CA1073458A - Pyrimidone derivatives - Google Patents
Pyrimidone derivativesInfo
- Publication number
- CA1073458A CA1073458A CA267,385A CA267385A CA1073458A CA 1073458 A CA1073458 A CA 1073458A CA 267385 A CA267385 A CA 267385A CA 1073458 A CA1073458 A CA 1073458A
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- CA
- Canada
- Prior art keywords
- pyrimidone
- methyl
- pyridylmethyl
- pyridyl
- ethylamino
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical 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)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (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; Y is sulphur or a methylene group; Z is hydrogen or lower alkyl (preferably methyl); X is oxygen or sulphur; W is methylene, oxygen or sulphur: p and q 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; Het' is a 5 or 6 membered heterocycle such as pyridine, furan,thiophen, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine or pyridazine,which ring is optionally substituted by lower alkyl, lower alkoxy, or may have a benzene ring or substituted benzene ring fused to it. The compounds have been found to be histamine H2- antagonists and are useful as inhibitors of gastric acid secrection, as anti-inflammatory agents and as agents which act on the cardiovascular system.
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; Y is sulphur or a methylene group; Z is hydrogen or lower alkyl (preferably methyl); X is oxygen or sulphur; W is methylene, oxygen or sulphur: p and q 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; Het' is a 5 or 6 membered heterocycle such as pyridine, furan,thiophen, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine or pyridazine,which ring is optionally substituted by lower alkyl, lower alkoxy, or may have a benzene ring or substituted benzene ring fused to it. The compounds have been found to be histamine H2- antagonists and are useful as inhibitors of gastric acid secrection, as anti-inflammatory agents and as agents which act on the cardiovascular system.
Description
`` lO~Y3~
1 This invention relates to pharmacologically active compounds, to methods for preparing these compounds, to pharmaceutical compositions containing these compounds and to methods o~
blocking histamine H2- receptors by administering these compounds. The compounds of the invention can exist as acid addition salts but, for convenience, reference will be made throughout this specification to the parent compounds.
Many physiologically active substances elicit their biological actions by interaction with specific sites kno~n as receptors.
Histamine is such a substance and has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines" of which mepyramine, diphenhydramine and chloropheniramine are examples, are mediated through histamine Hl- receptors (Ash and Schild, Brit. J. Pharmac. Chemother, 27, 427, (1966)), and drugs with this activity are hereinafter referred to as histamine Hl-antagonists. However, other of the biological actions of histamine are not inhibited by histamine Hl- antagonists and
1 This invention relates to pharmacologically active compounds, to methods for preparing these compounds, to pharmaceutical compositions containing these compounds and to methods o~
blocking histamine H2- receptors by administering these compounds. The compounds of the invention can exist as acid addition salts but, for convenience, reference will be made throughout this specification to the parent compounds.
Many physiologically active substances elicit their biological actions by interaction with specific sites kno~n as receptors.
Histamine is such a substance and has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines" of which mepyramine, diphenhydramine and chloropheniramine are examples, are mediated through histamine Hl- receptors (Ash and Schild, Brit. J. Pharmac. Chemother, 27, 427, (1966)), and drugs with this activity are hereinafter referred to as histamine Hl-antagonists. However, other of the biological actions of histamine are not inhibited by histamine Hl- antagonists and
2 actions of this type which are inhibited by a compound descr~bed by Black et al. (Nature, ~36, 385, (1972)) and called burimamide are mediated through receptors wh~ch are defined by Black et al. as histamine H2- receptors. Thus histamine H2- receptors may be defined as those histamine receptors which are not blocked by mepyramine but are blocked by burimamide. Compounds which block histamine H2- receptors are referred to as histamine H2- antagonists.
Blockade of histamine H2- receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by - histamine Hl- antagonists. Histamine H2- antagonists are therefore useful, for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cardiovascular system, for example, as inhibitors of the effects of histamine on blood pressure. In the treat-ment of certain conditions, for example, inflammation and in _ 2 -.: ~ , . `
` ` 10~3~qS8 1 inhibiting the actions of histamine on blood pressure, a combination of histamine Hl- and H2- antagonists is useful.
The compounds of this invention have both histamine Hl-antagonist and histamine H2- antagonist activity, and are useful in the treatment of conditions wherein histamine H2-antagonists are useful and conditions wherein a combination of histamine Hl- and H2- antagonists are use~ul.
.
The compounds of this invention are represented by the ~ollowing general formula:
Z
~ ~,(CH2)p-W- (CH2) q-EIet ' 2 . 2 2 X
wherein Het is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl (preferably methyl) J 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; Y is sulphur or a methylene group; Z is hydrogen or lo~er alkyl . (pre~erably methyl); X is oxygen or sulphur; ~ is methylene, oxygen or sulphur: p and q are such that theirlsum is from 1 to 4 when W is oxygen or sulphur, or from O to 4 when W is methylene; Het' is a 5 or 6 membered heterocycle such as pyridine, furan,thiophen, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine or pyridazine~which ring is optionally substituted by lower alkyl, lower alkoxy, or may have a benzene ring or ~0'~3~58 1 substituted benzene ring fused to iy, or a pharmaceutically acceptable salt thereof.
Preferably Het is a 2-thiazolyl, 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl,
Blockade of histamine H2- receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by - histamine Hl- antagonists. Histamine H2- antagonists are therefore useful, for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cardiovascular system, for example, as inhibitors of the effects of histamine on blood pressure. In the treat-ment of certain conditions, for example, inflammation and in _ 2 -.: ~ , . `
` ` 10~3~qS8 1 inhibiting the actions of histamine on blood pressure, a combination of histamine Hl- and H2- antagonists is useful.
The compounds of this invention have both histamine Hl-antagonist and histamine H2- antagonist activity, and are useful in the treatment of conditions wherein histamine H2-antagonists are useful and conditions wherein a combination of histamine Hl- and H2- antagonists are use~ul.
.
The compounds of this invention are represented by the ~ollowing general formula:
Z
~ ~,(CH2)p-W- (CH2) q-EIet ' 2 . 2 2 X
wherein Het is a 2- or 4-imidazolyl ring optionally substituted by lower alkyl (preferably methyl) J 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; Y is sulphur or a methylene group; Z is hydrogen or lo~er alkyl . (pre~erably methyl); X is oxygen or sulphur; ~ is methylene, oxygen or sulphur: p and q are such that theirlsum is from 1 to 4 when W is oxygen or sulphur, or from O to 4 when W is methylene; Het' is a 5 or 6 membered heterocycle such as pyridine, furan,thiophen, thiazole, oxazole, isothiazole, imidazole, pyrimidine, pyrazine or pyridazine~which ring is optionally substituted by lower alkyl, lower alkoxy, or may have a benzene ring or ~0'~3~58 1 substituted benzene ring fused to iy, or a pharmaceutically acceptable salt thereof.
Preferably Het is a 2-thiazolyl, 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3-bromo-2-pyridyl, 3-chloro-2-pyridyl,
3-methoxy-2-pyridyl or 3-hydroxy-2-pyridyl ring.
Preferably Y is sulphur.
Preferably X is oxygen.
Preferably Z is hydrogen.
In a preferred group of compounds W is methylene and p and q are both 0.
Preferably Het' is a 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, ?-thiazolyl, 2-imidazolyl, 2-pyrimidyl, 2-pyrazyl or 3-pyridazyl ring, which ring is optionally sub-~ stituted by lower alkyl or lower alkoxy. More preferably Het' is a 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or 2-thiazolyl ring. Particularly preferab~y Het' is a 3-pyridyl ring.
Throughout this specification by the term "lower alkyl"
we mean an alkyl group containing from 1 to 4 carbon atoms, and by the term "}ower alkoxy" we mean an alkoxy group con-taining from 1 to 4 carbon atoms.
The compounds of Formula 1 are shown and described as 4-pyrimidone and 4-thione derivatives and these derivatives exist in equilibrium with the corresponding 6-one and 6-thione tautomers. These compounds also exist to a lesser extent as the mercapto and hydroxy tautomers, and the pyrimidine ring may also exist in the follouing tautomeric forms:
-N n x -N ~ ~ X~ -N ~ ~ X~
Certain Het and Het' may also exist in several tautomeric forms, and it will be understood that all these tautomeric forms are within the scope of the present invention. Hydrates of compounds of Formula 1 and pharmaceutically acceptable hydrated salts of compounds of Formula 1 are also within the scope of this invention.
- . - . . , . .. -- , ... . .
. , , - ., ,: -Oq3~1S8 1 Some specific compounds which fall within the scope of the present invention are:- .
2-~2-(5-methyl-4-imidazolylmethylthiojethylamino]-5-(4-pyridylmethyl)-4-pyrimidone 2-[2-~2-thiazolylmethylthio)ethylamino]-5-(4-pyridyl-methyl)-4-pyrimidone 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone io 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thienylmethyl)-4-pyrimidone 2-[2 (5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-` pyridylmethyl)-4-pyrimidone . 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(2-pyridyl-methyl)-4-pyrimidone 2-12-(S-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thiazolylmethyl)-4-pyrimidone 2-12-(2-thiazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-- 4_pyrimidone 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridyl-- methyl)-4-pyrimidone.
The compounds of Formul? 1 may be prepared by a process which comprises treating an isocytosine of Formula 2.
~ (CH2)p-W-(CH2)q-Hett ` Q ~ ~ ~ 0 wherein Z, ., W, p, q and Het' are as defined in Formula 1 and Q is loweralkylthio, benzylthio, halogen or other grouping which is conveniently displaced by an amine, with an amine of Formula 3: .
35 . Het-cH2-y-(cH2)2-NH2 . . . . . . . . - . . . , . , . . . --, .
. . . . . .. .
- ;,. ,,. . : . - . .. , ~., . -.~ . . . . . ~ ... . :
- : ,.. . ..
. ~ lOq3458 i wherein Het and Y are as defined in Formula 1. Pre~erably this reaction is carried out in the absence of a solvent at an elevated temperature, e.g., 150C, or in the presence ~ o~ a solvent, such as in refluxing pyridine.
Compounds of Formula 1 wherein W is sulphur may alternatively .be prepared by a process which comprises treating an isocytosine of Formula 4: Z
~(CH2 )p-V
L
10 ~ Het-CH2-Y-(CH2)2-NH ~ ~N~ O
wherein Het, Y, Z and p are as defined in Formula 1, and V
is a mercapto, chloro or bromo group, with a compound of Formula 5:
U-(CH2)q-Het ' wherein Het' is as defined in Formula 1, U is S~ when V is chloro or bromo and U is chloro or bromo when V is mercapto, provided that when U is chloro or bromo q may only be O if U is an'active`halogen (i.e. ortho or para to a`heterocyclic nitrogen atom).
The intermediates of Formula 2 wherein W is methylene, Z is hydrogen and Q is lo~eralkylthio (shown as Formula 7) may be prepared according to Scheme 1:- -.
3~
. . .
;, . ;
~ ,` . ` ~
(wherein Het' is as defined in Formula l, a is 0 to 4 and Alk is lower alkyl).
s Het~(cH2)acH2cH2~o2Et l) Na, HCO~Et HN ~ ~2(CH2)aHet 2) thiourea ~ N ~ 0 Formula 5 Formula 6 alkyl halide ; or sulphate ~ , HN ~ 2(CH2)aHet AlkS ~ N 0 Formula 7 The esters of Formula 5 may be prepared by general me~thods known to the art, ~or example co~pounds wherein a is ~ may be prepared by condensing an aldehyde Het'-CHO with malonic . acid in the presence of pyridine and piperidine, and hydro-genating and esterifying the product.
2S The lntermediates o~ Formula 2 wherein W is methylene, Z is lower alkyl, and Q is loweralkylthio (shown as Formula 8) may - be prepared according to Scheme 2:- :
3~ -(wperein Het' is as de~ined in Formula 1, a is 0 to 4, Hal is chlorine or bromine, and Alk is lower alkyl).
.
. ~: . .; . . : . .
.. , , , .. , ~- . . .... ., . .
; ~;. ' ', - ;... :::. ' - -; ,: - .
, .: , , ~ .... -. . . .
2 ( 2 ) aHet ZCOCH2C02Et NaOEt,HalCH2(CH2)aHet~ Z-COCHC02Et 6 ¦ thiourea ~I .
. - Z
Alk ~ ~ O ~sulphate ~ , 2 2 a - ` S5~ N
Formula 8 - ~
- 15 . .The intermediates of Formula 2 wherein Q is halogen and.W is - methylene (shown as Formula 10) may be prepared according to - Scheme 3:-.
