon ln inhibiting the vasodilator action o~ hi~tamine can also be demonstrated. The level of activity o~ the compounds of this lnvention is illustrated by the e~ectlve dose producing 50% inhibition o~ gastrlc acid secretion in the anaesthetised rat (which i'or manr of the compounds o~ Formula 3 is ~rom 1 to 10 micro-moles per kilogram) and the dose producing 50~ inhibition of histamine-~nduced tachycardia ln the isolated guinea pig atrium, (which for many of the compounds of Formula 3, is below 10 5M) . , .
`
``` ~067~76 .. . ...... .
;~ The eompound~ o~ Formula 3 also bloe~ histamine ~l-receptors, that is they lnhlbit the biologieal actions o~ bistamine which are inhibited by mepyramine, diphenpydramine and chlorpheniramine For example the eompoundsf o~ this invention hav- been ~ound to inhibit the action o~ histamine in the isolated~Zgulnea-plg lleum For manr o~ the eo~pounds o~ Formula 3 a dose o~ ~rom 10 5 ~olar inhlblta the histamine-stimulated eontraetion-q o~ the Zgui~ea pig lleum ~f ~
10 ~For therapeutie u~e, the pharmacologically aetive eompounds oi-tbe oresent invention ~ill nor~allg be adminlstered as a pharm-eeutieal eomposition eompri~lng as the or an essential wt~ive ingredient at l-ast one sueh eompound ln the basic ~orm or in the ~orm o~ an addition salt ~lth a pharmaeeutieally 15 ~ aeeeptable acid and in assoeiated with a pharmaceutical earrier therefor~ Sueh addition salt~ inelude those ~ith hydxoehlor~e, h~drobromle, hydriodle, ~ulphur~e and maleie aeids and may eo~venientl~ be ~ormed ~rom the eorresponding bases oi' Formula 3 by standard~procedures~ ~or e~a~ple b~ treatl~g the base ~ith an~aeld in a lower~alkanol or br the use o~ ion esehange re~ins to Sorm th- requlred salt either direetly ~r the base or ~rom dl~er-nt~-dtltion salt ~ , -Pharmaeeutleal eamposltions eomprlslng a phar~aceutieal earrierand~a~eompou~d o~Formula 3 or a Pharmaeeutical~y aeeeptable ;aeZid~ additlon salt~th-reo~and ~thods o~ bloe~lng hlsta~ine rec-ptor~ ~hleh;oompri admlnlstering a cZ~mpound o~
Fo ~ la 3; or a ~phar~aceuticallr~aceeptable acid addition salt th~reo~ are~ o obJcct~ or this ln~ention. The phar~aceutical carrier; employed may be, ~ox esa~ple, either a ~olid or llquld E~amplary o~ solld carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectln, acacia, magneslum stearate, stearlc aeid~and the like Exemplary of liquid carxiers axe syrup, peasut ol~, oliYe oll, water and the like , . ~::
~: -,", .
.
- A ~ide ~ariety 0~ pharmaceutlcal ~orms can be employed 'Thus, 1~ a solid carrier ls u~ed, the preparation can be tableted, placed in a hard gelatin capsule ln p~der or pellet i'orm, or in the iorm o~ a troche or lozonge The amount oi solid carrler ; 5 ~11~ ~ary ~idelr but pre~erably ~ill be from about 25 mg to abou* 1 g Ii' a liquid carrier is usèd, the preparation may bo in tho i'orm o~ a syrup, emulsion, so~t gelatin capsule, '~ sterile ln~ectable llquld contalned ~or e~ample ln an ampoule, or an~aqueous or nonaquoous llquld suspen~ion The~pharmaceutical camposltions are prepared bg conventlonal ~h~ technlqué involvlng Focedures such as mixing, granulating u~d~co~presslng or~dissolvi~g the ingredlents as appropriate to the~deslred preparation 15 ~ ~
The actlve lngredient will be present in the eompositions in an e~iectlve amount to block hlstamine ~2-reeeptor~ The ; route'o~ ad~lnl tratlon may be oral or parenteral ~; ~ Pre~erably, -aeh dosage unlt ~ill eontaln the actlve lngredient an ~ount oi iro~about 50 mg to about 250 mg activo~in F-dient~ preierablr ba admi~istered one to lx'times~er d-y~' The dally dosage regimen ~ill prei'erably bo~rom~about lS0 mg to~about l ~ mg Adranta~e~uslr the eo~po~ltion ~111 be ~ade up in a dosage ~or~
app¢o~rlate to the deslr-d ~ode o~ ad~iuistration ~or esa~ple, a~;a~tabl-t~ capsule~ inJ-ctable solution or as a eream or olntment ~or topieal appllcatlon ~ , ~
.,, ~ . . .. .
~ .
.
``` 1067076 1 The invention is illustrated but in no way limited by the $ollow~ng Examples in which all temperatures are in degrees Centigrade:
2-12-(5-Methyl -4-imidazolylmethylthio)ethylamincl-5-(4-chlorobenzyl~4-prrimidone (i~ A solution of 5-(4-ehlorobenzyl)-2-thlouracil (S0.5 g), methyl iodide (28.4 g) and sodium hydroxlde (8.2 g) in water (200 ml) and ethanol (400 ml) ~as stirred at 60 for 30 minute~ then allowed to cool. The crystalline product ~m ~ was i'iltered and washed with water to give 5-(4-ck~robenzyl)-; ~ 2-methylthio-4-pyrimidone (48.6 g), m.p. 193-194 (methanol/
ethanol).
(ii) An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (17.7 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (11.4 g) was heated at 145-150 ~or 5 hours. After coo}ing, the reaction mixture was triturated with water to give the free base, which was separated by decantation and ; ~ recrystallised from methanol to give 2-[2-(S-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone ; m.p. 204.5 - 206.
(Found: C, 5S.45; H, 5.2; N, 18.0: S, 8.3 Cl, 8.9;
Cl ~22ClN50S requiros; C, SS.45; H, 5.2; N, 18.0: S, 8.2:
/ . :
~ EXAMPLE 2 , ... . .
2-[2-(5-Methyl-4-imldazolylmethylthio)ethylamlnOl-5-(2-phenvleth ~ 4-pyrimidone dihydrochloride ; 5-(2-Phenyleth~4-2-thiouracil (1.8 g) was converted into 5-phenyl-ethyl-2-methylthio-4-pyrimidone (m.p. 160-161 ex ethanol) by the method described in Example l(i). Reaction of this ~ . .
~ ~ -15~
.
1 pyrimidone (1.55 g) with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.1 g) by the method described in Example l(ii) gave an oil which was dissolved in 2N hydrochloric acid, the solution evaporated to dryness and the residue recrystallised ~rom~methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(2-phenylethyl)-4-pyrimidone dihydrochloride,m.p.
214-218.
(Found: C, 51.3; H, 5.6; N, 15.8; S, 7.1; Cl, 15.8;
.
C19H23N50S. 2 HCl requires: C, 51.6; H, 5.7; N, 15.8;
S, 7.25; ~1, 16.0%) ,,' ~ ` 10 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-~4-methylbenzyl)-4ipyrimidone dihydrochloride
~' 1 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-~ benzyloxy-4-pyrimidone :~ 2-12-(5-methyl-4-imidazolylmethylthio)ethylaminol-5-(3-' methoxybenzyl)-4-pyrimidone 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-, chlorobenzyl)-4-pyrimidone , 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenyl-~; butyl)-4-pyrimidone ~, 2-[2-(5-methyl-4-lmidazolylmethylthio)ethylamino]-5-(S-(1,3-benzodioxolyl)m,et~yl)-4-pyrimidone 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-ethox~-benzyl)-4-pyrimidone ,2-[2~-(5 _ethg,1-4-imidazolylmethylthio)ethyla ino]-5-(3-benzyloxybenzyl)-4-pyrimidone ' 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-naphthylmethyl)-4-pyrimidone.
The compound~ of Formula 3 are shown and described as 4-one and 4-thione derivatives and these derivatives exist in~equilibrium ~ith the corresponding 6-one and 6-t~ione , 20~ ~ tautomers. These compound# al80 exi#t to a les~er extent a~ the~mercapto and hydro~y tautomers and the p~rimidine ring may~also esist in the i'ollowing tautomeric forms:
N ~ ~ ~
Het' m q al#0 exist in #everal tautomeric forms,and it ill be understood tha~ all these tautomeri¢ forms are ~w1thin the ~ope of the present lnvention.
The compounds oi' thi~ invention may be prepared by treating an amine oi' Formula 4:
~-CH2ZCH2CH2NH2 Formula 4 106'70'76 1 wherein Het' and Z are as de~ined in Formula 3, with a compound of Formula 5: 3 Y
~ (CH2)mW(cH2)n ~
Q N X
.
. Formula 5 , .
wherein X, Y3, m, W,. n and A are as deiined in Formula 3 and Q iB loweralkylthio, benzylthio, halogen, or other ,~
reactive grouping which is conveniently displaced with aD amine. Preierably thi;s reaction is carried out in the ; absence o~ a solvent ~at about:l50C or in the presence .:
~ 15;;~ oi a solvent, SUch as re~iluxing pyridine.
I ~ ~ The intermediates o~ Formula 5 wherein W is methylene, Y3 20~ hgdrogen and Q is loweralkylthio (shown as Formula.8) may be prepared according to Scheme 1:-: Scheme 1 (wh-r-in A is as:del'ined in Formula 3 and a is 0 to 4 and Alk:i~ lo~er alkyl) CH2(CH2)aA
( ~ )ao~2cH2Qo2Et 1) Na, HC02Et ~ > S N
.- ,,~ - :, ormula ~ 2) thiourea : Formula 7 alkyl halide or sulphate HN ~ CH2(CH2)aA
- ~::: AlkS'~N ~ ~0 i ~
Formula 8 7-.
~' .
: :
`` 1067076 l The esters of Formula 6 wherein a is O may be prepared by eonden~ing a sub8tituted benzaldehyde ~ith malonie aeid, and hydrogenating and esteriiying the produet ~he intermediates oi' Formula 5 wherein ~ is methylene, Y3 is loweralkyl and~Q is loweralkylthio (shown a- Formula 9) may be prepared according to Scheme 2 -;~ ~
Scheme 2 (wh-rein A i8 as de~inea in Formula 3, i8 0 to 4, Hal is chlorlne or bromine, and Alk i8 lower alkyl) Y3-cccH2co2Et NaOEt, Hal~H2(CH2)aA Y3-CoCHCo2Et lS;~ ~ thiourea 3 ~ y3 I alkyl halide or H ~ CH2(CH2)aA gulphate H ~ CH2(CH2)aA
; Alk ~ N ~ O H
For~ul- 9~
The ~1nbermed1-t-s~o~ Formula S wherein Q i8 halogen (~hown-as For~ula~ may be prepared according to Scheme 3 -Sohem- 3 (~herein A and Y3 are as ~e$ined in i'~rmula 3, a is O to 4- and Hal;ls ehlorine or bromine : ' ~:
-' :~:
.:
~067076 CH2(CH2)aA
Y COCHC02Et sodium salt \guanidine Formula 10 ~CH2 (CH2) aA
: . H2N 1 N ~ 0 1) HCl, NaNOa.
2) CU2Hal2 .~ ~ ` y3 HN~2 (CH2) aA
Ha~N O
Formula 11 The campoundg oi iormula 10 wherein Y3 i~ hydrogen may : be prepared ~rom a compound oi Formula 6, sodium and ethyl iormate, and the compounds oi Formula 10 wherein Y3 is lower alkyl may be prepared as shown in Scheme 2.
~ ~ 25 ,~ The intermediates o$ Formula 5 wherein W is oxygen or sulphur may be prepared by the ~ollowing methods:-~ 30 :: (a) m is 0 A(CH2)nWCH2C02Et 1) HC02Et, Na ~ W(CH2)nA
2) thiourea AlkS ~ N 0 3) alkyl halide or W is oxygen or sulphate sulphur _9_ -~ 1067076 l (b) m is l These compounds may be prepared by the route:-~ CH20H l)SOCl2 or HBr ~ CH2W(CH2)nA
H2N O2)A(CH2)nO Na or H2 N
: H A(CH2)nS Na o W i8 oxygen or sulphur :~ . l) HClJNaN02 2) CU2 Hal2 ', ::
15~ `
:
HN ~ 2W(CH2)nA
Hal ~ N ~ O
; :. - 20: W i8 oxygen or sulphur , ~
~ : or alternatively, irom ethyl 4-benzyloxybutyrate, or a similar protected derivative o~ ethyl 4-hydroxybutyrate, by a proces~ analogous to that outlined in Scheme l, ~ollowed ~ucce~s1vely by deprotection,treatment with thionyl chloride, and treatment with the sodium derivative oi' A~CH2)nOH or ', `;, ~ A~ (Cll~) nSH .
::
1 (c) m is 2 to 4 :
O O
2 eth~l iormate,~odium CH2Jm (CH2 ` . l)thiourea :i~ 10 ; . 2)alkyl halide ~ . or-sulphate ~ , ~ (CH2)mW(CH2)nA HN ~ (CH )mOH
Alk N o 2)A(CH2) O~Na+ or Alk ~ N
is oxygen or sulphur n m is 2 to 4 A(CH2)nS Na ; 20 Compounds of Formula 3 wherein X is sulphur may be prepared by treating the compounds o~ Formula 3 wherein X is oxygen with phosphorus pentasulphide in a solvent such as ~yridine.
The amines o~ Formula 4 may be prepared by methods described in British Patent Speciiications 1305547 and 1338169, and ~ C~nad~an Patents 945,17I a~d 9.47,767.
: "
~:~ 30 C
`- 1067076 , The compounds of Formula 3 block histamipe H2-receptors, that is they inhibit the biological actions of histamine which are not inhibited by hi8tamine Hl-antagonists such as mepyramine but are inhibited by burimamide. For example, the compounds oi' this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 16 micro~oles per kilogram intravenously.
Many oi the compounds o~ the present invention produce at least 50% inhibition in this test at a dose of from 1 to 10 micromoles per kilogram. This procedure is re~erred to in the above-mentioned paper of Ash and Schild. The activlty of these compounds as histamine H2-antagonists is also demQnstrated by their ability to inhibit other actions of histamine ~hich, according to the above-mentioned paper of Ash & Schild, are not mediated by histamine Hl-receptors.
For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.
The compound~ oS thls lnventlon inhiblt the basal secretion of gastric 8cid and also that stimulated by pentagastrin or by ~ood.
In addition, the compounds of this invention show anti-inflammatory activlty in conventional tests such as the rat paw oedema test, where the oedema is induced by an lrrltant, the rat paw volume is reduced by subcutaneous inlec*lon of doses of about 500 micromoles/kg. of a compound oS Formula 3. In a con~entional te8t, such as the measure-ment o~ blood pressure ln the anae8thetised cat, the action o~ the compound8 o~ this lnventlon ln inhibiting the vasodilator action o~ hi~tamine can also be demonstrated. The level of activity o~ the compounds of this lnvention is illustrated by the e~ectlve dose producing 50% inhibition o~ gastrlc acid secretion in the anaesthetised rat (which i'or manr of the compounds o~ Formula 3 is ~rom 1 to 10 micro-moles per kilogram) and the dose producing 50~ inhibition of histamine-~nduced tachycardia ln the isolated guinea pig atrium, (which for many of the compounds of Formula 3, is below 10 5M) . , .
`
``` ~067~76 .. . ...... .
;~ The eompound~ o~ Formula 3 also bloe~ histamine ~l-receptors, that is they lnhlbit the biologieal actions o~ bistamine which are inhibited by mepyramine, diphenpydramine and chlorpheniramine For example the eompoundsf o~ this invention hav- been ~ound to inhibit the action o~ histamine in the isolated~Zgulnea-plg lleum For manr o~ the eo~pounds o~ Formula 3 a dose o~ ~rom 10 5 ~olar inhlblta the histamine-stimulated eontraetion-q o~ the Zgui~ea pig lleum ~f ~
10 ~For therapeutie u~e, the pharmacologically aetive eompounds oi-tbe oresent invention ~ill nor~allg be adminlstered as a pharm-eeutieal eomposition eompri~lng as the or an essential wt~ive ingredient at l-ast one sueh eompound ln the basic ~orm or in the ~orm o~ an addition salt ~lth a pharmaeeutieally 15 ~ aeeeptable acid and in assoeiated with a pharmaceutical earrier therefor~ Sueh addition salt~ inelude those ~ith hydxoehlor~e, h~drobromle, hydriodle, ~ulphur~e and maleie aeids and may eo~venientl~ be ~ormed ~rom the eorresponding bases oi' Formula 3 by standard~procedures~ ~or e~a~ple b~ treatl~g the base ~ith an~aeld in a lower~alkanol or br the use o~ ion esehange re~ins to Sorm th- requlred salt either direetly ~r the base or ~rom dl~er-nt~-dtltion salt ~ , -Pharmaeeutleal eamposltions eomprlslng a phar~aceutieal earrierand~a~eompou~d o~Formula 3 or a Pharmaeeutical~y aeeeptable ;aeZid~ additlon salt~th-reo~and ~thods o~ bloe~lng hlsta~ine rec-ptor~ ~hleh;oompri admlnlstering a cZ~mpound o~
Fo ~ la 3; or a ~phar~aceuticallr~aceeptable acid addition salt th~reo~ are~ o obJcct~ or this ln~ention. The phar~aceutical carrier; employed may be, ~ox esa~ple, either a ~olid or llquld E~amplary o~ solld carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectln, acacia, magneslum stearate, stearlc aeid~and the like Exemplary of liquid carxiers axe syrup, peasut ol~, oliYe oll, water and the like , . ~::
~: -,", .
.
- A ~ide ~ariety 0~ pharmaceutlcal ~orms can be employed 'Thus, 1~ a solid carrier ls u~ed, the preparation can be tableted, placed in a hard gelatin capsule ln p~der or pellet i'orm, or in the iorm o~ a troche or lozonge The amount oi solid carrler ; 5 ~11~ ~ary ~idelr but pre~erably ~ill be from about 25 mg to abou* 1 g Ii' a liquid carrier is usèd, the preparation may bo in tho i'orm o~ a syrup, emulsion, so~t gelatin capsule, '~ sterile ln~ectable llquld contalned ~or e~ample ln an ampoule, or an~aqueous or nonaquoous llquld suspen~ion The~pharmaceutical camposltions are prepared bg conventlonal ~h~ technlqué involvlng Focedures such as mixing, granulating u~d~co~presslng or~dissolvi~g the ingredlents as appropriate to the~deslred preparation 15 ~ ~
The actlve lngredient will be present in the eompositions in an e~iectlve amount to block hlstamine ~2-reeeptor~ The ; route'o~ ad~lnl tratlon may be oral or parenteral ~; ~ Pre~erably, -aeh dosage unlt ~ill eontaln the actlve lngredient an ~ount oi iro~about 50 mg to about 250 mg activo~in F-dient~ preierablr ba admi~istered one to lx'times~er d-y~' The dally dosage regimen ~ill prei'erably bo~rom~about lS0 mg to~about l ~ mg Adranta~e~uslr the eo~po~ltion ~111 be ~ade up in a dosage ~or~
app¢o~rlate to the deslr-d ~ode o~ ad~iuistration ~or esa~ple, a~;a~tabl-t~ capsule~ inJ-ctable solution or as a eream or olntment ~or topieal appllcatlon ~ , ~
.,, ~ . . .. .
~ .
.
``` 1067076 1 The invention is illustrated but in no way limited by the $ollow~ng Examples in which all temperatures are in degrees Centigrade:
2-12-(5-Methyl -4-imidazolylmethylthio)ethylamincl-5-(4-chlorobenzyl~4-prrimidone (i~ A solution of 5-(4-ehlorobenzyl)-2-thlouracil (S0.5 g), methyl iodide (28.4 g) and sodium hydroxlde (8.2 g) in water (200 ml) and ethanol (400 ml) ~as stirred at 60 for 30 minute~ then allowed to cool. The crystalline product ~m ~ was i'iltered and washed with water to give 5-(4-ck~robenzyl)-; ~ 2-methylthio-4-pyrimidone (48.6 g), m.p. 193-194 (methanol/
ethanol).
(ii) An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (17.7 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (11.4 g) was heated at 145-150 ~or 5 hours. After coo}ing, the reaction mixture was triturated with water to give the free base, which was separated by decantation and ; ~ recrystallised from methanol to give 2-[2-(S-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone ; m.p. 204.5 - 206.
(Found: C, 5S.45; H, 5.2; N, 18.0: S, 8.3 Cl, 8.9;
Cl ~22ClN50S requiros; C, SS.45; H, 5.2; N, 18.0: S, 8.2:
/ . :
~ EXAMPLE 2 , ... . .
2-[2-(5-Methyl-4-imldazolylmethylthio)ethylamlnOl-5-(2-phenvleth ~ 4-pyrimidone dihydrochloride ; 5-(2-Phenyleth~4-2-thiouracil (1.8 g) was converted into 5-phenyl-ethyl-2-methylthio-4-pyrimidone (m.p. 160-161 ex ethanol) by the method described in Example l(i). Reaction of this ~ . .
~ ~ -15~
.
1 pyrimidone (1.55 g) with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.1 g) by the method described in Example l(ii) gave an oil which was dissolved in 2N hydrochloric acid, the solution evaporated to dryness and the residue recrystallised ~rom~methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(2-phenylethyl)-4-pyrimidone dihydrochloride,m.p.
214-218.
(Found: C, 51.3; H, 5.6; N, 15.8; S, 7.1; Cl, 15.8;
.
C19H23N50S. 2 HCl requires: C, 51.6; H, 5.7; N, 15.8;
S, 7.25; ~1, 16.0%) ,,' ~ ` 10 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-~4-methylbenzyl)-4ipyrimidone dihydrochloride
5-(4-Methylbenzyl)-2-thiouracil(4.65 g) was converted into ` 5~4-methylbenzyl)-2~nethyithio-4-pyrimidone (m.p. 208.5-211 ex methanol/ethanol) by the method described in Example l(i). Reaction oi this pyrimidone (1.6 g) with 2-(5-methyl-4-lmidazolylmethylthio)ethylamine (1.2 g) by the method N described in Example l(ii) and acidliicatlon with dilute ethanollc hydrogen chloride iollowed by evaporation to dryness and recrystallisation from ethanol gave 2-[2-(5-methyl-4-imidazolylmethylthia)ethylamino]-5-(4-methylbenzyl)-4-pyrimidone dihydrochloride, m.p. 197-198.5.
(Found: C, 51.9; H, 5.7; N, 15.9: S, 7.3: Cl, 15.4;
; ClgH23N50S. 2HCl. requires: C, 51.6; H, 5.7; N, 15.8;
S, 7.25; Cl, 16.0%).