20(wherein Het' and Z are as defined in Formula 1, a is O to 4 and Hal is chlorine or bromine) ~ H2 ~CH2) aHet Z
2SZCOCHC02Et guanidine N ~ H2(CH2)aHet sodium salt . H2 ~ H
or.mula 9 1) HCl, NaN02 2) CU2Hal2 . ' ~ ~
Z
,~CH2 (CH2 ) a~Iet ' Hal~N ~ ~0 :_J Formula 10 ,. : ~ . . : .. : ~
` ' 10~3458 i The intermediates of Formula2 wherein W is oxygen or sulphur may be prepared by the ~ollowing methods:-(a) p is 0 Het'(CH2)qWCH2C02Et 1) HC02Et, Na HN ~ W(CH2)qHet~
2) thiourea AlkS ~ N ~ 0 3) alkyl hal1de or W ~ oxygen or sulphur (b) p is 1 ~
These compounds may be prepared ~rom ethyl 3-benzyloxy-propionate, or a similar protected derivative of ethyl 3-hydroxypropionate, by a process analogous to that outlined in Scheme 1, ~ollowed successively by deprotection, treatment with thionyl chloride, and treatment with the sodium derivative oi Het(CH2)qOH or Het'(CH2)qSH.
.- ~ .
. ~ . .
- .. ~... . , ,. ,, ,- .
=: : ~ ., -:.- , - . , . - . ;- , -: ,- . ~ : . . . : . .
- . -, .~ - ~ . -.. . . ~. .
. ., .
' 1073458 (c) p is 2 to 4 . _ O
~ H o ~ CH 0 Na+
5 ~ ~ 2 ethyl iormate, sod~um~ 1) thiourea 2) alkyl halide . or sulphate 10. ' ~ .
.
~ (cH2)pw(cH2)q~et~ (CH2)pOH
Al~S ~ N 1) SOC12 ~ AlkS ~ ~ 0 2) Het'(CH2)qO ~a+ or -Hetl(C ~ )qS Na+
~ is oxygen or sulphur p is 2 to 4 Compounds o~ Formula 1 wherein X is sulphur may be prepared by treating the compounds of Formula 1 wherein X is oxygen with phosphorus pentasulphide in a solvent such as pyridine.
The amines o~ Formula 3 may be prepared by mëthods described in British Patent Specifications 1305547 and 1338169, ~~ i -. , .
-- ~
~0~3~58 1 The compounds of Formula 1 block histamine H2-receptors, that is they inhibit the biological actions o~ histamine which are not inhibited by histamine Nl-antagonists such as mepyramine but are inhibited by burimamide. For example, the compounds of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane9 at doses of from 0.5 to 16 micromoles per kilogram intra-venously. Th~s procedure is referred to in the above-mentioned paper of Ash and Schild. The activity of these compounds as histamine H2-antagonists is also demonstrated C` by their ability to inhibit other actions of histamine which, according to the above mentioned paper of Ash and Schild, are not mediated by histamine Hl-receptors. For ex~mple, they inhibit the actions of histamine on the iæolated guinea pig atrium and isolated rat uterus.
The compounds of this invention inhibit the basal secretion o~ gastric acid and also that stimulated by pentagastrin or by food.
In addition, the compounds of this invention show anti-ini'lammatory activity in conventional tests such as the rat paw oedema test, where the oedema is induced by an ( irritant, the rat paw volume is reduced by subcutaneous in~ection of doses of a compound of Formula 1. In a conventional test, æuch as the measurement of blood pressure in the anaesthetised cat, the action of the compounds of this invention in inhibiting the vasodilator action of histamine can also be demonstrated. The level of activity of the compounds of this invention is illustrated by the effective dose producing 50% inhibition of gastric acid secrètion in the anaesthetised rat (which for many of the compounds of Formula 1 is from 1 to 10 mic~omoles per kilogram) and the dose producing 50~0 inhibition of histamine-induced tachycardia in the isolated guinea pig atrium.
- . . . - . , . , . . . ,- .. ' ..
.. : ~ ,, ~ . ~.... .. . -, , - . ~ -, ..
, ,. ... :.
10~34S8 .
1 The compounds of Formula 1 also block histamine Hl-receptors,that is they inhibit the biological actions of histamine which are inhibited by mepyramine, diphen-hydramine and chlorpheniramine. For example the compounds of this invention have been found to inhibit the action of histamine in the isolated guinea-pig ileum. For many of the compounds of Formula 1 a dose of from 10 5 Molar inhibits the histamine-stimulated contractions of the guinea pig ileum.
For therapeutic use, the pharmacologically active compounds /~ of the present invention will normally be administered as a pharmaceutical composition comprisin~ as the or an essential active ingredient at least one such..compound in the basic form or in the form of an addition salt with a pharmaceutically acceptable acid and in association ~ith a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids`and may co~veniently be ~ormed from the corresponding . ~ bases of Formula 1 by standard procedures, for example by treating the base with an acid in a lo~er aIkanol or by the use o~ ion exchange resins to ~orm the reqùired salt either directly from the base or from a different addition salt.
(.
Pharmaceutical compositions comprising a pharmaceutical carrier and a compound of Formula 1 or a pharmaceutically acceptable acid addition salt thereof and methods of b.l.ocking histamine H2-receptors which comprise administering to an animal a compound o$ Formula 1 or a pharmaceutically acceptable acid addition salt thereo~ are also objects of this invention. The pharmaceutical carrier employed may be, for example, either a solid or liquid. Examplary of solid carriers are lactose, terra alba, sucrose, talc,gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary - 35 of liquid carriers are syrup; peanut oil, olive oil, water and the li~e.
.. ` . . . .. . `: . ` -. .. .,. . . . - -. ,.~.. . . . - ` .
.: . , ... , :: " :
. - . - -. . ~`- . . .... .. - . .
- - , ''' :, `
. ,: - . ,. . - ., . . ::
... ~ ` -1 A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The active ingredient will be present in the compositions in an e~fective amount to block histamine H2-receptors.
The route of administration may be oral or parenteral.
- ~ Preferably, each dosage unit will contain the active ingredient in an amount of from about S0 mg to about 250 mg.
The active ingredient will preferably be administered one ( - to six times per day. The daily dosage regimen will preferably be from about 150 mg to about 1500 mg.
Advantaseously the composition will be made up in a dosage form appropriate to the desired mode of administration for example, as a tablet, capsule, injectable solution or as a cream or ointment for topical application.
The invention is illustrated but in no way limited by the.
following examples in which all temperatures are in degrees centigrade.
- - . . .
. :- .. . . . - ' '~
.. .
.
10~3~1S~3 2-[2-(5~Methyl-4-imidazolylmethylthio)ethylamino~ -5-(4-pyridylmethyl)-4-pyrimidone trihydrochl~ride (i) Ethyl ~-(4-pyridyl)propionate (43.45 g) and ethyl iormate (19.6 g) were added over a period o~ 6 hours to a stirred mixture o~ sodium wire (5.6 g) and dry ether (150 ml) cooled by an ice-salt bath.
- ~he mixture was stirred for 18 hours at room , -.
temperature, evaporated to dryness and the residue treated with thiourea (18.45 g) and ethanol (130 ml) and re~luxed for 7 hours. The mixture was evaporated to dryness and the residue dissolved in water and the solid product precipitated by adding glacial acid to pH4. The white solid was filtered and washed with ethanol~to give 5-(4-pyridylmethyl)-2-thiouracil m.p. 320-324 (decomp).
- (ii) A solution of 5-(4-pyridylmethyl)-2-thiouracil (11.0 g), methyl iodide (?. 2 g) and sodium hydroxide - (2.1 g) in water (50 ml) and ethanol ~100 ml) was stirred at 60 ~or 30 minutes J allowed to cool and '. i! ~iltered to give 5-(4-pyridylmethyl)-~-methylthio-
Preferably Y is sulphur.
Preferably X is oxygen.
Preferably Z is hydrogen.
In a preferred group of compounds W is methylene and p and q are both 0.
Preferably Het' is a 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, ?-thiazolyl, 2-imidazolyl, 2-pyrimidyl, 2-pyrazyl or 3-pyridazyl ring, which ring is optionally sub-~ stituted by lower alkyl or lower alkoxy. More preferably Het' is a 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or 2-thiazolyl ring. Particularly preferab~y Het' is a 3-pyridyl ring.
Throughout this specification by the term "lower alkyl"
we mean an alkyl group containing from 1 to 4 carbon atoms, and by the term "}ower alkoxy" we mean an alkoxy group con-taining from 1 to 4 carbon atoms.
The compounds of Formula 1 are shown and described as 4-pyrimidone and 4-thione derivatives and these derivatives exist in equilibrium with the corresponding 6-one and 6-thione tautomers. These compounds also exist to a lesser extent as the mercapto and hydroxy tautomers, and the pyrimidine ring may also exist in the follouing tautomeric forms:
-N n x -N ~ ~ X~ -N ~ ~ X~
Certain Het and Het' may also exist in several tautomeric forms, and it will be understood that all these tautomeric forms are within the scope of the present invention. Hydrates of compounds of Formula 1 and pharmaceutically acceptable hydrated salts of compounds of Formula 1 are also within the scope of this invention.
- . - . . , . .. -- , ... . .
. , , - ., ,: -Oq3~1S8 1 Some specific compounds which fall within the scope of the present invention are:- .
2-~2-(5-methyl-4-imidazolylmethylthiojethylamino]-5-(4-pyridylmethyl)-4-pyrimidone 2-[2-~2-thiazolylmethylthio)ethylamino]-5-(4-pyridyl-methyl)-4-pyrimidone 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone io 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thienylmethyl)-4-pyrimidone 2-[2 (5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-` pyridylmethyl)-4-pyrimidone . 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(2-pyridyl-methyl)-4-pyrimidone 2-12-(S-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thiazolylmethyl)-4-pyrimidone 2-12-(2-thiazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-- 4_pyrimidone 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridyl-- methyl)-4-pyrimidone.
The compounds of Formul? 1 may be prepared by a process which comprises treating an isocytosine of Formula 2.
~ (CH2)p-W-(CH2)q-Hett ` Q ~ ~ ~ 0 wherein Z, ., W, p, q and Het' are as defined in Formula 1 and Q is loweralkylthio, benzylthio, halogen or other grouping which is conveniently displaced by an amine, with an amine of Formula 3: .
35 . Het-cH2-y-(cH2)2-NH2 . . . . . . . . - . . . , . , . . . --, .
. . . . . .. .
- ;,. ,,. . : . - . .. , ~., . -.~ . . . . . ~ ... . :
- : ,.. . ..
. ~ lOq3458 i wherein Het and Y are as defined in Formula 1. Pre~erably this reaction is carried out in the absence of a solvent at an elevated temperature, e.g., 150C, or in the presence ~ o~ a solvent, such as in refluxing pyridine.
Compounds of Formula 1 wherein W is sulphur may alternatively .be prepared by a process which comprises treating an isocytosine of Formula 4: Z
~(CH2 )p-V
L
10 ~ Het-CH2-Y-(CH2)2-NH ~ ~N~ O
wherein Het, Y, Z and p are as defined in Formula 1, and V
is a mercapto, chloro or bromo group, with a compound of Formula 5:
U-(CH2)q-Het ' wherein Het' is as defined in Formula 1, U is S~ when V is chloro or bromo and U is chloro or bromo when V is mercapto, provided that when U is chloro or bromo q may only be O if U is an'active`halogen (i.e. ortho or para to a`heterocyclic nitrogen atom).
The intermediates of Formula 2 wherein W is methylene, Z is hydrogen and Q is lo~eralkylthio (shown as Formula 7) may be prepared according to Scheme 1:- -.
3~
. . .
;, . ;
~ ,` . ` ~
(wherein Het' is as defined in Formula l, a is 0 to 4 and Alk is lower alkyl).
s Het~(cH2)acH2cH2~o2Et l) Na, HCO~Et HN ~ ~2(CH2)aHet 2) thiourea ~ N ~ 0 Formula 5 Formula 6 alkyl halide ; or sulphate ~ , HN ~ 2(CH2)aHet AlkS ~ N 0 Formula 7 The esters of Formula 5 may be prepared by general me~thods known to the art, ~or example co~pounds wherein a is ~ may be prepared by condensing an aldehyde Het'-CHO with malonic . acid in the presence of pyridine and piperidine, and hydro-genating and esterifying the product.
2S The lntermediates o~ Formula 2 wherein W is methylene, Z is lower alkyl, and Q is loweralkylthio (shown as Formula 8) may - be prepared according to Scheme 2:- :
3~ -(wperein Het' is as de~ined in Formula 1, a is 0 to 4, Hal is chlorine or bromine, and Alk is lower alkyl).
.
. ~: . .; . . : . .
.. , , , .. , ~- . . .... ., . .
; ~;. ' ', - ;... :::. ' - -; ,: - .
, .: , , ~ .... -. . . .
2 ( 2 ) aHet ZCOCH2C02Et NaOEt,HalCH2(CH2)aHet~ Z-COCHC02Et 6 ¦ thiourea ~I .
. - Z
Alk ~ ~ O ~sulphate ~ , 2 2 a - ` S5~ N
Formula 8 - ~
- 15 . .The intermediates of Formula 2 wherein Q is halogen and.W is - methylene (shown as Formula 10) may be prepared according to - Scheme 3:-.
20(wherein Het' and Z are as defined in Formula 1, a is O to 4 and Hal is chlorine or bromine) ~ H2 ~CH2) aHet Z
2SZCOCHC02Et guanidine N ~ H2(CH2)aHet sodium salt . H2 ~ H
or.mula 9 1) HCl, NaN02 2) CU2Hal2 . ' ~ ~
Z
,~CH2 (CH2 ) a~Iet ' Hal~N ~ ~0 :_J Formula 10 ,. : ~ . . : .. : ~
` ' 10~3458 i The intermediates of Formula2 wherein W is oxygen or sulphur may be prepared by the ~ollowing methods:-(a) p is 0 Het'(CH2)qWCH2C02Et 1) HC02Et, Na HN ~ W(CH2)qHet~
2) thiourea AlkS ~ N ~ 0 3) alkyl hal1de or W ~ oxygen or sulphur (b) p is 1 ~
These compounds may be prepared ~rom ethyl 3-benzyloxy-propionate, or a similar protected derivative of ethyl 3-hydroxypropionate, by a process analogous to that outlined in Scheme 1, ~ollowed successively by deprotection, treatment with thionyl chloride, and treatment with the sodium derivative oi Het(CH2)qOH or Het'(CH2)qSH.
.- ~ .
. ~ . .
- .. ~... . , ,. ,, ,- .
=: : ~ ., -:.- , - . , . - . ;- , -: ,- . ~ : . . . : . .
- . -, .~ - ~ . -.. . . ~. .
. ., .
' 1073458 (c) p is 2 to 4 . _ O
~ H o ~ CH 0 Na+
5 ~ ~ 2 ethyl iormate, sod~um~ 1) thiourea 2) alkyl halide . or sulphate 10. ' ~ .
.
~ (cH2)pw(cH2)q~et~ (CH2)pOH
Al~S ~ N 1) SOC12 ~ AlkS ~ ~ 0 2) Het'(CH2)qO ~a+ or -Hetl(C ~ )qS Na+
~ is oxygen or sulphur p is 2 to 4 Compounds o~ Formula 1 wherein X is sulphur may be prepared by treating the compounds of Formula 1 wherein X is oxygen with phosphorus pentasulphide in a solvent such as pyridine.
The amines o~ Formula 3 may be prepared by mëthods described in British Patent Specifications 1305547 and 1338169, ~~ i -. , .
-- ~
~0~3~58 1 The compounds of Formula 1 block histamine H2-receptors, that is they inhibit the biological actions o~ histamine which are not inhibited by histamine Nl-antagonists such as mepyramine but are inhibited by burimamide. For example, the compounds of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane9 at doses of from 0.5 to 16 micromoles per kilogram intra-venously. Th~s procedure is referred to in the above-mentioned paper of Ash and Schild. The activity of these compounds as histamine H2-antagonists is also demonstrated C` by their ability to inhibit other actions of histamine which, according to the above mentioned paper of Ash and Schild, are not mediated by histamine Hl-receptors. For ex~mple, they inhibit the actions of histamine on the iæolated guinea pig atrium and isolated rat uterus.
The compounds of this invention inhibit the basal secretion o~ gastric acid and also that stimulated by pentagastrin or by food.
In addition, the compounds of this invention show anti-ini'lammatory activity in conventional tests such as the rat paw oedema test, where the oedema is induced by an ( irritant, the rat paw volume is reduced by subcutaneous in~ection of doses of a compound of Formula 1. In a conventional test, æuch as the measurement of blood pressure in the anaesthetised cat, the action of the compounds of this invention in inhibiting the vasodilator action of histamine can also be demonstrated. The level of activity of the compounds of this invention is illustrated by the effective dose producing 50% inhibition of gastric acid secrètion in the anaesthetised rat (which for many of the compounds of Formula 1 is from 1 to 10 mic~omoles per kilogram) and the dose producing 50~0 inhibition of histamine-induced tachycardia in the isolated guinea pig atrium.
- . . . - . , . , . . . ,- .. ' ..
.. : ~ ,, ~ . ~.... .. . -, , - . ~ -, ..
, ,. ... :.
10~34S8 .
1 The compounds of Formula 1 also block histamine Hl-receptors,that is they inhibit the biological actions of histamine which are inhibited by mepyramine, diphen-hydramine and chlorpheniramine. For example the compounds of this invention have been found to inhibit the action of histamine in the isolated guinea-pig ileum. For many of the compounds of Formula 1 a dose of from 10 5 Molar inhibits the histamine-stimulated contractions of the guinea pig ileum.
For therapeutic use, the pharmacologically active compounds /~ of the present invention will normally be administered as a pharmaceutical composition comprisin~ as the or an essential active ingredient at least one such..compound in the basic form or in the form of an addition salt with a pharmaceutically acceptable acid and in association ~ith a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids`and may co~veniently be ~ormed from the corresponding . ~ bases of Formula 1 by standard procedures, for example by treating the base with an acid in a lo~er aIkanol or by the use o~ ion exchange resins to ~orm the reqùired salt either directly from the base or from a different addition salt.
(.
Pharmaceutical compositions comprising a pharmaceutical carrier and a compound of Formula 1 or a pharmaceutically acceptable acid addition salt thereof and methods of b.l.ocking histamine H2-receptors which comprise administering to an animal a compound o$ Formula 1 or a pharmaceutically acceptable acid addition salt thereo~ are also objects of this invention. The pharmaceutical carrier employed may be, for example, either a solid or liquid. Examplary of solid carriers are lactose, terra alba, sucrose, talc,gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary - 35 of liquid carriers are syrup; peanut oil, olive oil, water and the li~e.
.. ` . . . .. . `: . ` -. .. .,. . . . - -. ,.~.. . . . - ` .
.: . , ... , :: " :
. - . - -. . ~`- . . .... .. - . .
- - , ''' :, `
. ,: - . ,. . - ., . . ::
... ~ ` -1 A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The active ingredient will be present in the compositions in an e~fective amount to block histamine H2-receptors.
The route of administration may be oral or parenteral.
- ~ Preferably, each dosage unit will contain the active ingredient in an amount of from about S0 mg to about 250 mg.
The active ingredient will preferably be administered one ( - to six times per day. The daily dosage regimen will preferably be from about 150 mg to about 1500 mg.
Advantaseously the composition will be made up in a dosage form appropriate to the desired mode of administration for example, as a tablet, capsule, injectable solution or as a cream or ointment for topical application.
The invention is illustrated but in no way limited by the.
following examples in which all temperatures are in degrees centigrade.
- - . . .
. :- .. . . . - ' '~
.. .
.
10~3~1S~3 2-[2-(5~Methyl-4-imidazolylmethylthio)ethylamino~ -5-(4-pyridylmethyl)-4-pyrimidone trihydrochl~ride (i) Ethyl ~-(4-pyridyl)propionate (43.45 g) and ethyl iormate (19.6 g) were added over a period o~ 6 hours to a stirred mixture o~ sodium wire (5.6 g) and dry ether (150 ml) cooled by an ice-salt bath.
- ~he mixture was stirred for 18 hours at room , -.
temperature, evaporated to dryness and the residue treated with thiourea (18.45 g) and ethanol (130 ml) and re~luxed for 7 hours. The mixture was evaporated to dryness and the residue dissolved in water and the solid product precipitated by adding glacial acid to pH4. The white solid was filtered and washed with ethanol~to give 5-(4-pyridylmethyl)-2-thiouracil m.p. 320-324 (decomp).
- (ii) A solution of 5-(4-pyridylmethyl)-2-thiouracil (11.0 g), methyl iodide (?. 2 g) and sodium hydroxide - (2.1 g) in water (50 ml) and ethanol ~100 ml) was stirred at 60 ~or 30 minutes J allowed to cool and '. i! ~iltered to give 5-(4-pyridylmethyl)-~-methylthio-
4-pyrimidone m.p. 179-182 (ethanol).
(iii) An ~ntimate mixture o~ 5-~4-pyridylme~hyl)-2-methyl-thio-4-pyrimidone (5.9 g) and 2-(5-methyl-4-imidazolyl-methylthio)-ethylamine (4.3 g) ~as heated at 145-150 ~or 5 hours and allowed to cool. ~he residue was triturated with water, and treated with ethanolic hydrogen chloride to give the title compound m.p. 228-- (Found: C, 43.6; H, 5.1; N, 17.6; S, 7.2; 233 Cl, 1.95; C17H23C13N6~
requires: C, 43.8; H, 5.0; N, 18.0; S, 6.9;
Cl, 22.8%).
, . . .. . . .. . . . .. . . . .................... .
i' -. ,:. ~ . ,. ... '. :' ' . ., ,.:
. ~ , .. . . .. .. - ... . ... . .
. . .
`` lOq3458 2- ~-(2-Thiazolylmethylthio)ethylamino~-5-(4-Pyridylmethyl)-- 4-pyrimidone trihydrochloride hemihydrate An intimate mixture of 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone (1.55 g) and 2-(2-thiazolylmethylthio)ethyl-amine (1.16 g) was heated at 135-140 with ~requent stirring.
A~ter cooling, the reaction mixture was triturated under water, acidi~ied with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue recrystallised ~rom methanol to g~ve the title compound m.p. 190-195.
(Found: C, 40.3; H, 4.4; N, 14.5; S, 13.3; Cl, 21.7;
. C16H17N50S2 3Hcl~ ~H20 requires: C, 40.2; H, 4.4;
N, 14.7; S, 13.4; Cl, 22.3%).
-~ ~ 2-~2-~3-Bromo-2-~yridylmethylthio)eth~lamino~-5-(4-~yridyl-methyl)-~-pyrim one dihydrochloride.
(iii) An ~ntimate mixture o~ 5-~4-pyridylme~hyl)-2-methyl-thio-4-pyrimidone (5.9 g) and 2-(5-methyl-4-imidazolyl-methylthio)-ethylamine (4.3 g) ~as heated at 145-150 ~or 5 hours and allowed to cool. ~he residue was triturated with water, and treated with ethanolic hydrogen chloride to give the title compound m.p. 228-- (Found: C, 43.6; H, 5.1; N, 17.6; S, 7.2; 233 Cl, 1.95; C17H23C13N6~
requires: C, 43.8; H, 5.0; N, 18.0; S, 6.9;
Cl, 22.8%).
, . . .. . . .. . . . .. . . . .................... .
i' -. ,:. ~ . ,. ... '. :' ' . ., ,.:
. ~ , .. . . .. .. - ... . ... . .
. . .
`` lOq3458 2- ~-(2-Thiazolylmethylthio)ethylamino~-5-(4-Pyridylmethyl)-- 4-pyrimidone trihydrochloride hemihydrate An intimate mixture of 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone (1.55 g) and 2-(2-thiazolylmethylthio)ethyl-amine (1.16 g) was heated at 135-140 with ~requent stirring.
A~ter cooling, the reaction mixture was triturated under water, acidi~ied with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue recrystallised ~rom methanol to g~ve the title compound m.p. 190-195.
(Found: C, 40.3; H, 4.4; N, 14.5; S, 13.3; Cl, 21.7;
. C16H17N50S2 3Hcl~ ~H20 requires: C, 40.2; H, 4.4;
N, 14.7; S, 13.4; Cl, 22.3%).
-~ ~ 2-~2-~3-Bromo-2-~yridylmethylthio)eth~lamino~-5-(4-~yridyl-methyl)-~-pyrim one dihydrochloride.
5-(4-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.1 g) was - reacted with 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.15 g) according to the procedure of Example 2. The reaction mixture was triturated under hot water, acidi~ied with diluteethanolic hydrogen chloride, evaporated to dryness and the residue recrystallised ~rom ethanol to give the title compolmd m.p. 211-215 (decomp).
(Found: C, 42.65; H, 3.9; N, 13.9; S, 6.3, C18H18Br N50S.2HCl requires: C, 42.8; H, 4.0; N, 13.9; S, 6.35%) 2- ~-(5-Methyl-4-imidazolylmethylthio)ethylamino~-5-(2-thienylmethyl)-4-pyrimidone dihydrochloride (i? Ethyl 2-thienylpropionate (33.3 g), ethyl formate ` 35 (14.1 g) and sodium (4.2 g) were reacted together __ ~.r 0`7;~58 in ether (120 ml), the mixture being cooled with an ice-salt bath. The ether was removed by evaporation, and the residue was refluxed with thiourea (13.8 g) and ethanol (100 ml). The ethanol was removed by evaporation and the residue was dissolved in water, and acetic acid was added to precipitate 5-(2-thienylmethyl)-2-thiouracil (38%) m.p. 212-215 (ethanol).
(ii) 5-(2-Thienylmethyl)-2-thiouracil (4.5 g) was warmed at - .65 with a mixture of methyl iodide (2.8 g), sodium hydroxide (0.8g), water (75 ml) and ethanol (150 ml) to give 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone (89~) m.p. 170.5-171.5 (ethanol).