.; ~: :
, ~
EXA~PLE 4 2-~2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5~3-chlorobenzyl)-4~yrimidone dlhydrochloride Ethyl 3-(3-chlorophenyl)propionate (39.3 8) and ethyl formate.(14.9 g) were added over a period oi 6 hours to a stirred mixture of sodium wire (4.25 g) and dry ether (110 ml) cooled with an ice-salt bath. The mixture was stirred for ~ , ~ -16-.
~0670~6 18 hours at room temperature and evaporated to dryness.
The residue was refluxed for 7 hours with thiourea (14.05 g) and ethanol (100 ml). The mixture was evaporated t~ dryness and the residue was dissolved in water. Acetic acid was added until the mixture had pH 4. The white precipitate was filtered and washed to give 5-(3-chlorobenzy~-2-thiouracil, m.p. 192-195 (ethanol).
(ii3 5-(3-Chlorobenzyl~2-thiouracil (3.1 g) was converted into 5-(3-chlorobenzyl)-2-methylthio-4-pyrimidone, m.p. 17~.5-180.5 (ethanol) by the method described in Example l(i) andthis latter compound (1.8 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.14 g) as described in Example l(ii) to give a residue which was treated with ethanolic hydrogen chloride to give Z-[2-(5-methyl-4-imidazolyl-methylthio)ethylamino]-5-(~chlorobenzy~-4-pyrimidone - dihydrochloride, m.p. 212.5-216 (crystallised from ethanol).
(Found: C, 46.8; H, 4.7; N, 14.9: S, 6.9: Cl, 22.7.
C18H20Cl N50S. 2 HCl. requires: C, 46.7; H, 4.8; N, 15.1;
S, 6.9; Cl, 23.0%) 2-(2-(5-Methyl-4-imidazolylmethylthio)ethylaminol-5-(3,4-.
dichlorobenzyl)-4-pyrimidone dihydrochloride ( (i) Ethyl 3-(3,4-dichlorophenyl)propionate (48.9 g) was converted into 5-(3,4-dichlorobenzyl)-2-thiouracil m.p.
232.5-233.5 (ex methanol/ethanol) by the procedure of Example 4(~).
(ii) 5-(3,4-Dichlorobenzyl)-2-thiouracil (5.7 g) was converted into 5-(3,4-dichlorobenzyl)-2-methylthio-4-pyrimid~ne, m.p. 216-218 (acetic acid) by the procedure of Example l(i).
(iii) 5-(3,4-Dichlorobenzyl)-2-met~hylthio-4-pyrimidone (2.1 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.2 g) by the procedure of Example 3 to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3,4-dichlor~benzyl)-4-pyrimidone dihydrochloride, m.p. 235.5-238.5(aqueous methanol) (Found: C, 43.3; H, 4.3; N, 13.8; S, 6.4; Cl, 27.8;
C18HlgC12N50S.2HCl. requires; C, 43.5: H, 4.3; N, 14.1;
S, 6.45: Cl, 28.5%) .
2-[2-(2-thiazolylmethylthio)ethylaminOl-5--(4-chlorobenzyl~-4-pyrimidone monohydrochloride ( ~ An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.36 g) and 2-(2-thiazolylmethylthio)ethylamine (0.9 g) was heated at 130-135 for 3~hours. After cooling the reaction mixture was treated with 2N hydrochloric acid.
Evaporation to dryness followed by recrystallisation from ; isopropanol/methanol gave 2-12-(2-thiazolyl-methylthio)-ethylaminol-5-(4-chlorobenzyl)-4-pyrimidone monohydrochloride, m.p. 172.5-174.5.
(Found: C, 47.4; H, 4.3; N, 13.0; S, 14.7; Cl, 16.5;
C16H18Cl N40S2.HCl. requires; C, 47.55; H, 4.2: N, 13.05;
S, 14.9; Cl, 16.5%).
~ ~ ' EXAMP~E 7 2-[2-(5-~ethyl-4-imidazolylmethylthio)ethylaminol-5-(4-methoxybenzyl~4-pyrimidone dihydrochloride , An ~ntimate mixture oi 5-(4,methoxybenzyl)~2-methylthio-4-pyrimidone (3.0 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.95 g) was heated at 135-140 with frequent stirring for 6 hours. After cooling, the reaction mixture was triturated with hot water, filtered, washed with dry ether and dissolved in propan-2-ol. The solution was acidified with dilute ethanolic hydrogen chloride, evaporated to dryness, and the residue recrystallised from ethanol to give 2-[2-(5- ~
methyl-4-imidazolylme~pylthio)ethylamino¦~5-(4-methoxybenzyl)-~1067076 -4-pyrimidone dihydrochloride m.p. 198-200.
(Found: C, 49.0; H, 5.5; N, 15.0; S, 6.9; Cl, 14.7;
C19H23N502S.2HCl requires; C, 49.8; H, 5.S; N, 15.3;
S, 7.0; Cl, 15.5%) 2-~2-(5-Methyl-4-imidazolylmethylthio)ethylaminol-5-(4-chlorobenzyl)-6-methyl-4-pyrimidone dihydrochloride_ (i) 5-(4-Chlorobenzyl)-6-methyl-2-thiouracil was methylated with methyl iodide as described in Example 1 (i) to give 5-(4-chlorobenzyl)-6-methyl-2-methylthio-4-pyrimidone (m.p. 248-251).
(Found: C, 55.6; H, 4.7; N, 10.0; S, 11.4; C13H13ClN20S
requires: C, 55.3; H, 4.6; N, 9.9; S, 11.4%) (ii) Reaction of 5-(4-chlorobenzyl)-6-methyl-2-methylthio-4-pyrimidone (1.95 g) with 2-(5-methyl-4-imidazolylmethylthio)-- 20 ethylamine (1.19 g) by the method described in Example (ii) gave the title compound, m.p. 203-206.5. (Crystallised from ethanol).
(Found: C, 47.7; H, 5.1; N, 14.4; S, 6.6; Cl, 21.3;
C19H22ClN50S.2HCl requires: C, 47.9; H, 5.1; N, 14.7;
S, 6.7; Cl, 22.3%).
E~AMPLE 9 2-[2-(3-Bromo-2-pyridylmethylthio)ethylamino~5-(4-c loro-benzyl)-4-pyrimidone monohydrochloride 5-(4-Chlorobenzyl)-2-methylthio-4-pyrimidone (~-.2 g? was reacted wlth 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.1 g) according to the procedure of Example 2. The reaetion mixture ~a8 acidified with dilute ethanollc hydrogen chloride, e~aporated to dryness and the reqidue recrystallised fro~
ethanol/~ter to give 2-~2-(3-bromo-2-pyri dylmethylt hio)ethyl-ami~o]-5-(4-chlorobenæyl~4pyrlmidone monohydrochloride, m. p.
215-218 Cdecomposes).
(Found C, 45.4; ~, 3.8; ~, 11.1; S, 6.3; C12H18Br Cl N40S-HCl ` re~uire~ C, 45.4; H, 3.8; N, 11.2: S, 6.4%) ., ~ .
. .. .
Example 10 2-~2-(5-~ethyl-4-imidazolylmethylthio)ethylaminol-s-(2 phenylethyl)-6-methyl-4-pyrimidone (1) Ethyl a-(phenylethyl)acetoacetate t23.4g) and thiourea (10.45g) ~ere added to B ~olution of sodium ethoxide ln ethanol (100 ml) prepared from sod~um (4.6g). The mixture ~as refluxed for 5~ hours and evaporated to dryne-~s. The solid resldue wa~ dissolved in water and ( acetic acid was added to pH 4. The white precipitate was ~iltered off and recr~stallised from ethanol to give 5-(2-phenylethyl)-6-methyl-2-thiouracil m.p. 210-214.
(2) Sub~tltutlon o~ 5-(2-phenylethyl)-6-methyl-2-thiouracil for 5-(4-chlorobenzyl)-2-thiouracil in the general procedure of Example 1 ga~e the title compound m.p.
222.5 - 224.5 ~methanol) (Found- C, 62.75; H, 6.5; N, 18.1; S, 8.3; C20H25N50S
req~ires C, 62.6; H, 6.6; N, 18.2; S, 8.4%) -2-[2-(5-Methyl-4-imidazolylme~ o)eth~lamino3-5-benzyloxy-4-pyrimidone dihydrochloride (i) Ethyl benzyloxyacetate (60.0 g) was converted into 5-benzyloxy-2-thiouracil m.p. 240-241 (ex. acetonitrile/
ethyl acetate, 1:1) by the procedure of Example 4(i).
(ii) 5-Benzyloxy-2-thiouracil (10.0 g) was converted into 5-benzyloxy-2-methylthio-4-pyrimidone m.p. 184-185 (ex methanol) by the procedure of Example l(i).
(iii) 5-Benzyloxy-2-methylthio-4-pyrimidone (4.13 g) was reacted with 2-t5-methyl-4-imidazolyl)ethylamine (2.83 g) by the procedure of Example 3 to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-benzyloxy-4-pyrimidone dihydrochloride, m.p. 161-162 (ethanol).
2-~2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone dihydrochloride.
5-(3-Methoxybenzyl)-2-thiouracil (16.1 g) was converted into 5-(3-methoxybenzyl)-2-methylthio-4-pyrimidone, m.p. 143-144C
(ex ethanol) by the procedure of Example l(i), 5-(3-~ethoxybenzyl)-2-methylthio-4-pyrimidone (3.0 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (2.1 g) aæ described in Example l(ii), to give a residue, which, on treatment with ethanolic hydrogen chloride gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone dihydrochloride, m.p. 173-175.5 (ex ethanol).
(Found: C, 49.6; H, 5.3; N, 15.1; S, 7.1; Cl, 15.8;
ClgH25C12N502S requires: C, 49.8; H, 5.5; N, 15.3; S, 7.0;
Cl, 15.5%).
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-chlor benzyl)-4-pyrimidone dihydrochloride s (i) Ethyl 3-~2-chlorophenyl)propionate (48.4 g) was converted into 5-(2-chlorobenzyl)-2-thiouracil m.p.223-224 (ex methanol by the procedure described in Example 4(i).
(ii) 5-(2-Chlorobenzy~2-thiouracil (5.05 g) wa~ converted into 5-(2-chlorobenzyl~2-methylthio-4-pyrimidone, m.p. 171-173C (ex ethanol) by the procedure of Example l(i). 5-(2-Ch~l-orobenzyl)-2-methylthio-4-pyrimidone (1.6 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.03 g) 15 as described in Example l(ii), to give a residue, which on treatment with dilute ethanolic hydrogen chloride, gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino-5-(2-chloro-benzyl)-4-pyrimidone dihydrochloride, m.p. 215-219 (ex methanol-ethanol).
(Found: C, 46.7; H, 4.9; N, 14.9; S, 6.8; Cl, 22.4;
C18H22C13N50S requires; C, 46.7; H, 4.8; N, 15.1; S, 6.4;
Cl, 23.0%).
EXAllPLE 14 2 2-~2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenylbutyl)-4-pyrimidone dihydrochloride.
(i) Ethyl 6-phenylhexanoate (43.5 g) was converted to 5-(4-phenylbutyl)-2-thiouracil, m.p. 177~5-181 (ex ethanol-water~, as described in Example 4(i).
(ii) 5-(4-Phenylbutyl)-2-thiouracil (3.05 g) was converted into 5-(4-phenylbutyl)-2-methylthio-4-pyrimidone m.p. 146-149 (ex ethanol), by the procedure of Example l(i).5-(4-Phenylbutyl)-2-methylthio-4-pyrimidone (1.89 g)was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.18 g) as described in Example l(ii) to give a residue, which on treatment with di~ute ethanolic hydrogen chloride, gave 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(4-phenylbutyl)-4-pyrimidone dihydrochloride, m.p. 207-209.5 (ex ethanol) (Found: C, 53.3; H, 6.2; N, 14.8; S, 6.8; Cl, 14.8.