(iii) An intimate mixture of 5-(2-thienylmethyl)-2-methyl-thio-4-pyrimidone (1.43 g) and 2-(5-methyl-4-imidazolyl-methylthio)ethylamine (1.03 g) was heated at 140 for 6 hours. The cooled residue was washed ~rith water and treated ~vith dilute ethanolic HCl to give the title com-pound-in 40% yield, m.p. 172-176 (ethanol-acetonitrile).
The dihydrochloride was passed down an ion-exchange column of IRh 400 eluting with IN hydrobromic acid, and the eluate was evaporated to dryness and recrystallised from ethanol-acetonitrile to give the corresponding dihydrobromide m.p. 199-203.
(Found: C, 36.7; H, 4.2; N, 13.5; S, 12.1; Br, 30.6;
C16H19N50S2.2HBr requires C, 36.7; H, 4.0; N, 13.4;
S, 12.2; Br, 30.5%) E~AMPLE 5 2-r2-(5-methYl-4-imidazolylmethylthio)ethylaminol -5-(2-pyrid~lmethyl)-4-pyrimidone trihydrochloride hemihydrate (i) Ethyl ~ -(2-pyridyl)-propionate (19.24 g) and ethyl formate ~8.5 g) were added over a period of 1~ hours to a stirred mixture of sodium wire (2.5 g) and dry ether (~0 ml) cooled by a carbon dioxide bath. The mixture was stirred for 21 hours at room temperature, evaporated to dryness and the 3~ residue was treated with thiourea (8.2 g) and ethanol (70 ml) and refluxed for 7~ hours. The mixture was evaporated to dryness and the residue was dissolved in water and --: ~. . -: , . .
r,..
.--. ' . '' ~ ,. : , . , `" lOq3458 glacial acid was added to pH 5. The white precipitate was ~iltered oPf, washed with water and recrystallised from water-acetic acid to give 5-(2-pyridylmethyl)-2-thiouracil, m.p. 262-7 1 (decomp.).
, (ii) A solution o~ 5-(2-pyridylmethyl)-2-thiouracil (6.6 g), methyl iodide ~4.3 g) and sodium hydroxide (2.5 g) in water (100 ml) and ethanol (100 ml) was stirred at 70 ~or 30 minutes, allowed to cool and glacial acetic acid added to pH5. The solution wa~ partially evaporated and cooled in an ice-bath.
The precipitate was iiltered off and recrystalled ~rom ethanol-to give 5-(2-pyridylmethyl)-2-methyl-thlo-4-pyrimidone, m.p. 195-197.5.
(iii) An intimate mixturè o~ 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (4.7 g) and 2-(5-methyl-- 4-imidazolylmethylthio)-ethylamine (3.4 g) was 2 ~ heated at 130-135 for 7 hours. The cooled residue was triturated with hot water and treated with dilute ethanolic HCl to give the title compound m.p. 207-210 (agueous ethanol) (Found: C, 42.8; H, 4.9; N, 17.8; S, 6.9;
2S Cl, 21.8, Cl ~2oN6os.3Hcl~3H2o requires: C, 43.0; ~, 5.1; N, 17.7; S, 6.8;
C1, 22.4%) - . ' , . - , :
- . EgAMPT~ 6 2-r2-(5-Methyl-4-imidazolylmethylthio)-ethylamino~-5-(3-~yridylmethyl)-4-pyrimidone trihydrochloride thyl ~-(3-pyridyl)-propionate (38.9 g) and ethyl ~ormate (17.0 g) were added over a period of 2~ -hours to a stirred mixture o~ sodium wire (5.0 g) and dry ether (150 ml) cooled by an ice bath. The .
.. . .
.
iO~458 .
1 mixture was stirred ~or 22 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (16.5 g) and ethanol (130 ml) and refluxed ior 8 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acetic added to pEI5 to give 5-(3-pyridylmethyl)-2-thiouracil, m.p.
271-4 (decomp.) (acetic acid-water) (ii) A solution o~ 5-(3-pyridylmethyl)-2-thiouracil (11.0 g), methyI iodide (7.1 g) and sodium hydroxide (4.2 g) in water (150 ml) and ethanol (150 ml) ~as stirred at 65 for 40 minutes, allowed to cool-and ~cetic acid was added to pH5. The lB solution was partially evaporated, cooled and filtered to give 5-(3-pyridylmethyl)-2-methylthio-- 4-pyrimidone, m.p 247-9 (ex. ethanol-acetic acid).
.
2 (iii) An intimate mixture o~ 5-(3-pyridyl~ethyl)-2-methylthio-4-pyrimidone (6.55 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (4.8 g) was heated at 130-135 ~or 7 hours. The cool mixture was triturated with hot water and treated with dilute ethanolic HCl to give the title compound m.p 237-241 ~thanol-water) (Found: C, 43.7; H, 5.2; N, 17.4; S, 6.5;
C1-22Ø Cl ~2o~60S.3HCl requires C, 43.8;
- H, 5.0; N, 18.0; S, 6.9; Cl, 22.8%) .
2-C2-(3-Bromo-2-~yridylmethylthio)-ethylaminoJ-5-(2-pyridylmethyl)-4-~yrimidone t~ihydrobromide An intimate mixture o~ 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (1.5 g) and 2-(3-bromo-2-pyridylmethylthio)-,, . .
..... .
....
` ~ 1073~8 1 ethyiamine ~1.6 g) was heated at 130 ior 6 hours. A~ter cooling, the residue was triturated with hot water and treated with dilute hydrobromic acid to give the title compound, in 44.5% yteld~ m.p. 225-230 (decomp.) (ex methanol-water).
(Found: C, 32.1; H, 3.1; N, 10.5; S, 4.8; Br 35.0%.
C18H18BrN50S.3HBr requires C, 32.0; H, 3.1; N, 10.4;
S, 4.8; Br , 35.5X)~
.
2- ~-(5-methyl-4-imidazolylmethylthio)-ethylamino~-5-(2-t ~ -pyrimidone trihydrochloride (i) A solution of 2-thiazoleacrylic acid (26.76 g) and concentrated sulphuric acid (10 ml) in ethanol ~150 ml) was refluxed for 18 hours. The solution was partially evaporated and dissolved - in water. This solution was extracted with ether and the etheral extracts were evaporated to give ethyl 2-thlazoleacrylate.
(ii) Ethyl 2-thiazoleacrylate (14.8 g) was dissolved in ethanol (170 ml) and hydrogenated at 40 and-a pressure o~ 50 ps~ using 10% Palladium on charcoal to give ethyl 2-thiazolepropionate.
(iii) Ethyl 2-thiazolepropionate (14.2 g) and ethyl formate (5.9 g) were added over a period of 2~ hours to a stirred mixture of sodium wire (1.8 g) and dry ether (65 ml) cooled by an ice-bath. The mixture *
- was stirred for 21 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (5.8 g) and ethanol (60 ml) and refluxed for 9 hours. The solid product was ob-tained according to the procedure of Example S(i) to give 5-(2-thiazolemethyl)-2-thiouracil, . ~ . . ~ . - .- .
" - - - - - . : - -~, ~ . ::- -, . - ; ,.. -. ,.
. , - :
- . .
~073~158 m.p. 275-280 (decomp.) (ex acetic acid).
(iv) A solution of 5-(2-thiazolemethyl)-2-thiouracil (4.8 g) methyl lodide (3.0 g.) and sodium hydroxide (0.9 g.) in water (75 ml) and ethanol (150 ml) was stirred at 70 ~or 30 minutes.
The solid product was obtained according to the procedure OI Example 5(ii), giving 5-(2-thiazole-methyl)-2-methylthio-4-pyrimidone, m.p. 181-182.5 (ex ethanol).
(v) An intimate mixture OI 5-(2-thiazolemethyl)-2-methylthio-4~pyrimidone (1.4 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.0 g) was heated at 145-150 ~or 6 hours. The cooled residue was triturated with hot water and treated with dilute ethanolic HCl to give the title compound m.p. 20~-211 (ex. ethanol water) - (Found~ C, 38.9; H, 4.7; N, 17.9; S, 13.5;
Cl, 21,6. C15H18N60S2.3~Cl requires C, 38,2;
- H, 4.5; N, 17.8; S, 13.6; Cl, 22.5%) .~
~XAMPIE 9 2-12-(2-Thiazolylmethyl hio)-ethylamino~-5.(3-pyridylmethyl)-4-pyrimidone trihyidrobromide 5-(3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.74 gj was reacted with 2-~2-thi~zolylmethylthio)-ethylamine (1.30 g) according to the procedure 1n Example 2. The reaction mixture was triturated in ho~ water and treated w~th dilute hydrobromic acid to give the title compound, m.p. 229-233.5 ~ex. methanol-water).
(Found: C, 32.1; H, 3.4; N, 11.7; S, 10.3; Br, 39.9;
C16H17N50S2.3HBr requires: C, 31.9; Hj- 3.4; N, 11.6;
S, 10.7; Br 39.8%) -i ,~,.
- ' .
.,~ .. . .... .. . . ...... . .
'':: . ': , .
2-C2-(3-Bromo-2-pyridylmethylthio)-ethylaminol-5-(3-pyridylmethyl)-4-pyrimidone trihydrobromide 5-(3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.27 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)-ethyl-amine (1.35 g) according to the procedure in Example 2.
The reaction mixture was triturated ~ith hot water and treated with dilute hydrobromic acid to give the tltle compound, m.p. 217-220.. 5 (ex-methanol) ~
(Found: C, 32.1; H, 3.2; N, 10.2; S, 4.5; Br 47.5;
C18H18BrN50S.3HBr requires: C, 32.0; H, 3.1; N, 10.4;
S, 4.8; Br, 47.4%) - Substitution oi' (a) ethyl ~-(2-methoxy-3-pyridyl)propionate (b) ethyl ~-(3-methoxy-2-pyridyl)propionate (c) ethyl ~-(3,4-dimethoxy-2-pyridyl)-propionate (d) ethyl ~-(3-quinolyl)propionate (e) ethyl ~-(4-isoquinolyl)propionate ior ethyl ~-(4-pyridyl)propionate in the procedure of ~. ~ Example 1 leads to the pr~ uction oi (a) 2-~2-(5-methyl-4-imidazoly}methylthio)ethylamino~-5-(2-methoxy-3-pyridylmethyl)-4-pyrimidone (b) 2- ~-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(3-methoxy-2-pyridylmethyl)-4-pyrimidone (c~ 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(3,4-dimethoxy-2-pyridylmethyl~-4-pyrimidone (d) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(3-quinolylmethyl)-4-pyrimidone (e) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamin~ -5-(4-isoquinolylmethyl)-4-pyrimidone The starting materials may be made from the corresponding _ 21 -- - ~- . .
.. -, ~` . .. - ,-,: ~. , '` . : .
, : - ... . . , ~ ,....... . .
: ~ ,: ;
'. ~ , 0~3458 ` heterocycllc carboxaldehyde by condensation ~ith malonic acid and subsequent hydrogenation and esterification.
Substitution o~: (a) 2-(2-imidazolylmethylthio)ethylamine (b) 2-t4-imidazolylmethylthio)ethylamine (c) 2-(5-bromo-4-imidazolylmethylthio)-ethylamine . (d) 2-(5-trifluoromethyl-4-imidazolyl-. methylthio)ethylamine (e) 2-(5-hydroxymethyl-4-imidazolyl-methylthio)ethylamine (f) 2-(2-pyridylmethylthio~ethylamine (g) 2-(3-methyl-2-pyridylmethylthio)-16 . ethylamlne (h) 2-~3-methoxy-2-pyridylmethylthio)-ethylamine (i) 2-(3-chloro-2-pyridylmethylthio)-` ethylamine (;) 2-(3-amino-2-pyridylmethylthio)-ethylamine (k) 2-(3-hydroxy-2-pyridylmethylthio)-ethylamine (1) 2-(3-isothiazolylmethylthio)ethylamlne (m) 2-~4-bromo-3-isothiazolylmethylthio)-ethylamine (n) 2-(3-(1,2,5)-thiadiazolylmethylthio)-ethylamine ~o) 2-(4-chloro-3-(1,2,5)-thiadiazolyl-- methylthio)ethylamine - (p) 2-(5-amino-2-(1,3,4)-thiadiazolyl-methylthio)ethylamine for 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure of Example 6 leads to the production of:-(a) 2-~2-(2-imidazolylmethylthio)ethylamino3-5-(3-pyridyl-: methyl)-4-pyrimidone , . . : ,, ; . .
`" ~ 1073~58 1 (b) 2-~2-(4-imidazolylmethylthio)ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone (c) 2-~2-(5-bromo-4-imidazolylmethylthio)ethylamino~ -5-(3-pyridylmethyl)-4-pyrimidone (d) 2-~2-(5-trifluoromethyl-4-imidazolylmethylthio)-ethylamin~ -5-(3-pyridylmethyl)-4-pyrimidone te) 2- ~2-(5-hydroxymethyl-4-imidazolylmethylthio)-ethylamino~-5-(3-pyridylmethyl)-4~pyrimidone (f) 2-~2-(2-pyridylmethylthio)ethylamino3-5-(3-pyridyl-methyl)-4-pyrimidone ~, (g~ 2-~2-(3-methyl-2-pyridylmethylthio)ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone (h) 2-~2-(3-methoxy-2-pyridylmethylthio,)ethylamino~-5-t3-pyridylme*hyl)-4-pyrimidone (i,) 2-~2-(3-chloro-2-pyridylmethylthio)ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone (~) 2-~2-(3-amino-2-pyridylmethylthio)ethylamino~-5-- (3-pyrldylmethyl)-4-pyrimidone - (k) 2-~2-(3-hydroxy-2-pyridylmethylthio)ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone (1) 2-~2-(3-isothiazolylmethylthio)ethylamino~-5-' . (3-pyridylmethyl)-4-pyrimidone (m) 2- ~-(4-bromo-3-isothiazolylmethylthio)ethylamino~ -5-' (3-pyridylmethyl)-4-pyrimidone ' (n) 2-L2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamino3-5-(3-pyridylmethyl)-4-pyrimidone ~o) 2-~2 (4-chloro-3-(1,2,5)-thiadiazolylmethylthio)ethyl-amino~-5-~3-pyridylmethyl)-4-pyrimidone (p) 2-~2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio~ethyl-- amino~-5-(3-pyridylmethyl)-4-pyrimidone , EXAMPLE 13 (i) Reaction of 2-chloro-3-nitropyridine with 2-(2-cyanoethyl)malonic acid diethyl ester and ' sodium hydride in tetr~hydrofuran gives 1-(3-nitro-2-pyridyl~-1,1-bis-(carbethoxy)-- . - -. i: .. . , . .,, ;....... .. . ........ ..
''' ' " " ~ ': '` ' ~ . . . .. .
iO73~1~i8 butyronitrile, m.p. 93.5-94.5, which aiter alkaline hydrolysis and acidi~ication glves 2-(3-cyanopropyl)-3-nitropyridine hydrochloride 142-145.5. Reduction with hydrogen and palladium on charcoal gives 3-amino-2-(3-cyanopropyl)pyridine, and treatment o~ this with sodium nitrite and sulphùric acid and subsequent warming gives 2-(3-cyanopropyl)-3-hydroxypyridine.
~ethylation with methyl iodide and sodium ethoxide in dimethylsulphoxide and subsequent reduction with lithium a,luminium hydride gives 4-(3-methoxy-2-pyridyl)butylamine. Reductio,n o~ 3-amino-2-(3-cyanopropyl)-3-hydroxypyridine with lithium aluminium hydride gives 4-(3-amino-2-pyridyl)-~ butylamine. Diazotisation of 4-(3-amino-2-pyridyl)-butylamine at pH 1 and treatment with cuprous chloride or cuprcus bromide gives 4-(3-chloro-2-pyridyl)butylamine and 4-(3-bromo-2-pyridyl)-butylamine, respectively.
(ii) Substitution o~ (a~ 4-(4-imidazolyl)butylamine (b) 4-(3-methoxy-2-pyridyl)-butylamine ' (c) 4-(3-chloro-2-pyridyl)-~ ' butylamine ~ td) 4-(3-bromo-2-pyridyl)butylamine (e) 4-(3-amino-2-pyridyl)butylzmine ior 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure o~ Example 6 leads to the production o~: , . 30 (a) 2-¦4-(4-imidazolyl)butylamino~-5-(3-pyridylmethyl)-4-pyrimidone (b) 2- ~-(3-methoxy-2-pyridyl)butylamino3-5-(3-pyridylmethyl)-4-pyrimidone (c) 2-L4-(3-chloro-2-pyridyl)butylamino~-5-(3-pyridylmethyl)-4-pyrimidone . ~, . . , .. . . ,. .... .... .,~. . .
', ', ,' ~: ' '' ~, ',, :
'' ' lOq3458 . (d) 2-r4-(3-bromo-2-py~idyl)butylamino~-5-(3-pyridylmethyl)-4-pyrimidone (e) 2- ~-(3-amino-2-pyridyl)butylamino~-5-(3-pyridylmethyl)-4-pyrimidone Reaction of ethyl acetoacetate with sodium ethoxide and 3-(chloromethyl)pyridine gives ethyl ~-(3-pyridylmethyl)acet~-acetate which gives 5-(3-pyridylmethyl)-6-methyl-2-thio-uracil when treated with thiourea and sodium ethoxide.
Substitution o~ 5-(3-pyridylmethyl)-6-methyl-2-thiouracil ~or 5-(4-pyridylmethyl)-2-thiouracil in the general procedure oi' Example 1 gives 2-~2-(5-methyl-4-imidazolylmethylthio)-ethylamino3-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone.
2-~2-(5-Methyl-4-imidazolylmethylthio)ethylaminol-5-(3-pyridylmethyl)-6-propyl-4-p~yrimidone may be prepared in a similar manner starting with ethyl butyroacetate.
.....
' EXAMPLE 15 Treatment o~ 2-~2-{5-methyl-4-imidazolylmethylthio)ethyl--- amino~-5-(3-pyridylmethyl)-4-pyrimidone with phosphorus pentasulphide in hot pyridine leads to the production oi 2- ~-(5-methyl-4-imidazolylmethylthio~ethylami~o~-5-(3-pyridylmethyl~pyrimid-4-thione - (i) Butyrolactone is treated with sodium and-ethyl ~or~ate, and the product is successively treated with thiourea aid methyl 1odide to give 5-(2-3~ hydroxyethyl)-2-methylthio-4-pyrimidone.
(ii) 5-(2-Hydroxyethyl)-2-methylthio-4-pyrimidone is treated with thionyl chloride and the product is reacted with the sodium derivative of ta) 3-(hydroxy-methyl)pyridine and ~ ) 3-(mercaptomethyl)pyridine ,, . , , . . , - , , -, . - : . , , -~ ~- : :
~:
` ` 10~3~1S8 to give: (a) 5-t2-(3-pyridylmethoxy)ethyl)-2-methylthio-4-pyrimidone (b) 5-(2-(~-pyridylmethylthio)ethyl)-2-methylthio-4-pyrimidone (iii) substitution of:
(a) 5-(2-(3-pyridylmethoxy)ethyl)-2-methylthio-4-pyrimidone (b) 5-(2-(3-pyridylmethylthio)ethyl)-2-methylthio-4-pyrimidone for 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone in the general procedure of Example 6 lea~s to the production oi: .
(a) 2- ~-(5-methyl-4-imidazolylmethylthio)ethyl-amino~-5-(2-(3-pyridylmethoxy)ethyl?-4-pyrimidone (b) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-aminol-5-(2-(3-pyr.idylmethylthio)ethyl)-4-. pyrimidone - 20 (iv) subst~tution of: --. . (a) 3-hydroxypyridine and (b) 3-mercaptopyridine for 3-(hydroxymethyl)pyridine in procedure (ii) and (iii) above leads to the production of:
(a) 2-L2-(5-methyl-4-imidazolylmethylthio)ethyl-amino~-5-(2-(3-pyridyloxy)ethyl)-4-pyrimidone (b) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-amino~-5-(2-t3-pyridylthio)ethyl)-4-pyrimidone - (v) substitution of:
(.a) 3-(2-hydroxyethyl)pyridine and - - (b) 3-(2-mercaptoethy~)pyridine for 3-(hydro~ymethyl)pyridine in procedure (ii) and (iii) above leads to the production of (a) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-aminol-5-(2-(2-(3-pgridyl)ethoxy)ethyl)-4-pyrimidone (b) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-amino~-5-(2-(2-(3-pyridyl)ethylthio)ethyl)-4-pyrimidone (vi) substitution of caprolactone ~or butyrolactone in procedure (i) (ii) and (iii) above leads to the production o~ .
(a) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-amino~ -5-(3-(3-pyridylmethoxy)propyl)-4-pyrimidone (b) 2-~2-(5-met~yl-4-imidazolylmethylthio)ethyl-amino~-5-(3-(3-pyridylmethylthio)propyl)-4-pyrimidone E~AMPLE 17 Ethyl 3-pyridylmethoxyacetate is converted into 5-(3-pyridylme~hoxy)-2-thiouracil by the general procedure o~ -Example 1 (i). Substitution o~ 5-(3-pyridylmethoxy)-2-thiouracil for 5-(4-pyr~dylmethyl)-2-thiouracil in the general procedure o~ Example 1 gives 2-~2-(5-methyl-4--- imidazolylmethylthio)ethylamino~-5-(3-pyridylmethoxy)-4-pyrimidone.
2- L2-(5-Methyl-4-imidazolylmethylthio)ethylamino~-5-(3-t3-PYridYlProPo2Y)-4-Pyrimidone and 2- ~2-t5-methyl-4-imidazolylmethylthio)ethylamino~-5-(3-(3-pyridy ~ ropylthio) -4-pyrimidone may be prepared in a similar manner starting - with et4yl 3-(3-pyridyl)propoxyacetate-and ethyl 3-(3-pyridyl)propylthioglycolate, respectively.
.
, ~` ' . ` ' , ' :
, ! , ;
': ': ; '; ' ' ` ' ` ' ` .
. ' ' ` ` ''' :
lOq3458 Substit`ution oi (a) ethyl ~-(2-iuryl)propionate (b) ethyl ~-(5-oxazolyl)propionate (c) ethyl ~-(3-isothiazolyl)propionate (d) ethyl h-(2-pyrimidyl)propionate (e) ethyl ~-(5-pyrimidyl)propionate (i) ethyl k-(2-pyrazyl)propionate (g) ethyl ~-(4-pyridazyl)propionate for ethyl ~-(4-pyridyl)propionate in the procedure oi Example 1 leads to the production of (a) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-iurylmethyl)-4-pyrimidone ~b) 2-~2-(5-methyl-4-imidazolylmethylthiojethylamino~-5-(2-oxazolylmethyl)-4-pyrimidone ~c) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-~3-isothiazolylmethyl)-4-pyrimidone r (d) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino7-5- --(2-pyrimidylmethyl)-4-pyrimidone (e) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-~5-pyrimidylmethyl~-4-pyrimidone (~) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylàminol-5-(2-pyrazylmethyl)-4-pyrimidone (g) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5- -(4-pyridazylmethyl)-4-pyr~midone The starting materials (b) to ~g) above may be prepared by condensing the corresponding heterocyclic carboxaldehyde w~th malonic acid and hydrogenating and esterifying the .product.
.
Treatment oi 1-(4-methoxybenzyl)-2-imidazole carboxyaldehyde - with malonic acid in the presence o~ pyridine and piperidine gives 2~ (4-methoxybenzyl)imidazoly~ acrylic acid. S-~b-stitution of 2-~ 4-methoxybenzyl)imidazolyl~acrylic acid for 2-thiazoleacrylic acid in the procedure of Example 8.
,, . : . ~::.~- . ....... , , :
.
- ~ . - :: . .. , . :
-, : . . . . . .
0~3~5~
and deprotection of the product with anisole and hydrogen bromide in acetic acid gives 2-~2-(5-methyl-4-imidazolyl-methylthio)ethylamino~-5-(2-imidazolylmethyl)-4-pyrimidone.
Pharmaceutical composition:-Ingredients Amounts 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride 75 mg Sucrose 75 mg Starch 25 mg Talc - 5 mg Stearic Acid 2 mg The ingredients are screen~ed, mixed and filled into a hard gelatin capsule.
EXA~PLE 21 20Pharmaceutical composition:-Ingred~ents Amounts - 2-~2-(5-methyl-4-imidazolylmethylthio)-ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride 100 mg Lactose 100 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.
Similarly, the- other compounds of Formula 1 may be formulated into pharmaceutical compositions by the procedures of Examples 20 and 21.
The pharmaceutical compositions prepared as in the foregoing examples are administered to a subject within the dose-ranges given hereabove to block histamine H2-receptors.
- ~ :
'~ ' '~ ', .
. . ~
lOq34S8 SUPPIEMENTARY DISCLOSURE
In accordance with the teachings of the Principal Disclosure there is outlined the preparation of compounds of the formula:
HN~(CH2 )p-W- (CH2 )q-Het ' Het_cH2_y_(cH2)2-NH ~ X
wherein Het, Y, Z, W, p, q and Het' have been previously described.
In accordance with the Supplementary Disclosure ~ `
teachings additional Examples are provided which illustrate ~ -other compounds within the scope of the formula of the Principal Disclosure. Each of the compounds produced was found to have the histamine H, and H2- antagonist activity -of the compounds of the Principal Disclosure. -~
,, ~: ` '' ''- ~' `
~0'~3458 EXAMPLE 22 ¦~, Substitution of: -~
(a) 2-(3-methoxy-2-pyridylmethylthio)-ethylamine (b) 2-(3-chloro-2-pyridylmethylthio)-ethylamine (c) 2-(3-fluoro-2-pyridylmethylthio)-ethylamine l~ -(d) 2-(3-iodo-2-pyridylmethylthio)-ethylamine ~ -for 2-(5-methyl-4-imidazolylmethylthlo)ethylamine in the procedure of Example 6 gave:-(a) 2-[2-(3-methoxy-2-pyridylmethylthio)ethylamino]-5- .3-(3-pyridylmethyl)-4-pyrimidone m.p. 155-156.5 (b) 2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]-5- ~';
- (3-pyridylmethyl)-4-pyrimidone m.p. 134-135.5.