C21H29C12N50S requires: C, 53.6; H, 6.2; N, 14.9; S, 6.8;
Cl, 15.1%).
EL~J~PI,E 15 2-~2-(5-Methyl-4-imidazolylmethyl~hio)ethylaminol-5-(5-(1,3-benzodioxolyl)methyl)_4 pyrimidone dihydrochloride (i) Ethyl 3-(5-(1,3-benzodioxolyl)propionate (17.5 g) was converted into 5-(5-(1,3-benzodioxolyl)methyl)-2-thiouracil m.p. 158-159 (ex ethanol/methanol, 1:1), by the procedure described in Example 4(i).
.
(ii) 5-(B-(1,3-Benzodioxolyl)methyl)-2-thiouracil (2.9 g) wa~ converted into 5-(5-(1,3-benzodioxolyl)methyl)-2-methylthio-4-pyrimidone, m.p. 197-198 (ex acetonitrile) by the procedure of Example l(i).
5-(5(1,3-Benzodioxolyl)methyl)-2-methylthio-4-pyrimidone (1.2 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (0.77 g) as described in Example 1 (ii), to give a re~idue, which, on treatment with ethanolic hydrogen chloride, gave the title product m.p. 230-232 (ex ethanol).
~Found: C, 48.5; H, 5.1; N, 14.5; S, 6.7; Cl, 14.7;
C10H23C12N503S requires: C, 48.3; H, 4.9; N, 14.8; S, 6-8;
Cl, 15.0%).
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-ethoxybenzyl)-4-pyrimidone dihydrochloride 5-(3-Ethoxybenzyl)-2-thiouracil (5.0 g) was converted into 5-(3-ethoxybenzyl)-2-meShylthio-4-pyrimidone, m.p. 136-138.
--~3--1 (ex acetonitrile) by the procedure o~ Example l(i).
5-(3-Ethoxybenzyl)-2-methylthio-4-pyrimidone (2.0 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.25 ~) as described in Example l(ii), to give a residue which, on treatment with ethanolic hydrogen chloride gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-ethoxybenzyl)-4-pyrimidone dihydrochloride m.p. 176-178 (ex ethanol).
(Found: C, 50.6; H, 5.7; N, 14.7; S, 7.1; Cl, 14.7; C20H27 C12N502S requires; C, 50.9; H, 5.8; N, 14.8; S, 6.8; Cl,15.0%).
.
.
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylaminOl-5-(3-benzyloxybenzyl)-4-pyrimidone dihydrochloride 5-(3-Benzyloxybenzyl)-2-thiouracil (4.6 g) was converted into 5-(3-benzyloxybenzyl)-2-methylthio-4-pyrimidone, m.p.
176-178 (ex ethyl acetate), by the procedure of Example l(i).
5-(3-Benzyloxybenzyl)-2-methylthio-4-pyrimidone (2.0 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.0 g) as described in Example l(ii), to give a residue which, on treatment with ethanolic hydrogen chloride gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-benzyloxybenzyl)-4-pyrimidone dihydrochloride m.p. 193-194 2S (e~ ethano}/methanol, 1:1).
(Found: C, 55.7; H, 5.4; N, 12.9; S, 6.0; Cl, 13.0;
C25H29C12N~02S reguires; C,5S.2; H, 5.5; N, 13.1; S, 6.Q;
Cl, 13.3%).
2-12-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(1-naphthylmethyl)-4-pyrimidone dihydrochloride 5-(1-Naphthylmethyl)-2-thiouracil (6.7 g) was converted into 5-(1-naphthylmethyl)-2-methylthio-4-pyrimidone, m.p. 178-180 (ex methanol) by the procedure of Example l(i).
. .
~067076 1 5~ Naphthylmethyl)-2 methylthio-4-pyrimidone (0.4 g) ~as reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.25 g) as described in Example l(ii), to give a residue which, on treatment with ethanolic hydrogen chloride gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-naphthylmethyl)-4-pyrimidone dihydrochloride, m.p. 228-230 (ex ethanol).
(Found: C, 55.0; H, 5.3; N, 14.4; S, 6.6; Cl, 14.5;
C22H25ClN50S requires: C, 55.2; H, 5.3; N, 14.6; S, 6.7;
1 Cl, 14.8%).
Substitution of ethyl 3-(3,4,5-trimethoxyphenyl)propionate for ethyl 3-(3-chlorophenyl)propionate in the general procedure of Example 4 leads to the production of 2-[2-(5-methyl-4-imidazolylmethylthio)ethyla~ino]-5-(3,4,5-trimethoxybenzyl)-4-pyrimidone.
Treatment of 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-(5-(4-methoxybenzy ~ 4-pyrimidone with phosphorus pentasulphide in hot pyridine leads to the production of 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]_5_(4-m~thoxybenzyl~pyrimid-4-thione EXA~PLE 21 , Substitution o~: (a) 2-(2-imidazolylmethylthio)ethylamine (b) 2-~4-imidazolylmethylthio)ethylamine (c) 2-(5-bromo-4-imidazolylmethylthio)-ethylamine (d) 2-(5-trifluoromethyl-4-imidazolylmethl-thio)ethylamine (e) 2-(5-hydroxymethyl-4-imidazolylmethyl-thio)ethylamine 1 . (f) 2-(2-pyridylmethylthio)ethylamine (g~ 2-(3-methyl-2-pyridylmethylthio)-ethylamine (h) 2-(3-methoxy-2-pyridylmethylthio)-ethylamine (i) 2-(3-chloro-2-pyridylmethylthio)-ethylamine (j) 2-(3-amino-2-pyridylmethylthio)ethyl-amine (k) 2-(3-hydroxy-2-pyridylmethylthio)ethyl-amin~
(1) 2-(3-isothiazolylmethylthio)ethylamine (m) 2-(4-bromo-3-isothiazolylmethylthio)-ethylamine (n) 2-(3-(1,2,5)-thiadiazolylmethylthio)-ethylamine (o) 2-(4-chloro-3-(1;.2j5)-thiadiazolyl-methylthio)ethylamine (p) 2-(5-amino-2-(1,3,4)-thiadiazolyl-methylthio)ethylamine . ao ior 2-(5-methyl-4-imidazolylmethylth~o)ethylamine in the procedure o~ Example 7 leads to the production o$:-.
(a) 2-[2-(2-imida~olylmethylthio)ethYlamino]-5-(4-methoxyben 4-pyrimidone . (b) 2-[2-(4-imidazolylmethylthio)ethylamino]-6-(4-methoxybenzyl)-4-pyrimidone ' (c) 2-[2-55-bromo-4-imidazolylmethy~thio~ethylamino]-5-(4_ methoxybenzy~ ~-py,rimidone (d) 2-[2-(5-tri~luoromethyl-4-imidazolylmethylthio)ethylamino]--5-(4-methoxybenzyl)-4-pyrimidone (e) 2-[2-(5-hydroxymethyl-4-imidazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyri~idone (f) 2-[2-(2-pyridylmethylthio)ethylamino~-5-(4-methoxybenzyl)--4-pyri~idone.
(g) 2-[2-(3-methyl-2-pyridylmethylthio)ethylamino]-5-(4-~ethoxybenzyl) 4-pyrimidone (h) 2-[2-(3-methoxy-2-pyridylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (i) 2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (~) 2-~2-(3-amino-2-pyridylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (k) 2-[2-(3-hydroxy-2-pyridylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (1) 2-[2-(3-isothiazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (m) 2-[2-(4-bromo-3-isothiazolylmethylthio)ethylamino]-5-(4methoxybenzjl)-4-pyrimidone (n) 2-[2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (o) 2-~2-(4-chloro-3-(1,2,5)-thiadiazolylmethylthio)ethyl-amino]-5-(4-methoxybenzyl)-4-pyrimidone (p) 2-[2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio)ethyl-amino]-5-(4-methoxybenzyl)-4-pyrimidone Substitution o~ 4-(4-imidazolyl)butylamine ~or a-(5-methyl-4-imidazolylmethylthio)ethylamine in the pr~cedure o~ Example 121ead~ to the production of 2-[4-(4-imidazolyl)butylamino~-5-(3-methoxybenzyl)-4-pyrimidone, m.p. 193-194.
Treatment of ethyl butyroacetate with sodium ethoxide and 4-methoxybenzyl chloride gives ethyl a-(4-methoxyb~nzyl)-butyroacetate which is refluxed with thiourea and sodium ethoxide to give 5-(4-methoxybenzyl)-6-propyl-2-thiouracil.
Substitution of 5-(4-methoxybenzyl)-6-propyl-2-thiouracil for 5-(4-chlorobenzyl)-2-thiouracil in the general procedure of Example 1 gives 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4 methoxy-benzyl)-6-propyl-4-pyr~midone.
~.
Substitution of (a) ethyl 3-(2-naphthyl)propionate (b) ethyl 3-(4-tri~luoromethylphenyl)propionate (c) ethyl 3-(4-dimethylaminQphenyl)prop~onate (d) ethyl 3-(4-phenoxyphenyl)propionate (e) ethyl 3-(4-(4-chlorophenoxy~phenyl)-propionate (f) ethyl 3-(4-(4-methoxyphenoxy)phenyl-propionate (g) ethyl 3-(4-biphenylyl)propionate (h) ethyl 3-(4-chloro-4-biphenylyl)propionate (i) ethyl 3-(4'-methoxy-4-biphenylyl)propionate ~or ethyl 3-(3-chlorophenyl)propionate in the procedure o~
Example 4 lead~ to the production of:
(a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-naphthylmethyl~-4-pyrimidone (b) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-tri~luoromethylbenzyl)-4-pyrimidone (c) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-dimethylaminobenzyl)-4-pyrimidone (d) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenoxybenzyl)-4-pyrimidone ~e) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-(4-chlorophenoxy)benzyl)-4-pyrimidone (f) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-~4-methoxyphenoxy)benzyl)-4-pyrimidone (g) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenylbenzyl)-4-pyrimidone (h) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-4-(4-chlorophenyl)benzyl)-4-pyrimidone (i) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-4-(4-methoxyphenyl~benzyl))-4-pyrimidone Treatment o~ 2-[2-(5-methyl-4-imidazolylmethylthio)ethylaminol-5-(3-benzyloxybenzyl)-4-pyrimidone with hydrogen bromide in acetic acid leads to the producti`on of 2-[2-(5-methyl-4-imldazolylmethylthlo)ethylamino]-5-(3-hydroxy-benzyl)-4-pyrimidone.
(a) Butyrolactone is treated with sodium and ethyl form~te, and the pro'duct is successively treated with thiourea and methyl iodide to give 5-(2-hydroxyethyl)-2-methylthio-4-pyrimidone.