(c) 2-[2-(3-fluoro-2-pyridylmethylthio)ethylamino]-5-- (3-pyridylmethyl)-4-pyrimidone m.p. 107.5-lQ9.5.
` (d) 2-[2-(3-iodo-2-pyridylmethylthio)ethylamino]-5- r -~
(3-pyridylmethyl)-4-pyrimidone m.p. 118-125.5.
(i) Reaction of 2-chloro-3-nitropyridine with 2-(2-cyanoethyl)-malonic acid diethyl ester and sodium hydride in tetrahydrofuran gave l-(3-nitro-2-pyridyl)-1,1-bis-`(carbethoxy)-butyronitrile, m.p. 93.5-94.5, which after alkaline hydrolysis and acidificat-ion gave 2-(3-cyanopropyl)-3-nitropyridine hydrochloride, m.p. `
142-145.5. Reduction with hydrogen and palladium on charcoal gave 3-amino-2-(3-cyanopropyl)pyridine, and treatment of this with sodium nitrite and sulphuric acid and subsequent warming gave 2-(3-cyanopropyl)-3-hydroxypyridine.
Alkylation uith methyl iodide and sodium ethoxide in ~
dimethylsulphoxide and subsequent reduction with lithium _ aluminium hydride gave 4-~3-methoxy-2-pyridyl)butylamine.
Alkylation with ethyl iodide and sodium ethoxide in dimethyl-sulphoxide and subsequent reduction with lithium aluminium ~ -31-11~73~58 hydride gave 4-(3-ethoxy-2-pyridyl)butylamine. Reductlon of 3-amino-2-(3-cyanopropyl)pyridine with lithium aluminium hydride gave 4-(3-amino-2-pyridyl)-butylamine. Diazotisation of 4-(3-amino_2-pyridyl)butylamine in hydrochloric acid with cuprous chloride or in hydrobromic acid with cuprous bromide gave 4-(3-chloro-2-pyridyl)butylamine and 4-(3-bromo-2-pyridy.l)- .
butylamine, respectively. F
(ii) Substitution of:
(a) 4-(5-methyl-4-imidazolyl)butylamine (b) 4-(3-methoxy-2-pyridyl)butylamine ~
(c) 4-(3-ethoxy-2-pyridyl)butylamine ;~-(d) 4-(3-chloro-2-pyridyl)butylamine (e~ 4-(3-bromo-2-pyridyl)butylamine for-2-(5-methyl-4-imidazolylmethylthio~ethylamine in the procedure of ~xample 6 gave: , (a) 2-[4-(5-methyl-4-imidazolyl)butylamino]-5- ~ -(3-pyridylmethyl)-4-pyrimidone isolated as ~ -~
the trihydrochloride m.p. 242-246 (b) 2-[4-(3-~ethoxy-2-pyridyl)butylamino]-5-(3-pyridylmethyl) 4-pyrimidone m.p. 117-118 (c) 2-~4-(3-ethoxy-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 135-136 `
(d) 2-[4-(3-chloro-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 146-147.5 (e) 2-[4-(3-bromo-2-pyridyl)butylamino]-5-(3- - .~
pyridylmethyl)-4-pyrinidone m.p. 159-162, _ (i) A solution of 3-quinolylacrylic acid (63.71 g) and concentrated sulphuric acid (25 ml) in ethanol (350 ml) was refluxed for 18 hours. The product was isolated according to the procedure of Example 8(i) giving ethyl 3-quinolylacrylate, m.p. 86.5-88 (Ex ethanol-water).
_ i~ ~ -32-, ~ ~
....
- ~
1073458 .
(Found: C, 73.8; H, 5.8; N, 6.0; C14H13N02 requires! C,74.0; H,5.8; N, 6.2%).
(ii) Ethyl-3-(3-quinolyl)acrylate (51.68 g) was dissolved in ethanol (170 ml) and hydrogenated at 37 and a pressure of 50 p.s.i. using 10% Palladium on charcoal to give ethyl-3-(3-quinolyl)propionate.
(iii) Ethyl-3-(3-quinolyl)propionate (47.99 g) and ethyl formate (16.3 g) were added over a period of 3 hours to a stirred mixture of sodium wire (4.8 g) and dry ether (150 ml) cooled by an ice-bath. The mixture was stirred for 20 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (15.9 g) and ethanol (130 ml) and refluxed for 7 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acetic acid was added to pH 4. The mixture was filtered to give 5-(3-quinolylmethyl)-2-thiouracil, m.p. 281.6 (decomp.) (ex acetic acid-water).
(iv) A solution of 5-(3-quinolylmethyl)-2-thiouracil (17.51 g), methyl iodide (9.2 g) and sodium hydroxide (5.4 g) in water (200 ml) and ethanol (200 ml) was stirred at 75 for 1 hour, allowed to cool and acetic acid was added to pH 4 and the solid filtered off to give 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone, m.p. 215.5-218 (ex ethanol).
(v) An intimate mixture of 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone (2.1 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.3 g) was heated at 150-5 for 6 hours. The cooled mixture was triturated with hot water and treated with dilute ethanolic HCl to give 2-[2-(5-methyl-4-imidazolyl-methylthio)ethylamino~-5-(3-quinolylmethyl)-4-pyrimidone trihydrochloride, m.p. 184-9 (ex ethanol-water).
_33-10~34S8 EXAMPLE 25 1 ;
An intimate mixture of 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone (2.0 g) and 2--(2-thiazolylmethylthio)ethylamine (1~2 g) was heated at 145 for 4 hours. After cooling the residue was triturated with hot water and treated with dilute ethanolic HCl to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(3-quinolylmethy~ ~-pyrimidone trihydrochloride, m.p. I~.
202-205 (ex ethanol-water). _ ,. ,~
- EXAMPLE 26 ;
L
(i) A mixture of pyridine-3-carboxaldebyde (48 g), ethyl -~ ~
acetoacetate (52 g)~aqueous piperidine acetate (40%,4.8 g) _;
and 5% palladium on charcoal catalyst (50% wet, 2.48 g) was -~
hydrogenated at 100 p.s.i. and 30 for 22 hours. The mixture was diluted with ether, and filtered, and the filtrate was ;
evaporated and distilled under reduced pressure to give ethyl 2-(3-pyridylmethyl)acetoacetate (b.p. 146/1 mmHg). This ester was refluxed with thourea and sodium ethoxide in ethanol, and the mixture was s~bsequently acidified to give 5-(3-pyridylmethyl)-6-methyl-2-thiouracil m.p. 328-331.
~ii) Treatment of 5-(3-pyridylmethyl)-6-methyl-2-thiouracil with methyl iodide and sodium ethoxide in ethanol at 0 followed by acidification gave 2-methylthio-5-(3-pyridyl-methy)-6-methyl-4-pyrimidone m.p. 208-211.
(iii) Fusion of 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone at 160-170 with (a)2-(2-thiazolylmethylthio)ethylamine (b)2-(3-bromo-2-pyridylmethylthio)ethylamine gave (a) 2-L~-(2-thiazolylmethylthio)ethylamino~-5-(3- .
pyridylmethyl]-6-methyl-4-pyrimidone, m.p. 118-121.
(b) 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone m.p. 159-162.
10'~34~8 (c) ~reatment of 2-methylthio-5-(3-pyridylmethyl)-
(Found: C, 42.65; H, 3.9; N, 13.9; S, 6.3, C18H18Br N50S.2HCl requires: C, 42.8; H, 4.0; N, 13.9; S, 6.35%) 2- ~-(5-Methyl-4-imidazolylmethylthio)ethylamino~-5-(2-thienylmethyl)-4-pyrimidone dihydrochloride (i? Ethyl 2-thienylpropionate (33.3 g), ethyl formate ` 35 (14.1 g) and sodium (4.2 g) were reacted together __ ~.r 0`7;~58 in ether (120 ml), the mixture being cooled with an ice-salt bath. The ether was removed by evaporation, and the residue was refluxed with thiourea (13.8 g) and ethanol (100 ml). The ethanol was removed by evaporation and the residue was dissolved in water, and acetic acid was added to precipitate 5-(2-thienylmethyl)-2-thiouracil (38%) m.p. 212-215 (ethanol).
(ii) 5-(2-Thienylmethyl)-2-thiouracil (4.5 g) was warmed at - .65 with a mixture of methyl iodide (2.8 g), sodium hydroxide (0.8g), water (75 ml) and ethanol (150 ml) to give 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone (89~) m.p. 170.5-171.5 (ethanol).
(iii) An intimate mixture of 5-(2-thienylmethyl)-2-methyl-thio-4-pyrimidone (1.43 g) and 2-(5-methyl-4-imidazolyl-methylthio)ethylamine (1.03 g) was heated at 140 for 6 hours. The cooled residue was washed ~rith water and treated ~vith dilute ethanolic HCl to give the title com-pound-in 40% yield, m.p. 172-176 (ethanol-acetonitrile).
The dihydrochloride was passed down an ion-exchange column of IRh 400 eluting with IN hydrobromic acid, and the eluate was evaporated to dryness and recrystallised from ethanol-acetonitrile to give the corresponding dihydrobromide m.p. 199-203.
(Found: C, 36.7; H, 4.2; N, 13.5; S, 12.1; Br, 30.6;
C16H19N50S2.2HBr requires C, 36.7; H, 4.0; N, 13.4;
S, 12.2; Br, 30.5%) E~AMPLE 5 2-r2-(5-methYl-4-imidazolylmethylthio)ethylaminol -5-(2-pyrid~lmethyl)-4-pyrimidone trihydrochloride hemihydrate (i) Ethyl ~ -(2-pyridyl)-propionate (19.24 g) and ethyl formate ~8.5 g) were added over a period of 1~ hours to a stirred mixture of sodium wire (2.5 g) and dry ether (~0 ml) cooled by a carbon dioxide bath. The mixture was stirred for 21 hours at room temperature, evaporated to dryness and the 3~ residue was treated with thiourea (8.2 g) and ethanol (70 ml) and refluxed for 7~ hours. The mixture was evaporated to dryness and the residue was dissolved in water and --: ~. . -: , . .
r,..
.--. ' . '' ~ ,. : , . , `" lOq3458 glacial acid was added to pH 5. The white precipitate was ~iltered oPf, washed with water and recrystallised from water-acetic acid to give 5-(2-pyridylmethyl)-2-thiouracil, m.p. 262-7 1 (decomp.).
, (ii) A solution o~ 5-(2-pyridylmethyl)-2-thiouracil (6.6 g), methyl iodide ~4.3 g) and sodium hydroxide (2.5 g) in water (100 ml) and ethanol (100 ml) was stirred at 70 ~or 30 minutes, allowed to cool and glacial acetic acid added to pH5. The solution wa~ partially evaporated and cooled in an ice-bath.
The precipitate was iiltered off and recrystalled ~rom ethanol-to give 5-(2-pyridylmethyl)-2-methyl-thlo-4-pyrimidone, m.p. 195-197.5.
(iii) An intimate mixturè o~ 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (4.7 g) and 2-(5-methyl-- 4-imidazolylmethylthio)-ethylamine (3.4 g) was 2 ~ heated at 130-135 for 7 hours. The cooled residue was triturated with hot water and treated with dilute ethanolic HCl to give the title compound m.p. 207-210 (agueous ethanol) (Found: C, 42.8; H, 4.9; N, 17.8; S, 6.9;
2S Cl, 21.8, Cl ~2oN6os.3Hcl~3H2o requires: C, 43.0; ~, 5.1; N, 17.7; S, 6.8;
C1, 22.4%) - . ' , . - , :
- . EgAMPT~ 6 2-r2-(5-Methyl-4-imidazolylmethylthio)-ethylamino~-5-(3-~yridylmethyl)-4-pyrimidone trihydrochloride thyl ~-(3-pyridyl)-propionate (38.9 g) and ethyl ~ormate (17.0 g) were added over a period of 2~ -hours to a stirred mixture o~ sodium wire (5.0 g) and dry ether (150 ml) cooled by an ice bath. The .
.. . .
.
iO~458 .
1 mixture was stirred ~or 22 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (16.5 g) and ethanol (130 ml) and refluxed ior 8 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acetic added to pEI5 to give 5-(3-pyridylmethyl)-2-thiouracil, m.p.
271-4 (decomp.) (acetic acid-water) (ii) A solution o~ 5-(3-pyridylmethyl)-2-thiouracil (11.0 g), methyI iodide (7.1 g) and sodium hydroxide (4.2 g) in water (150 ml) and ethanol (150 ml) ~as stirred at 65 for 40 minutes, allowed to cool-and ~cetic acid was added to pH5. The lB solution was partially evaporated, cooled and filtered to give 5-(3-pyridylmethyl)-2-methylthio-- 4-pyrimidone, m.p 247-9 (ex. ethanol-acetic acid).
.
2 (iii) An intimate mixture o~ 5-(3-pyridyl~ethyl)-2-methylthio-4-pyrimidone (6.55 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (4.8 g) was heated at 130-135 ~or 7 hours. The cool mixture was triturated with hot water and treated with dilute ethanolic HCl to give the title compound m.p 237-241 ~thanol-water) (Found: C, 43.7; H, 5.2; N, 17.4; S, 6.5;
C1-22Ø Cl ~2o~60S.3HCl requires C, 43.8;
- H, 5.0; N, 18.0; S, 6.9; Cl, 22.8%) .
2-C2-(3-Bromo-2-~yridylmethylthio)-ethylaminoJ-5-(2-pyridylmethyl)-4-~yrimidone t~ihydrobromide An intimate mixture o~ 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (1.5 g) and 2-(3-bromo-2-pyridylmethylthio)-,, . .
..... .
....
` ~ 1073~8 1 ethyiamine ~1.6 g) was heated at 130 ior 6 hours. A~ter cooling, the residue was triturated with hot water and treated with dilute hydrobromic acid to give the title compound, in 44.5% yteld~ m.p. 225-230 (decomp.) (ex methanol-water).
(Found: C, 32.1; H, 3.1; N, 10.5; S, 4.8; Br 35.0%.
C18H18BrN50S.3HBr requires C, 32.0; H, 3.1; N, 10.4;
S, 4.8; Br , 35.5X)~
.
2- ~-(5-methyl-4-imidazolylmethylthio)-ethylamino~-5-(2-t ~ -pyrimidone trihydrochloride (i) A solution of 2-thiazoleacrylic acid (26.76 g) and concentrated sulphuric acid (10 ml) in ethanol ~150 ml) was refluxed for 18 hours. The solution was partially evaporated and dissolved - in water. This solution was extracted with ether and the etheral extracts were evaporated to give ethyl 2-thlazoleacrylate.
(ii) Ethyl 2-thiazoleacrylate (14.8 g) was dissolved in ethanol (170 ml) and hydrogenated at 40 and-a pressure o~ 50 ps~ using 10% Palladium on charcoal to give ethyl 2-thiazolepropionate.
(iii) Ethyl 2-thiazolepropionate (14.2 g) and ethyl formate (5.9 g) were added over a period of 2~ hours to a stirred mixture of sodium wire (1.8 g) and dry ether (65 ml) cooled by an ice-bath. The mixture *
- was stirred for 21 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (5.8 g) and ethanol (60 ml) and refluxed for 9 hours. The solid product was ob-tained according to the procedure of Example S(i) to give 5-(2-thiazolemethyl)-2-thiouracil, . ~ . . ~ . - .- .
" - - - - - . : - -~, ~ . ::- -, . - ; ,.. -. ,.
. , - :
- . .
~073~158 m.p. 275-280 (decomp.) (ex acetic acid).
(iv) A solution of 5-(2-thiazolemethyl)-2-thiouracil (4.8 g) methyl lodide (3.0 g.) and sodium hydroxide (0.9 g.) in water (75 ml) and ethanol (150 ml) was stirred at 70 ~or 30 minutes.
The solid product was obtained according to the procedure OI Example 5(ii), giving 5-(2-thiazole-methyl)-2-methylthio-4-pyrimidone, m.p. 181-182.5 (ex ethanol).
(v) An intimate mixture OI 5-(2-thiazolemethyl)-2-methylthio-4~pyrimidone (1.4 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.0 g) was heated at 145-150 ~or 6 hours. The cooled residue was triturated with hot water and treated with dilute ethanolic HCl to give the title compound m.p. 20~-211 (ex. ethanol water) - (Found~ C, 38.9; H, 4.7; N, 17.9; S, 13.5;
Cl, 21,6. C15H18N60S2.3~Cl requires C, 38,2;
- H, 4.5; N, 17.8; S, 13.6; Cl, 22.5%) .~
~XAMPIE 9 2-12-(2-Thiazolylmethyl hio)-ethylamino~-5.(3-pyridylmethyl)-4-pyrimidone trihyidrobromide 5-(3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.74 gj was reacted with 2-~2-thi~zolylmethylthio)-ethylamine (1.30 g) according to the procedure 1n Example 2. The reaction mixture was triturated in ho~ water and treated w~th dilute hydrobromic acid to give the title compound, m.p. 229-233.5 ~ex. methanol-water).
(Found: C, 32.1; H, 3.4; N, 11.7; S, 10.3; Br, 39.9;
C16H17N50S2.3HBr requires: C, 31.9; Hj- 3.4; N, 11.6;
S, 10.7; Br 39.8%) -i ,~,.
- ' .
.,~ .. . .... .. . . ...... . .
'':: . ': , .
2-C2-(3-Bromo-2-pyridylmethylthio)-ethylaminol-5-(3-pyridylmethyl)-4-pyrimidone trihydrobromide 5-(3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.27 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)-ethyl-amine (1.35 g) according to the procedure in Example 2.
The reaction mixture was triturated ~ith hot water and treated with dilute hydrobromic acid to give the tltle compound, m.p. 217-220.. 5 (ex-methanol) ~
(Found: C, 32.1; H, 3.2; N, 10.2; S, 4.5; Br 47.5;
C18H18BrN50S.3HBr requires: C, 32.0; H, 3.1; N, 10.4;
S, 4.8; Br, 47.4%) - Substitution oi' (a) ethyl ~-(2-methoxy-3-pyridyl)propionate (b) ethyl ~-(3-methoxy-2-pyridyl)propionate (c) ethyl ~-(3,4-dimethoxy-2-pyridyl)-propionate (d) ethyl ~-(3-quinolyl)propionate (e) ethyl ~-(4-isoquinolyl)propionate ior ethyl ~-(4-pyridyl)propionate in the procedure of ~. ~ Example 1 leads to the pr~ uction oi (a) 2-~2-(5-methyl-4-imidazoly}methylthio)ethylamino~-5-(2-methoxy-3-pyridylmethyl)-4-pyrimidone (b) 2- ~-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(3-methoxy-2-pyridylmethyl)-4-pyrimidone (c~ 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(3,4-dimethoxy-2-pyridylmethyl~-4-pyrimidone (d) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(3-quinolylmethyl)-4-pyrimidone (e) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamin~ -5-(4-isoquinolylmethyl)-4-pyrimidone The starting materials may be made from the corresponding _ 21 -- - ~- . .
.. -, ~` . .. - ,-,: ~. , '` . : .
, : - ... . . , ~ ,....... . .
: ~ ,: ;
'. ~ , 0~3458 ` heterocycllc carboxaldehyde by condensation ~ith malonic acid and subsequent hydrogenation and esterification.
Substitution o~: (a) 2-(2-imidazolylmethylthio)ethylamine (b) 2-t4-imidazolylmethylthio)ethylamine (c) 2-(5-bromo-4-imidazolylmethylthio)-ethylamine . (d) 2-(5-trifluoromethyl-4-imidazolyl-. methylthio)ethylamine (e) 2-(5-hydroxymethyl-4-imidazolyl-methylthio)ethylamine (f) 2-(2-pyridylmethylthio~ethylamine (g) 2-(3-methyl-2-pyridylmethylthio)-16 . ethylamlne (h) 2-~3-methoxy-2-pyridylmethylthio)-ethylamine (i) 2-(3-chloro-2-pyridylmethylthio)-` ethylamine (;) 2-(3-amino-2-pyridylmethylthio)-ethylamine (k) 2-(3-hydroxy-2-pyridylmethylthio)-ethylamine (1) 2-(3-isothiazolylmethylthio)ethylamlne (m) 2-~4-bromo-3-isothiazolylmethylthio)-ethylamine (n) 2-(3-(1,2,5)-thiadiazolylmethylthio)-ethylamine ~o) 2-(4-chloro-3-(1,2,5)-thiadiazolyl-- methylthio)ethylamine - (p) 2-(5-amino-2-(1,3,4)-thiadiazolyl-methylthio)ethylamine for 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure of Example 6 leads to the production of:-(a) 2-~2-(2-imidazolylmethylthio)ethylamino3-5-(3-pyridyl-: methyl)-4-pyrimidone , . . : ,, ; . .
`" ~ 1073~58 1 (b) 2-~2-(4-imidazolylmethylthio)ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone (c) 2-~2-(5-bromo-4-imidazolylmethylthio)ethylamino~ -5-(3-pyridylmethyl)-4-pyrimidone (d) 2-~2-(5-trifluoromethyl-4-imidazolylmethylthio)-ethylamin~ -5-(3-pyridylmethyl)-4-pyrimidone te) 2- ~2-(5-hydroxymethyl-4-imidazolylmethylthio)-ethylamino~-5-(3-pyridylmethyl)-4~pyrimidone (f) 2-~2-(2-pyridylmethylthio)ethylamino3-5-(3-pyridyl-methyl)-4-pyrimidone ~, (g~ 2-~2-(3-methyl-2-pyridylmethylthio)ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone (h) 2-~2-(3-methoxy-2-pyridylmethylthio,)ethylamino~-5-t3-pyridylme*hyl)-4-pyrimidone (i,) 2-~2-(3-chloro-2-pyridylmethylthio)ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone (~) 2-~2-(3-amino-2-pyridylmethylthio)ethylamino~-5-- (3-pyrldylmethyl)-4-pyrimidone - (k) 2-~2-(3-hydroxy-2-pyridylmethylthio)ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone (1) 2-~2-(3-isothiazolylmethylthio)ethylamino~-5-' . (3-pyridylmethyl)-4-pyrimidone (m) 2- ~-(4-bromo-3-isothiazolylmethylthio)ethylamino~ -5-' (3-pyridylmethyl)-4-pyrimidone ' (n) 2-L2-(3-(1,2,5)-thiadiazolylmethylthio)ethylamino3-5-(3-pyridylmethyl)-4-pyrimidone ~o) 2-~2 (4-chloro-3-(1,2,5)-thiadiazolylmethylthio)ethyl-amino~-5-~3-pyridylmethyl)-4-pyrimidone (p) 2-~2-(5-amino-2-(1,3,4)-thiadiazolylmethylthio~ethyl-- amino~-5-(3-pyridylmethyl)-4-pyrimidone , EXAMPLE 13 (i) Reaction of 2-chloro-3-nitropyridine with 2-(2-cyanoethyl)malonic acid diethyl ester and ' sodium hydride in tetr~hydrofuran gives 1-(3-nitro-2-pyridyl~-1,1-bis-(carbethoxy)-- . - -. i: .. . , . .,, ;....... .. . ........ ..
''' ' " " ~ ': '` ' ~ . . . .. .
iO73~1~i8 butyronitrile, m.p. 93.5-94.5, which aiter alkaline hydrolysis and acidi~ication glves 2-(3-cyanopropyl)-3-nitropyridine hydrochloride 142-145.5. Reduction with hydrogen and palladium on charcoal gives 3-amino-2-(3-cyanopropyl)pyridine, and treatment o~ this with sodium nitrite and sulphùric acid and subsequent warming gives 2-(3-cyanopropyl)-3-hydroxypyridine.
~ethylation with methyl iodide and sodium ethoxide in dimethylsulphoxide and subsequent reduction with lithium a,luminium hydride gives 4-(3-methoxy-2-pyridyl)butylamine. Reductio,n o~ 3-amino-2-(3-cyanopropyl)-3-hydroxypyridine with lithium aluminium hydride gives 4-(3-amino-2-pyridyl)-~ butylamine. Diazotisation of 4-(3-amino-2-pyridyl)-butylamine at pH 1 and treatment with cuprous chloride or cuprcus bromide gives 4-(3-chloro-2-pyridyl)butylamine and 4-(3-bromo-2-pyridyl)-butylamine, respectively.
(ii) Substitution o~ (a~ 4-(4-imidazolyl)butylamine (b) 4-(3-methoxy-2-pyridyl)-butylamine ' (c) 4-(3-chloro-2-pyridyl)-~ ' butylamine ~ td) 4-(3-bromo-2-pyridyl)butylamine (e) 4-(3-amino-2-pyridyl)butylzmine ior 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure o~ Example 6 leads to the production o~: , . 30 (a) 2-¦4-(4-imidazolyl)butylamino~-5-(3-pyridylmethyl)-4-pyrimidone (b) 2- ~-(3-methoxy-2-pyridyl)butylamino3-5-(3-pyridylmethyl)-4-pyrimidone (c) 2-L4-(3-chloro-2-pyridyl)butylamino~-5-(3-pyridylmethyl)-4-pyrimidone . ~, . . , .. . . ,. .... .... .,~. . .
', ', ,' ~: ' '' ~, ',, :
'' ' lOq3458 . (d) 2-r4-(3-bromo-2-py~idyl)butylamino~-5-(3-pyridylmethyl)-4-pyrimidone (e) 2- ~-(3-amino-2-pyridyl)butylamino~-5-(3-pyridylmethyl)-4-pyrimidone Reaction of ethyl acetoacetate with sodium ethoxide and 3-(chloromethyl)pyridine gives ethyl ~-(3-pyridylmethyl)acet~-acetate which gives 5-(3-pyridylmethyl)-6-methyl-2-thio-uracil when treated with thiourea and sodium ethoxide.