(b) 5-(2-Hydroxyethyl)-2-methylthio-4-pyrimidone is treated with thionyl chloride and the product is reacted with the sodium derivative of (1) 4-methoxybenzyl alcohol and (2) 4-methoxybenzyl mercaptan, to give: 1. 5-(2-(4-methoxybenzyloxy)ethy~)-2-methylthio-4-,pyrimidone 2. 5-(2-(4-methoxybenzylthio)ethyl)-2-methylthio-4-! pyrimidone ; 25 (c) substitution of:
1. 5-(2-(4-methoxybenzyloxy)ethyl)-2-methyl-thio-4-pyrimidone ' 2. 5-(2-(4-methoxybenzylthio)ethyl)-2-methylthio-4-pyrimidone for 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone in the general procedure of Example l(ii) leads to the production oi' :
1. 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-(4-methoxybenzyloxy)ethyl)-4-pyrimidone 2, 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-(4-methoxybenzylthio)ethyl)-4-pyrimidone ; 1067076 1 (d) substitution of (1) phenol and (2) thiophenol for p-methoxybenzyl alcohol in procedure (bii) and (c) above leads to the production o~:
1. 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-phenoxyethyl)-4-pyrimidone 2. 2-[2-(5-methyl-4-imidaz~lylmethylthio)ethylamino]-5-(2-phenylthioethyl)-4-pyrimidone (e) substitution of (1) 2-phenylethanol and (2) 2-phenyl-ethyl mercaptan ior p-msthoxybenzyl alcohol in procedure (bii) and (c) above leads to the production of `
1. 2-[2-(5-methyl-4-imidazolylmethglthio)ethylamino]-5-(2-(2-phenylethoxy)ethyl)-4-pyrimidone 2. 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-(2-phenylethylthio)ethyl-4-pyrimidone (f) substitution of caprolactone for butyrolactone in procedure (a) (bii) and (c) above leads to the production of 1. 2-[2-(5-methyl-4-imidazolylmethyIthio)ethylamino]~5-(3-(4-methoxybenzyloxy)propyl)-4-pyrimidone 2. 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-(4-methoxybenzylthio)propyl)-4-pyrimidone.
, 25 Substitution o~ (a) ethyl 3-phenylpropoxyacetate (b) ethyl 3-phenylpropylthioglycolite for ethyl benzyloxyacetate in the procedure of Example 11 results in the preparation of:
(a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-phenylpropoxy)-4-pyrimidone (b) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-phenylpropylthio)-4-pyrimidone.
~067076 Substitution of (a) 5-~3-(2-(4-methoxyphenyl)ethoxy)benzy-1]-2-thiouracil (b) 5-[3-(3-chlorobenzyloxy)benzyl]-2-thiouracil for 5-(3-benzyloxybenzyl)-2-thiouracil in the general procedure of Example 17 leads to the production of:
(a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethy~amino]-5-[3-(2-(4-methoxyphenyl)ethoxy)benzyl]-4-pyrimidone ~b) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-[3-(3-chlorobenzyloxy)benzyl]-4-pyrimidone.
Substitution of (a) ethyl 3-(6-(2,3-dihydro-1,4-benzodioxinyl))-propionate (b) ethyl 3-(3-bromophenyl)propionate ~or ethyl 3-(3-chlorophenyl)propionate in the procedure oi Example 4 leadæ to the production o~:
(a) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-~6-(2,3-dihydro-1,4-benzodioxinyl)methyl]-4-pyrimidone 26 (b) 2-~2-(5-methyl-4-im~dazolylmethylthio)ethylamino]-5-(3-bromobenzyV-4-pyrimidone.
Treatment oi' ethyl 3-(3-hydroxyphenyl)propionate with dimethoxymethane and substitution o~ the product ~or ethyl 3-(3-chlorophenyl)propionate in the procedure oi' Example 4 leads to tbe production o~ 2-t5-methyl-4-imidazolylmethylthio)ethylamino]-5-~3-(methoxymethoxy)-benzyl]-4-pyrimidone. Treatment of thi~ product with hydrochloric acid give~ 2-[2-(5-methyl-4-imidazolylmethylthio) ethylamino]-5-(3-hydroxybenzyl)-4-pyrimidone.
Pharmaceutical composition:-Ingredients Amounts : :
2-~2-(5-methy~-4-imidazolylmethylthlo)-ethylamino]-5-(3-methoxybenzyl)-4-pyri~idone dihydrochloride 75 mg 10 Sucrose 75 mg Starch 25 mg Talc 5 mg Stearic Acid 2 mg The ingredients are screened, mixed and ~illed into a hard gelatin capsule.
E~AMPLE 32 .
Pharmaceutical compositlon:-. 20 edient 8 Amount 8 2-~2-(5-methyl-4-lmidazolylmethylthio)-ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone dihydrochloride 100 mg : Lactose 100 mg The i~gredient~ are screened, mixed and ~illed into a hard gelatin capsule.
-3~-
(Found: C, 51.9; H, 5.7; N, 15.9: S, 7.3: Cl, 15.4;
; ClgH23N50S. 2HCl. requires: C, 51.6; H, 5.7; N, 15.8;
S, 7.25; Cl, 16.0%).
.; ~: :
, ~
EXA~PLE 4 2-~2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5~3-chlorobenzyl)-4~yrimidone dlhydrochloride Ethyl 3-(3-chlorophenyl)propionate (39.3 8) and ethyl formate.(14.9 g) were added over a period oi 6 hours to a stirred mixture of sodium wire (4.25 g) and dry ether (110 ml) cooled with an ice-salt bath. The mixture was stirred for ~ , ~ -16-.
~0670~6 18 hours at room temperature and evaporated to dryness.
The residue was refluxed for 7 hours with thiourea (14.05 g) and ethanol (100 ml). The mixture was evaporated t~ dryness and the residue was dissolved in water. Acetic acid was added until the mixture had pH 4. The white precipitate was filtered and washed to give 5-(3-chlorobenzy~-2-thiouracil, m.p. 192-195 (ethanol).
(ii3 5-(3-Chlorobenzyl~2-thiouracil (3.1 g) was converted into 5-(3-chlorobenzyl)-2-methylthio-4-pyrimidone, m.p. 17~.5-180.5 (ethanol) by the method described in Example l(i) andthis latter compound (1.8 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.14 g) as described in Example l(ii) to give a residue which was treated with ethanolic hydrogen chloride to give Z-[2-(5-methyl-4-imidazolyl-methylthio)ethylamino]-5-(~chlorobenzy~-4-pyrimidone - dihydrochloride, m.p. 212.5-216 (crystallised from ethanol).
(Found: C, 46.8; H, 4.7; N, 14.9: S, 6.9: Cl, 22.7.
C18H20Cl N50S. 2 HCl. requires: C, 46.7; H, 4.8; N, 15.1;
S, 6.9; Cl, 23.0%) 2-(2-(5-Methyl-4-imidazolylmethylthio)ethylaminol-5-(3,4-.
dichlorobenzyl)-4-pyrimidone dihydrochloride ( (i) Ethyl 3-(3,4-dichlorophenyl)propionate (48.9 g) was converted into 5-(3,4-dichlorobenzyl)-2-thiouracil m.p.
232.5-233.5 (ex methanol/ethanol) by the procedure of Example 4(~).
(ii) 5-(3,4-Dichlorobenzyl)-2-thiouracil (5.7 g) was converted into 5-(3,4-dichlorobenzyl)-2-methylthio-4-pyrimid~ne, m.p. 216-218 (acetic acid) by the procedure of Example l(i).
(iii) 5-(3,4-Dichlorobenzyl)-2-met~hylthio-4-pyrimidone (2.1 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.2 g) by the procedure of Example 3 to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3,4-dichlor~benzyl)-4-pyrimidone dihydrochloride, m.p. 235.5-238.5(aqueous methanol) (Found: C, 43.3; H, 4.3; N, 13.8; S, 6.4; Cl, 27.8;
C18HlgC12N50S.2HCl. requires; C, 43.5: H, 4.3; N, 14.1;
S, 6.45: Cl, 28.5%) .
2-[2-(2-thiazolylmethylthio)ethylaminOl-5--(4-chlorobenzyl~-4-pyrimidone monohydrochloride ( ~ An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.36 g) and 2-(2-thiazolylmethylthio)ethylamine (0.9 g) was heated at 130-135 for 3~hours. After cooling the reaction mixture was treated with 2N hydrochloric acid.
Evaporation to dryness followed by recrystallisation from ; isopropanol/methanol gave 2-12-(2-thiazolyl-methylthio)-ethylaminol-5-(4-chlorobenzyl)-4-pyrimidone monohydrochloride, m.p. 172.5-174.5.
(Found: C, 47.4; H, 4.3; N, 13.0; S, 14.7; Cl, 16.5;
C16H18Cl N40S2.HCl. requires; C, 47.55; H, 4.2: N, 13.05;
S, 14.9; Cl, 16.5%).
~ ~ ' EXAMP~E 7 2-[2-(5-~ethyl-4-imidazolylmethylthio)ethylaminol-5-(4-methoxybenzyl~4-pyrimidone dihydrochloride , An ~ntimate mixture oi 5-(4,methoxybenzyl)~2-methylthio-4-pyrimidone (3.0 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.95 g) was heated at 135-140 with frequent stirring for 6 hours. After cooling, the reaction mixture was triturated with hot water, filtered, washed with dry ether and dissolved in propan-2-ol. The solution was acidified with dilute ethanolic hydrogen chloride, evaporated to dryness, and the residue recrystallised from ethanol to give 2-[2-(5- ~
methyl-4-imidazolylme~pylthio)ethylamino¦~5-(4-methoxybenzyl)-~1067076 -4-pyrimidone dihydrochloride m.p. 198-200.
(Found: C, 49.0; H, 5.5; N, 15.0; S, 6.9; Cl, 14.7;
C19H23N502S.2HCl requires; C, 49.8; H, 5.S; N, 15.3;
S, 7.0; Cl, 15.5%) 2-~2-(5-Methyl-4-imidazolylmethylthio)ethylaminol-5-(4-chlorobenzyl)-6-methyl-4-pyrimidone dihydrochloride_ (i) 5-(4-Chlorobenzyl)-6-methyl-2-thiouracil was methylated with methyl iodide as described in Example 1 (i) to give 5-(4-chlorobenzyl)-6-methyl-2-methylthio-4-pyrimidone (m.p. 248-251).
(Found: C, 55.6; H, 4.7; N, 10.0; S, 11.4; C13H13ClN20S
requires: C, 55.3; H, 4.6; N, 9.9; S, 11.4%) (ii) Reaction of 5-(4-chlorobenzyl)-6-methyl-2-methylthio-4-pyrimidone (1.95 g) with 2-(5-methyl-4-imidazolylmethylthio)-- 20 ethylamine (1.19 g) by the method described in Example (ii) gave the title compound, m.p. 203-206.5. (Crystallised from ethanol).
(Found: C, 47.7; H, 5.1; N, 14.4; S, 6.6; Cl, 21.3;
C19H22ClN50S.2HCl requires: C, 47.9; H, 5.1; N, 14.7;
S, 6.7; Cl, 22.3%).
E~AMPLE 9 2-[2-(3-Bromo-2-pyridylmethylthio)ethylamino~5-(4-c loro-benzyl)-4-pyrimidone monohydrochloride 5-(4-Chlorobenzyl)-2-methylthio-4-pyrimidone (~-.2 g? was reacted wlth 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.1 g) according to the procedure of Example 2. The reaetion mixture ~a8 acidified with dilute ethanollc hydrogen chloride, e~aporated to dryness and the reqidue recrystallised fro~
ethanol/~ter to give 2-~2-(3-bromo-2-pyri dylmethylt hio)ethyl-ami~o]-5-(4-chlorobenæyl~4pyrlmidone monohydrochloride, m. p.
215-218 Cdecomposes).
(Found C, 45.4; ~, 3.8; ~, 11.1; S, 6.3; C12H18Br Cl N40S-HCl ` re~uire~ C, 45.4; H, 3.8; N, 11.2: S, 6.4%) ., ~ .
. .. .
Example 10 2-~2-(5-~ethyl-4-imidazolylmethylthio)ethylaminol-s-(2 phenylethyl)-6-methyl-4-pyrimidone (1) Ethyl a-(phenylethyl)acetoacetate t23.4g) and thiourea (10.45g) ~ere added to B ~olution of sodium ethoxide ln ethanol (100 ml) prepared from sod~um (4.6g). The mixture ~as refluxed for 5~ hours and evaporated to dryne-~s. The solid resldue wa~ dissolved in water and ( acetic acid was added to pH 4. The white precipitate was ~iltered off and recr~stallised from ethanol to give 5-(2-phenylethyl)-6-methyl-2-thiouracil m.p. 210-214.
(2) Sub~tltutlon o~ 5-(2-phenylethyl)-6-methyl-2-thiouracil for 5-(4-chlorobenzyl)-2-thiouracil in the general procedure of Example 1 ga~e the title compound m.p.
222.5 - 224.5 ~methanol) (Found- C, 62.75; H, 6.5; N, 18.1; S, 8.3; C20H25N50S
req~ires C, 62.6; H, 6.6; N, 18.2; S, 8.4%) -2-[2-(5-Methyl-4-imidazolylme~ o)eth~lamino3-5-benzyloxy-4-pyrimidone dihydrochloride (i) Ethyl benzyloxyacetate (60.0 g) was converted into 5-benzyloxy-2-thiouracil m.p. 240-241 (ex. acetonitrile/
ethyl acetate, 1:1) by the procedure of Example 4(i).
(ii) 5-Benzyloxy-2-thiouracil (10.0 g) was converted into 5-benzyloxy-2-methylthio-4-pyrimidone m.p. 184-185 (ex methanol) by the procedure of Example l(i).
(iii) 5-Benzyloxy-2-methylthio-4-pyrimidone (4.13 g) was reacted with 2-t5-methyl-4-imidazolyl)ethylamine (2.83 g) by the procedure of Example 3 to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-benzyloxy-4-pyrimidone dihydrochloride, m.p. 161-162 (ethanol).
2-~2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone dihydrochloride.
5-(3-Methoxybenzyl)-2-thiouracil (16.1 g) was converted into 5-(3-methoxybenzyl)-2-methylthio-4-pyrimidone, m.p. 143-144C
(ex ethanol) by the procedure of Example l(i), 5-(3-~ethoxybenzyl)-2-methylthio-4-pyrimidone (3.0 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (2.1 g) aæ described in Example l(ii), to give a residue, which, on treatment with ethanolic hydrogen chloride gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone dihydrochloride, m.p. 173-175.5 (ex ethanol).
(Found: C, 49.6; H, 5.3; N, 15.1; S, 7.1; Cl, 15.8;
ClgH25C12N502S requires: C, 49.8; H, 5.5; N, 15.3; S, 7.0;
Cl, 15.5%).
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-chlor benzyl)-4-pyrimidone dihydrochloride s (i) Ethyl 3-~2-chlorophenyl)propionate (48.4 g) was converted into 5-(2-chlorobenzyl)-2-thiouracil m.p.223-224 (ex methanol by the procedure described in Example 4(i).
(ii) 5-(2-Chlorobenzy~2-thiouracil (5.05 g) wa~ converted into 5-(2-chlorobenzyl~2-methylthio-4-pyrimidone, m.p. 171-173C (ex ethanol) by the procedure of Example l(i). 5-(2-Ch~l-orobenzyl)-2-methylthio-4-pyrimidone (1.6 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.03 g) 15 as described in Example l(ii), to give a residue, which on treatment with dilute ethanolic hydrogen chloride, gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino-5-(2-chloro-benzyl)-4-pyrimidone dihydrochloride, m.p. 215-219 (ex methanol-ethanol).
(Found: C, 46.7; H, 4.9; N, 14.9; S, 6.8; Cl, 22.4;
C18H22C13N50S requires; C, 46.7; H, 4.8; N, 15.1; S, 6.4;
Cl, 23.0%).
EXAllPLE 14 2 2-~2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenylbutyl)-4-pyrimidone dihydrochloride.
(i) Ethyl 6-phenylhexanoate (43.5 g) was converted to 5-(4-phenylbutyl)-2-thiouracil, m.p. 177~5-181 (ex ethanol-water~, as described in Example 4(i).
(ii) 5-(4-Phenylbutyl)-2-thiouracil (3.05 g) was converted into 5-(4-phenylbutyl)-2-methylthio-4-pyrimidone m.p. 146-149 (ex ethanol), by the procedure of Example l(i).5-(4-Phenylbutyl)-2-methylthio-4-pyrimidone (1.89 g)was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.18 g) as described in Example l(ii) to give a residue, which on treatment with di~ute ethanolic hydrogen chloride, gave 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(4-phenylbutyl)-4-pyrimidone dihydrochloride, m.p. 207-209.5 (ex ethanol) (Found: C, 53.3; H, 6.2; N, 14.8; S, 6.8; Cl, 14.8.
C21H29C12N50S requires: C, 53.6; H, 6.2; N, 14.9; S, 6.8;
Cl, 15.1%).
EL~J~PI,E 15 2-~2-(5-Methyl-4-imidazolylmethyl~hio)ethylaminol-5-(5-(1,3-benzodioxolyl)methyl)_4 pyrimidone dihydrochloride (i) Ethyl 3-(5-(1,3-benzodioxolyl)propionate (17.5 g) was converted into 5-(5-(1,3-benzodioxolyl)methyl)-2-thiouracil m.p. 158-159 (ex ethanol/methanol, 1:1), by the procedure described in Example 4(i).
.
(ii) 5-(B-(1,3-Benzodioxolyl)methyl)-2-thiouracil (2.9 g) wa~ converted into 5-(5-(1,3-benzodioxolyl)methyl)-2-methylthio-4-pyrimidone, m.p. 197-198 (ex acetonitrile) by the procedure of Example l(i).
5-(5(1,3-Benzodioxolyl)methyl)-2-methylthio-4-pyrimidone (1.2 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (0.77 g) as described in Example 1 (ii), to give a re~idue, which, on treatment with ethanolic hydrogen chloride, gave the title product m.p. 230-232 (ex ethanol).
~Found: C, 48.5; H, 5.1; N, 14.5; S, 6.7; Cl, 14.7;
C10H23C12N503S requires: C, 48.3; H, 4.9; N, 14.8; S, 6-8;
Cl, 15.0%).
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-ethoxybenzyl)-4-pyrimidone dihydrochloride 5-(3-Ethoxybenzyl)-2-thiouracil (5.0 g) was converted into 5-(3-ethoxybenzyl)-2-meShylthio-4-pyrimidone, m.p. 136-138.
--~3--1 (ex acetonitrile) by the procedure o~ Example l(i).
5-(3-Ethoxybenzyl)-2-methylthio-4-pyrimidone (2.0 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.25 ~) as described in Example l(ii), to give a residue which, on treatment with ethanolic hydrogen chloride gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-ethoxybenzyl)-4-pyrimidone dihydrochloride m.p. 176-178 (ex ethanol).
(Found: C, 50.6; H, 5.7; N, 14.7; S, 7.1; Cl, 14.7; C20H27 C12N502S requires; C, 50.9; H, 5.8; N, 14.8; S, 6.8; Cl,15.0%).
.
.
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylaminOl-5-(3-benzyloxybenzyl)-4-pyrimidone dihydrochloride 5-(3-Benzyloxybenzyl)-2-thiouracil (4.6 g) was converted into 5-(3-benzyloxybenzyl)-2-methylthio-4-pyrimidone, m.p.
176-178 (ex ethyl acetate), by the procedure of Example l(i).
5-(3-Benzyloxybenzyl)-2-methylthio-4-pyrimidone (2.0 g) was reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.0 g) as described in Example l(ii), to give a residue which, on treatment with ethanolic hydrogen chloride gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-benzyloxybenzyl)-4-pyrimidone dihydrochloride m.p. 193-194 2S (e~ ethano}/methanol, 1:1).
(Found: C, 55.7; H, 5.4; N, 12.9; S, 6.0; Cl, 13.0;
C25H29C12N~02S reguires; C,5S.2; H, 5.5; N, 13.1; S, 6.Q;
Cl, 13.3%).
2-12-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(1-naphthylmethyl)-4-pyrimidone dihydrochloride 5-(1-Naphthylmethyl)-2-thiouracil (6.7 g) was converted into 5-(1-naphthylmethyl)-2-methylthio-4-pyrimidone, m.p. 178-180 (ex methanol) by the procedure of Example l(i).
. .
~067076 1 5~ Naphthylmethyl)-2 methylthio-4-pyrimidone (0.4 g) ~as reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.25 g) as described in Example l(ii), to give a residue which, on treatment with ethanolic hydrogen chloride gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-naphthylmethyl)-4-pyrimidone dihydrochloride, m.p. 228-230 (ex ethanol).
(Found: C, 55.0; H, 5.3; N, 14.4; S, 6.6; Cl, 14.5;
C22H25ClN50S requires: C, 55.2; H, 5.3; N, 14.6; S, 6.7;
1 Cl, 14.8%).
Substitution of ethyl 3-(3,4,5-trimethoxyphenyl)propionate for ethyl 3-(3-chlorophenyl)propionate in the general procedure of Example 4 leads to the production of 2-[2-(5-methyl-4-imidazolylmethylthio)ethyla~ino]-5-(3,4,5-trimethoxybenzyl)-4-pyrimidone.
Treatment of 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-(5-(4-methoxybenzy ~ 4-pyrimidone with phosphorus pentasulphide in hot pyridine leads to the production of 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]_5_(4-m~thoxybenzyl~pyrimid-4-thione EXA~PLE 21 , Substitution o~: (a) 2-(2-imidazolylmethylthio)ethylamine (b) 2-~4-imidazolylmethylthio)ethylamine (c) 2-(5-bromo-4-imidazolylmethylthio)-ethylamine (d) 2-(5-trifluoromethyl-4-imidazolylmethl-thio)ethylamine (e) 2-(5-hydroxymethyl-4-imidazolylmethyl-thio)ethylamine 1 . (f) 2-(2-pyridylmethylthio)ethylamine (g~ 2-(3-methyl-2-pyridylmethylthio)-ethylamine (h) 2-(3-methoxy-2-pyridylmethylthio)-ethylamine (i) 2-(3-chloro-2-pyridylmethylthio)-ethylamine (j) 2-(3-amino-2-pyridylmethylthio)ethyl-amine (k) 2-(3-hydroxy-2-pyridylmethylthio)ethyl-amin~
(1) 2-(3-isothiazolylmethylthio)ethylamine (m) 2-(4-bromo-3-isothiazolylmethylthio)-ethylamine (n) 2-(3-(1,2,5)-thiadiazolylmethylthio)-ethylamine (o) 2-(4-chloro-3-(1;.2j5)-thiadiazolyl-methylthio)ethylamine (p) 2-(5-amino-2-(1,3,4)-thiadiazolyl-methylthio)ethylamine . ao ior 2-(5-methyl-4-imidazolylmethylth~o)ethylamine in the procedure o~ Example 7 leads to the production o$:-.
(a) 2-[2-(2-imida~olylmethylthio)ethYlamino]-5-(4-methoxyben 4-pyrimidone . (b) 2-[2-(4-imidazolylmethylthio)ethylamino]-6-(4-methoxybenzyl)-4-pyrimidone ' (c) 2-[2-55-bromo-4-imidazolylmethy~thio~ethylamino]-5-(4_ methoxybenzy~ ~-py,rimidone (d) 2-[2-(5-tri~luoromethyl-4-imidazolylmethylthio)ethylamino]--5-(4-methoxybenzyl)-4-pyrimidone (e) 2-[2-(5-hydroxymethyl-4-imidazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyri~idone (f) 2-[2-(2-pyridylmethylthio)ethylamino~-5-(4-methoxybenzyl)--4-pyri~idone.
(g) 2-[2-(3-methyl-2-pyridylmethylthio)ethylamino]-5-(4-~ethoxybenzyl) 4-pyrimidone (h) 2-[2-(3-methoxy-2-pyridylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (i) 2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (~) 2-~2-(3-amino-2-pyridylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (k) 2-[2-(3-hydroxy-2-pyridylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (1) 2-[2-(3-isothiazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (m) 2-[2-(4-bromo-3-isothiazolylmethylthio)ethylamino]-5-(4methoxybenzjl)-4-pyrimidone (n) 2-[2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone (o) 2-~2-(4-chloro-3-(1,2,5)-thiadiazolylmethylthio)ethyl-amino]-5-(4-methoxybenzyl)-4-pyrimidone (p) 2-[2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio)ethyl-amino]-5-(4-methoxybenzyl)-4-pyrimidone Substitution o~ 4-(4-imidazolyl)butylamine ~or a-(5-methyl-4-imidazolylmethylthio)ethylamine in the pr~cedure o~ Example 121ead~ to the production of 2-[4-(4-imidazolyl)butylamino~-5-(3-methoxybenzyl)-4-pyrimidone, m.p. 193-194.
Treatment of ethyl butyroacetate with sodium ethoxide and 4-methoxybenzyl chloride gives ethyl a-(4-methoxyb~nzyl)-butyroacetate which is refluxed with thiourea and sodium ethoxide to give 5-(4-methoxybenzyl)-6-propyl-2-thiouracil.
Substitution of 5-(4-methoxybenzyl)-6-propyl-2-thiouracil for 5-(4-chlorobenzyl)-2-thiouracil in the general procedure of Example 1 gives 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4 methoxy-benzyl)-6-propyl-4-pyr~midone.
~.
Substitution of (a) ethyl 3-(2-naphthyl)propionate (b) ethyl 3-(4-tri~luoromethylphenyl)propionate (c) ethyl 3-(4-dimethylaminQphenyl)prop~onate (d) ethyl 3-(4-phenoxyphenyl)propionate (e) ethyl 3-(4-(4-chlorophenoxy~phenyl)-propionate (f) ethyl 3-(4-(4-methoxyphenoxy)phenyl-propionate (g) ethyl 3-(4-biphenylyl)propionate (h) ethyl 3-(4-chloro-4-biphenylyl)propionate (i) ethyl 3-(4'-methoxy-4-biphenylyl)propionate ~or ethyl 3-(3-chlorophenyl)propionate in the procedure o~
Example 4 lead~ to the production of:
(a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-naphthylmethyl~-4-pyrimidone (b) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-tri~luoromethylbenzyl)-4-pyrimidone (c) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-dimethylaminobenzyl)-4-pyrimidone (d) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenoxybenzyl)-4-pyrimidone ~e) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-(4-chlorophenoxy)benzyl)-4-pyrimidone (f) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-~4-methoxyphenoxy)benzyl)-4-pyrimidone (g) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenylbenzyl)-4-pyrimidone (h) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-4-(4-chlorophenyl)benzyl)-4-pyrimidone (i) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-4-(4-methoxyphenyl~benzyl))-4-pyrimidone Treatment o~ 2-[2-(5-methyl-4-imidazolylmethylthio)ethylaminol-5-(3-benzyloxybenzyl)-4-pyrimidone with hydrogen bromide in acetic acid leads to the producti`on of 2-[2-(5-methyl-4-imldazolylmethylthlo)ethylamino]-5-(3-hydroxy-benzyl)-4-pyrimidone.
(a) Butyrolactone is treated with sodium and ethyl form~te, and the pro'duct is successively treated with thiourea and methyl iodide to give 5-(2-hydroxyethyl)-2-methylthio-4-pyrimidone.
(b) 5-(2-Hydroxyethyl)-2-methylthio-4-pyrimidone is treated with thionyl chloride and the product is reacted with the sodium derivative of (1) 4-methoxybenzyl alcohol and (2) 4-methoxybenzyl mercaptan, to give: 1. 5-(2-(4-methoxybenzyloxy)ethy~)-2-methylthio-4-,pyrimidone 2. 5-(2-(4-methoxybenzylthio)ethyl)-2-methylthio-4-! pyrimidone ; 25 (c) substitution of:
1. 5-(2-(4-methoxybenzyloxy)ethyl)-2-methyl-thio-4-pyrimidone ' 2. 5-(2-(4-methoxybenzylthio)ethyl)-2-methylthio-4-pyrimidone for 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone in the general procedure of Example l(ii) leads to the production oi' :
1. 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-(4-methoxybenzyloxy)ethyl)-4-pyrimidone 2, 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-(4-methoxybenzylthio)ethyl)-4-pyrimidone ; 1067076 1 (d) substitution of (1) phenol and (2) thiophenol for p-methoxybenzyl alcohol in procedure (bii) and (c) above leads to the production o~:
1. 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-phenoxyethyl)-4-pyrimidone 2. 2-[2-(5-methyl-4-imidaz~lylmethylthio)ethylamino]-5-(2-phenylthioethyl)-4-pyrimidone (e) substitution of (1) 2-phenylethanol and (2) 2-phenyl-ethyl mercaptan ior p-msthoxybenzyl alcohol in procedure (bii) and (c) above leads to the production of `
1. 2-[2-(5-methyl-4-imidazolylmethglthio)ethylamino]-5-(2-(2-phenylethoxy)ethyl)-4-pyrimidone 2. 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-(2-phenylethylthio)ethyl-4-pyrimidone (f) substitution of caprolactone for butyrolactone in procedure (a) (bii) and (c) above leads to the production of 1. 2-[2-(5-methyl-4-imidazolylmethyIthio)ethylamino]~5-(3-(4-methoxybenzyloxy)propyl)-4-pyrimidone 2. 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-(4-methoxybenzylthio)propyl)-4-pyrimidone.
, 25 Substitution o~ (a) ethyl 3-phenylpropoxyacetate (b) ethyl 3-phenylpropylthioglycolite for ethyl benzyloxyacetate in the procedure of Example 11 results in the preparation of:
(a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-phenylpropoxy)-4-pyrimidone (b) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-phenylpropylthio)-4-pyrimidone.
~067076 Substitution of (a) 5-~3-(2-(4-methoxyphenyl)ethoxy)benzy-1]-2-thiouracil (b) 5-[3-(3-chlorobenzyloxy)benzyl]-2-thiouracil for 5-(3-benzyloxybenzyl)-2-thiouracil in the general procedure of Example 17 leads to the production of:
(a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethy~amino]-5-[3-(2-(4-methoxyphenyl)ethoxy)benzyl]-4-pyrimidone ~b) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-[3-(3-chlorobenzyloxy)benzyl]-4-pyrimidone.
Substitution of (a) ethyl 3-(6-(2,3-dihydro-1,4-benzodioxinyl))-propionate (b) ethyl 3-(3-bromophenyl)propionate ~or ethyl 3-(3-chlorophenyl)propionate in the procedure oi Example 4 leadæ to the production o~:
(a) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-~6-(2,3-dihydro-1,4-benzodioxinyl)methyl]-4-pyrimidone 26 (b) 2-~2-(5-methyl-4-im~dazolylmethylthio)ethylamino]-5-(3-bromobenzyV-4-pyrimidone.
Treatment oi' ethyl 3-(3-hydroxyphenyl)propionate with dimethoxymethane and substitution o~ the product ~or ethyl 3-(3-chlorophenyl)propionate in the procedure oi' Example 4 leads to tbe production o~ 2-t5-methyl-4-imidazolylmethylthio)ethylamino]-5-~3-(methoxymethoxy)-benzyl]-4-pyrimidone. Treatment of thi~ product with hydrochloric acid give~ 2-[2-(5-methyl-4-imidazolylmethylthio) ethylamino]-5-(3-hydroxybenzyl)-4-pyrimidone.
Pharmaceutical composition:-Ingredients Amounts : :
2-~2-(5-methy~-4-imidazolylmethylthlo)-ethylamino]-5-(3-methoxybenzyl)-4-pyri~idone dihydrochloride 75 mg 10 Sucrose 75 mg Starch 25 mg Talc 5 mg Stearic Acid 2 mg The ingredients are screened, mixed and ~illed into a hard gelatin capsule.
E~AMPLE 32 .
Pharmaceutical compositlon:-. 20 edient 8 Amount 8 2-~2-(5-methyl-4-lmidazolylmethylthio)-ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone dihydrochloride 100 mg : Lactose 100 mg The i~gredient~ are screened, mixed and ~illed into a hard gelatin capsule.
-3~-
Claims (40)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula:
wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by lower alkyl lower alkoxy , halogen, amino or hydroxy, a 2-thiazolyl ring, a 3-iso-thiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5)thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl)ring; Z is sulphur or a methylene group; X is oxygen or sulphur; W is methylene, oxygen or sulphur; m and n are such that their sum is from 1 to 4 when W is oxygen or sulphur, or from 0 to 4 when W is methylene; A is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4 benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring sub-stituted with one or more lower alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(loweralkyl) amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl groups and when -(CH2)mW(CH2)n- is not a methyl-ene group, A may also be phenyl; and Y3 is hydrogen or lower alkyl, which comprises treating an amine of the formula:
Het'-CH2ZCH2CH2NH2 wherein Het' and Z are as defined a8 above, with a compound of the formula:
wherein X, Y3, m, w, n and A are defined as above and Q is loweralkylthio, benzylthio, halogen or other reactive group which is displaceable with an amine.
wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by lower alkyl lower alkoxy , halogen, amino or hydroxy, a 2-thiazolyl ring, a 3-iso-thiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5)thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl)ring; Z is sulphur or a methylene group; X is oxygen or sulphur; W is methylene, oxygen or sulphur; m and n are such that their sum is from 1 to 4 when W is oxygen or sulphur, or from 0 to 4 when W is methylene; A is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4 benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring sub-stituted with one or more lower alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(loweralkyl) amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl groups and when -(CH2)mW(CH2)n- is not a methyl-ene group, A may also be phenyl; and Y3 is hydrogen or lower alkyl, which comprises treating an amine of the formula:
Het'-CH2ZCH2CH2NH2 wherein Het' and Z are as defined a8 above, with a compound of the formula:
wherein X, Y3, m, w, n and A are defined as above and Q is loweralkylthio, benzylthio, halogen or other reactive group which is displaceable with an amine.
2. A process according to claim 1 wherein Q is lower-alkylthio or halogen.
3. A process according to claim 1 wherein Q is methylthio.
4. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone which comprises treating 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine.
5. The process of claim 1 for preparing 2-[2-(2-thia-zolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone which comprises treating 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone with 2-(2-thiazolylmethylthio)ethylamine.
6. The process of claim 1 for preparing 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone which comprises treating 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone with 2-(3-bromo-2-pyridylmethylthio)ethylamine.
7. The process of claim 1 for preparing 2-[2-(5-methyl -4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-6-methyl-4-pyrimidone which comprises treating 5-(4-chlorobenzyl)-6-methyl-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imi-dazolylmethylthio)ethylamine.
8. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-chlorobenzyl)-4-pyrimi-done which comprises treating 5-(3-chlorobenzyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine.
9. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3,4-dichlorobenzyl)-4-pyrimidone which comprises treating 5-(3,4-dichlorobenzyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
10. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone which comprises treating 5-(4-methoxybenzyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
11. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-methylbenzyl)-4-pyrimidone which comprises treating 5-(4-methylbenzyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
12. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-phenylethyl)-4-pyrimi-done which comprises treating 5-phenylethyl-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine.
13. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-phenylethyl)-6-methyl-4-pyrimidone which comprises treating 5-(2-phenylethyl)-6-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
14. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-benzyloxy-4-pyrimidone which comprises treating 5-benzyloxy-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolyl)ethylamine.
15. The process of claim 1 for preparing 2-[2-(5-methyl-4-imldazolylmethylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone which comprises treating 5-(3-methoxybenzyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
16. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-chlorobenzyl)-4-pyrimidone which comprises treating 5-(2-chloxobenzyl)-2-methylthio-4-pyrLmidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
17. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenylbutyl)-4-pyrimi-done which comprises treating 5-(4-phenylbutyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine.
18. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(5-(1,3-benzodioxolyl)-methyl)-4-pyrimidone which comprises treating 5-(5-(1,3-benzo-dioxolyl)methyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine.
19. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-ethoxybenzyl)-4-pyrimidone which comprises treating 5-(3-ethoxybenzyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
20. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-benzyloxybenzyl)-4-pyrimidone which comprises treating 5-(3-benzyloxybenzyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
21. The process of claim 1 for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(1-naphthylmethyl)-4-pyrimidone which comprises treating 5-(1-naphthylmethyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethyl-thio)ethylamine.
22. A compound of the formula:
wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl , halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by lower alkyl lower alkoxy , halogen, amino or hydroxy, a 2-thiazolyl ring, a 3-iso-thiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5)thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl)ring; Z is sulphur or a methylene group; X is oxygen or sulphur; W is methylene, oxygen or sulphur; m and n are such that their sum is from 1 to 4 when w is oxygen or sulphur, or from 0 to 4 when W is methylene; A is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring sub-stituted with one or more lower alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(lower-alkyl)amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl groups and when -(CH2)mW(CH2)n-is not a methylene group, A may also be phenyl; and Y3 is hydrogen or lower alkyl; or a pharmaceutically acceptable acid addition salt thereof whenever prepared or produced by the process of claim 1 or any chemical equivalent thereof.
wherein Het' is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl , halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl ring optionally substituted by lower alkyl lower alkoxy , halogen, amino or hydroxy, a 2-thiazolyl ring, a 3-iso-thiazolyl ring optionally substituted by chlorine or bromine, a 3-(1,2,5)thiadiazolyl ring optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl)ring; Z is sulphur or a methylene group; X is oxygen or sulphur; W is methylene, oxygen or sulphur; m and n are such that their sum is from 1 to 4 when w is oxygen or sulphur, or from 0 to 4 when W is methylene; A is a 1- or 2-naphthyl ring, a 2,3-dihydro-1,4-benzodioxinyl or a 1,3-benzodioxolyl ring, a phenyl ring sub-stituted with one or more lower alkyl, lower alkoxy, halogen, arylalkoxy, hydroxy, alkoxyalkoxy, trifluoromethyl, di(lower-alkyl)amino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl, halophenyl or alkoxyphenyl groups and when -(CH2)mW(CH2)n-is not a methylene group, A may also be phenyl; and Y3 is hydrogen or lower alkyl; or a pharmaceutically acceptable acid addition salt thereof whenever prepared or produced by the process of claim 1 or any chemical equivalent thereof.
23. 2-[2-(5-Methy-4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 4 or by their obvious chemical equivalents.
24. 2-[2-(2-Thiazolylmethylthio)ethylamino]-5-(4-chloro-benzyl)-4-pyrimidone whenever prepared or produced by the process of claim 5 or by their obvious chemical equivalents.
25. 2-[2-(3-Bromo-2-pyridylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 6 or by their obvious chemical equivalents.
26. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-6-methyl-4-pyrimidone whenever prepared or produced by the process of claim 7 or by their obvious chemical equivalents.
27. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-chlorobenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 8 or by their obvious chemical equivalents.
28. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3,4-dichlorobenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 9 or by their obvious chemical equivalents.
29. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(4-methoxybenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 10 or by their obvious chemical equivalents.
30, 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(4-methylbenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 11 or by their obvious chemical equivalents.
31. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-phenylethyl)-4-pyrimidone whenever prepared or produced by the process of claim 12 or by their obvious chemical equivalents.
32. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-phenylethyl)-6-methyl-4-pyrimidone whenever prepared or produced by the process of claim 13 or by their obvious chemical equivalents.
33. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-benzyloxy-4-pyrimidone whenever prepared or produced by the process of claim 14 or by their obvious chemical equivalents.
34. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 15 or by their obvious chemical equivalents.
35. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-chlorobenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 16 or by their obvious chemical equivalents.
36. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(4-phenylbutyl)-4-pyrimidone whenever prepared or produced by the process of claim 17 or by their obvious chemical equivalents.
37. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(5-(1,3-benzodioxolyl)methyl)-4-pyrimidone whenever prepared or produced by the process of claim 18 or by their obvious chemical equivalents.
38. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-ethoxybenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 19 or by their obvious chemical equivalents.
39. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-benzyloxybenzyl)-4-pyrimidone whenever prepared or produced by the process of claim 20 or by their obvious chemical equivalents.
40. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(1-naphthylmethyl)-4-pyrimidone whenever prepared or produced by the process of claim 21 or by their obvious chemical equivalents,
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4034175 | 1975-10-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1067076A true CA1067076A (en) | 1979-11-27 |
Family
ID=10414412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA262,162A Expired CA1067076A (en) | 1975-10-02 | 1976-09-28 | Pyrimidone derivatives |
Country Status (36)
| Country | Link |
|---|---|
| JP (2) | JPS5246087A (en) |
| AR (1) | AR221682A1 (en) |
| AT (1) | AT358045B (en) |
| AU (1) | AU504897B2 (en) |
| BE (1) | BE846452A (en) |
| BG (1) | BG25224A3 (en) |
| CA (1) | CA1067076A (en) |
| CH (1) | CH625801A5 (en) |
| CS (1) | CS203003B2 (en) |
| DD (1) | DD126563A5 (en) |
| DE (1) | DE2643670C2 (en) |
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| FI (1) | FI61701C (en) |
| FR (1) | FR2326192A1 (en) |
| GR (1) | GR61307B (en) |
| HU (1) | HU175537B (en) |
| IE (1) | IE44845B1 (en) |
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| MW (1) | MW3476A1 (en) |
| MX (1) | MX4614E (en) |
| NL (1) | NL7609917A (en) |
| NO (1) | NO145792C (en) |
| NZ (1) | NZ181959A (en) |
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| PL (1) | PL105828B1 (en) |
| PT (1) | PT65590B (en) |
| RO (1) | RO73511A (en) |
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| MW5076A1 (en) * | 1975-12-29 | 1978-02-08 | Smith Kline French Lab | Pharmacologicalle active compounds |
| NZ186511A (en) | 1977-03-19 | 1980-11-14 | Smith Kline French Lab | 3-substituted alkylamino-6-substituted alkyl-1,2,4-triazin-5-ones and pharmaceutical compositions 3-substituted thio-1,2,4-triazin-5-ones |
| US4165378A (en) | 1977-04-20 | 1979-08-21 | Ici Americas Inc. | Guanidine derivatives of imidazoles and thiazoles |
| IE47044B1 (en) | 1977-04-20 | 1983-12-14 | Ici Ltd | Guanidine derivatives |
| JPS54104816A (en) * | 1978-01-27 | 1979-08-17 | Memorex Corp | Magnetic recorder tape reel |
| IN151188B (en) * | 1978-02-13 | 1983-03-05 | Smith Kline French Lab | |
| AU527202B2 (en) * | 1978-04-11 | 1983-02-24 | Smith Kline & French Laboratories Limited | 2-aminopyrimidones |
| ZA792608B (en) * | 1978-05-30 | 1980-06-25 | Smith Kline French Lab | Nitro compounds |
| ZA793443B (en) * | 1978-07-26 | 1980-12-31 | Glaxo Group Ltd | Heterocyclic derivatives |
| US4374836A (en) | 1978-10-16 | 1983-02-22 | Imperial Chemical Industries Ltd. | Antisecretory heterocyclic derivatives, process for their manufacture and pharmaceutical compositions containing them |
| US4496567A (en) * | 1978-11-13 | 1985-01-29 | Smith Kline & French Laboratories Limited | Phenyl alkylaminopyrimidones |
| US4521418A (en) * | 1979-02-21 | 1985-06-04 | Smith Kline & French Laboratories Limited | Guanidinothiazolyl derivatives |
| JPS55145683A (en) * | 1979-04-26 | 1980-11-13 | Smith Kline French Lab | Pyrimidone derivative |
| CA1155842A (en) * | 1980-03-29 | 1983-10-25 | Thomas H. Brown | Compounds |
| ZW21281A1 (en) * | 1980-10-01 | 1981-11-18 | Smith Kline French Lab | Amine derivatives |
| IE53068B1 (en) * | 1981-06-15 | 1988-05-25 | Merck & Co Inc | Diamino isothiazole-1-oxides and -1,1-dioxides as gastic secretion inhibitors |
| PT75074B (en) * | 1981-06-27 | 1986-02-26 | Smith Kline French Lab | Process for preparing certain pyrimidone derivatives and compositions containing them |
| NZ202797A (en) * | 1981-12-28 | 1985-08-30 | Lilly Co Eli | Pyrimidine derivatives and pharmaceutical compositions |
| JPS5993074A (en) * | 1982-10-01 | 1984-05-29 | スミス・クライン・アンド・フレンチ・ラボラトリ−ス・リミテツド | Pyrimidone derivative |
| DE8309239U1 (en) * | 1983-03-29 | 1983-09-29 | Basf Ag, 6700 Ludwigshafen | TAPE REEL, IN PARTICULAR FOR MAGNETIC TAPES |
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| GB1397436A (en) * | 1972-09-05 | 1975-06-11 | Smith Kline French Lab | Heterocyclic n-cyanoguinidines |
| GB1419994A (en) * | 1973-05-03 | 1976-01-07 | Smith Kline French Lab | Heterocyclicalkylaminotheterocyclic compounds methods for their preparation and compositions comprising them |
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1976
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- 1976-09-20 SE SE7610409A patent/SE431872B/en not_active IP Right Cessation
- 1976-09-22 BE BE170830A patent/BE846452A/en not_active IP Right Cessation
- 1976-09-24 FR FR7628824A patent/FR2326192A1/en active Granted
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- 1976-09-24 PH PH18943A patent/PH13921A/en unknown
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- 1976-09-28 CA CA262,162A patent/CA1067076A/en not_active Expired
- 1976-09-28 GR GR51794A patent/GR61307B/en unknown
- 1976-09-28 YU YU02372/76A patent/YU237276A/en unknown
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- 1976-10-01 NO NO763371A patent/NO145792C/en unknown
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- 1976-10-01 DK DK442476A patent/DK442476A/en not_active Application Discontinuation
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- 1976-10-01 HU HU76SI1543A patent/HU175537B/en unknown
- 1976-10-01 CH CH1248276A patent/CH625801A5/en not_active IP Right Cessation
- 1976-10-01 PL PL1976192809A patent/PL105828B1/en unknown
- 1976-10-01 BG BG034338A patent/BG25224A3/en unknown
- 1976-10-01 LU LU75922A patent/LU75922A1/xx unknown
- 1976-10-01 ZM ZM121/76A patent/ZM12176A1/en unknown
- 1976-10-01 JP JP51118904A patent/JPS5246087A/en active Granted
- 1976-10-02 RO RO7687887A patent/RO73511A/en unknown
-
1978
- 1978-12-11 IT IT7830708A patent/IT7830708A0/en unknown
-
1980
- 1980-12-09 JP JP55174447A patent/JPS609755B2/en not_active Expired
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