Substitution o~ 5-(3-pyridylmethyl)-6-methyl-2-thiouracil ~or 5-(4-pyridylmethyl)-2-thiouracil in the general procedure oi' Example 1 gives 2-~2-(5-methyl-4-imidazolylmethylthio)-ethylamino3-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone.
2-~2-(5-Methyl-4-imidazolylmethylthio)ethylaminol-5-(3-pyridylmethyl)-6-propyl-4-p~yrimidone may be prepared in a similar manner starting with ethyl butyroacetate.
.....
' EXAMPLE 15 Treatment o~ 2-~2-{5-methyl-4-imidazolylmethylthio)ethyl--- amino~-5-(3-pyridylmethyl)-4-pyrimidone with phosphorus pentasulphide in hot pyridine leads to the production oi 2- ~-(5-methyl-4-imidazolylmethylthio~ethylami~o~-5-(3-pyridylmethyl~pyrimid-4-thione - (i) Butyrolactone is treated with sodium and-ethyl ~or~ate, and the product is successively treated with thiourea aid methyl 1odide to give 5-(2-3~ hydroxyethyl)-2-methylthio-4-pyrimidone.
(ii) 5-(2-Hydroxyethyl)-2-methylthio-4-pyrimidone is treated with thionyl chloride and the product is reacted with the sodium derivative of ta) 3-(hydroxy-methyl)pyridine and ~ ) 3-(mercaptomethyl)pyridine ,, . , , . . , - , , -, . - : . , , -~ ~- : :
~:
` ` 10~3~1S8 to give: (a) 5-t2-(3-pyridylmethoxy)ethyl)-2-methylthio-4-pyrimidone (b) 5-(2-(~-pyridylmethylthio)ethyl)-2-methylthio-4-pyrimidone (iii) substitution of:
(a) 5-(2-(3-pyridylmethoxy)ethyl)-2-methylthio-4-pyrimidone (b) 5-(2-(3-pyridylmethylthio)ethyl)-2-methylthio-4-pyrimidone for 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone in the general procedure of Example 6 lea~s to the production oi: .
(a) 2- ~-(5-methyl-4-imidazolylmethylthio)ethyl-amino~-5-(2-(3-pyridylmethoxy)ethyl?-4-pyrimidone (b) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-aminol-5-(2-(3-pyr.idylmethylthio)ethyl)-4-. pyrimidone - 20 (iv) subst~tution of: --. . (a) 3-hydroxypyridine and (b) 3-mercaptopyridine for 3-(hydroxymethyl)pyridine in procedure (ii) and (iii) above leads to the production of:
(a) 2-L2-(5-methyl-4-imidazolylmethylthio)ethyl-amino~-5-(2-(3-pyridyloxy)ethyl)-4-pyrimidone (b) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-amino~-5-(2-t3-pyridylthio)ethyl)-4-pyrimidone - (v) substitution of:
(.a) 3-(2-hydroxyethyl)pyridine and - - (b) 3-(2-mercaptoethy~)pyridine for 3-(hydro~ymethyl)pyridine in procedure (ii) and (iii) above leads to the production of (a) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-aminol-5-(2-(2-(3-pgridyl)ethoxy)ethyl)-4-pyrimidone (b) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-amino~-5-(2-(2-(3-pyridyl)ethylthio)ethyl)-4-pyrimidone (vi) substitution of caprolactone ~or butyrolactone in procedure (i) (ii) and (iii) above leads to the production o~ .
(a) 2-~2-(5-methyl-4-imidazolylmethylthio)ethyl-amino~ -5-(3-(3-pyridylmethoxy)propyl)-4-pyrimidone (b) 2-~2-(5-met~yl-4-imidazolylmethylthio)ethyl-amino~-5-(3-(3-pyridylmethylthio)propyl)-4-pyrimidone E~AMPLE 17 Ethyl 3-pyridylmethoxyacetate is converted into 5-(3-pyridylme~hoxy)-2-thiouracil by the general procedure o~ -Example 1 (i). Substitution o~ 5-(3-pyridylmethoxy)-2-thiouracil for 5-(4-pyr~dylmethyl)-2-thiouracil in the general procedure o~ Example 1 gives 2-~2-(5-methyl-4--- imidazolylmethylthio)ethylamino~-5-(3-pyridylmethoxy)-4-pyrimidone.
2- L2-(5-Methyl-4-imidazolylmethylthio)ethylamino~-5-(3-t3-PYridYlProPo2Y)-4-Pyrimidone and 2- ~2-t5-methyl-4-imidazolylmethylthio)ethylamino~-5-(3-(3-pyridy ~ ropylthio) -4-pyrimidone may be prepared in a similar manner starting - with et4yl 3-(3-pyridyl)propoxyacetate-and ethyl 3-(3-pyridyl)propylthioglycolate, respectively.
.
, ~` ' . ` ' , ' :
, ! , ;
': ': ; '; ' ' ` ' ` ' ` .
. ' ' ` ` ''' :
lOq3458 Substit`ution oi (a) ethyl ~-(2-iuryl)propionate (b) ethyl ~-(5-oxazolyl)propionate (c) ethyl ~-(3-isothiazolyl)propionate (d) ethyl h-(2-pyrimidyl)propionate (e) ethyl ~-(5-pyrimidyl)propionate (i) ethyl k-(2-pyrazyl)propionate (g) ethyl ~-(4-pyridazyl)propionate for ethyl ~-(4-pyridyl)propionate in the procedure oi Example 1 leads to the production of (a) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-iurylmethyl)-4-pyrimidone ~b) 2-~2-(5-methyl-4-imidazolylmethylthiojethylamino~-5-(2-oxazolylmethyl)-4-pyrimidone ~c) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-~3-isothiazolylmethyl)-4-pyrimidone r (d) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino7-5- --(2-pyrimidylmethyl)-4-pyrimidone (e) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-~5-pyrimidylmethyl~-4-pyrimidone (~) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylàminol-5-(2-pyrazylmethyl)-4-pyrimidone (g) 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5- -(4-pyridazylmethyl)-4-pyr~midone The starting materials (b) to ~g) above may be prepared by condensing the corresponding heterocyclic carboxaldehyde w~th malonic acid and hydrogenating and esterifying the .product.
.
Treatment oi 1-(4-methoxybenzyl)-2-imidazole carboxyaldehyde - with malonic acid in the presence o~ pyridine and piperidine gives 2~ (4-methoxybenzyl)imidazoly~ acrylic acid. S-~b-stitution of 2-~ 4-methoxybenzyl)imidazolyl~acrylic acid for 2-thiazoleacrylic acid in the procedure of Example 8.
,, . : . ~::.~- . ....... , , :
.
- ~ . - :: . .. , . :
-, : . . . . . .
0~3~5~
and deprotection of the product with anisole and hydrogen bromide in acetic acid gives 2-~2-(5-methyl-4-imidazolyl-methylthio)ethylamino~-5-(2-imidazolylmethyl)-4-pyrimidone.
Pharmaceutical composition:-Ingredients Amounts 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride 75 mg Sucrose 75 mg Starch 25 mg Talc - 5 mg Stearic Acid 2 mg The ingredients are screen~ed, mixed and filled into a hard gelatin capsule.
EXA~PLE 21 20Pharmaceutical composition:-Ingred~ents Amounts - 2-~2-(5-methyl-4-imidazolylmethylthio)-ethylamino~-5-(3-pyridylmethyl)-4-pyrimidone trihydrochloride 100 mg Lactose 100 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.
Similarly, the- other compounds of Formula 1 may be formulated into pharmaceutical compositions by the procedures of Examples 20 and 21.
The pharmaceutical compositions prepared as in the foregoing examples are administered to a subject within the dose-ranges given hereabove to block histamine H2-receptors.
- ~ :
'~ ' '~ ', .
. . ~
lOq34S8 SUPPIEMENTARY DISCLOSURE
In accordance with the teachings of the Principal Disclosure there is outlined the preparation of compounds of the formula:
HN~(CH2 )p-W- (CH2 )q-Het ' Het_cH2_y_(cH2)2-NH ~ X
wherein Het, Y, Z, W, p, q and Het' have been previously described.
In accordance with the Supplementary Disclosure ~ `
teachings additional Examples are provided which illustrate ~ -other compounds within the scope of the formula of the Principal Disclosure. Each of the compounds produced was found to have the histamine H, and H2- antagonist activity -of the compounds of the Principal Disclosure. -~
,, ~: ` '' ''- ~' `
~0'~3458 EXAMPLE 22 ¦~, Substitution of: -~
(a) 2-(3-methoxy-2-pyridylmethylthio)-ethylamine (b) 2-(3-chloro-2-pyridylmethylthio)-ethylamine (c) 2-(3-fluoro-2-pyridylmethylthio)-ethylamine l~ -(d) 2-(3-iodo-2-pyridylmethylthio)-ethylamine ~ -for 2-(5-methyl-4-imidazolylmethylthlo)ethylamine in the procedure of Example 6 gave:-(a) 2-[2-(3-methoxy-2-pyridylmethylthio)ethylamino]-5- .3-(3-pyridylmethyl)-4-pyrimidone m.p. 155-156.5 (b) 2-[2-(3-chloro-2-pyridylmethylthio)ethylamino]-5- ~';
- (3-pyridylmethyl)-4-pyrimidone m.p. 134-135.5.
(c) 2-[2-(3-fluoro-2-pyridylmethylthio)ethylamino]-5-- (3-pyridylmethyl)-4-pyrimidone m.p. 107.5-lQ9.5.
` (d) 2-[2-(3-iodo-2-pyridylmethylthio)ethylamino]-5- r -~
(3-pyridylmethyl)-4-pyrimidone m.p. 118-125.5.
(i) Reaction of 2-chloro-3-nitropyridine with 2-(2-cyanoethyl)-malonic acid diethyl ester and sodium hydride in tetrahydrofuran gave l-(3-nitro-2-pyridyl)-1,1-bis-`(carbethoxy)-butyronitrile, m.p. 93.5-94.5, which after alkaline hydrolysis and acidificat-ion gave 2-(3-cyanopropyl)-3-nitropyridine hydrochloride, m.p. `
142-145.5. Reduction with hydrogen and palladium on charcoal gave 3-amino-2-(3-cyanopropyl)pyridine, and treatment of this with sodium nitrite and sulphuric acid and subsequent warming gave 2-(3-cyanopropyl)-3-hydroxypyridine.
Alkylation uith methyl iodide and sodium ethoxide in ~
dimethylsulphoxide and subsequent reduction with lithium _ aluminium hydride gave 4-~3-methoxy-2-pyridyl)butylamine.
Alkylation with ethyl iodide and sodium ethoxide in dimethyl-sulphoxide and subsequent reduction with lithium aluminium ~ -31-11~73~58 hydride gave 4-(3-ethoxy-2-pyridyl)butylamine. Reductlon of 3-amino-2-(3-cyanopropyl)pyridine with lithium aluminium hydride gave 4-(3-amino-2-pyridyl)-butylamine. Diazotisation of 4-(3-amino_2-pyridyl)butylamine in hydrochloric acid with cuprous chloride or in hydrobromic acid with cuprous bromide gave 4-(3-chloro-2-pyridyl)butylamine and 4-(3-bromo-2-pyridy.l)- .
butylamine, respectively. F
(ii) Substitution of:
(a) 4-(5-methyl-4-imidazolyl)butylamine (b) 4-(3-methoxy-2-pyridyl)butylamine ~
(c) 4-(3-ethoxy-2-pyridyl)butylamine ;~-(d) 4-(3-chloro-2-pyridyl)butylamine (e~ 4-(3-bromo-2-pyridyl)butylamine for-2-(5-methyl-4-imidazolylmethylthio~ethylamine in the procedure of ~xample 6 gave: , (a) 2-[4-(5-methyl-4-imidazolyl)butylamino]-5- ~ -(3-pyridylmethyl)-4-pyrimidone isolated as ~ -~
the trihydrochloride m.p. 242-246 (b) 2-[4-(3-~ethoxy-2-pyridyl)butylamino]-5-(3-pyridylmethyl) 4-pyrimidone m.p. 117-118 (c) 2-~4-(3-ethoxy-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 135-136 `
(d) 2-[4-(3-chloro-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 146-147.5 (e) 2-[4-(3-bromo-2-pyridyl)butylamino]-5-(3- - .~
pyridylmethyl)-4-pyrinidone m.p. 159-162, _ (i) A solution of 3-quinolylacrylic acid (63.71 g) and concentrated sulphuric acid (25 ml) in ethanol (350 ml) was refluxed for 18 hours. The product was isolated according to the procedure of Example 8(i) giving ethyl 3-quinolylacrylate, m.p. 86.5-88 (Ex ethanol-water).
_ i~ ~ -32-, ~ ~
....
- ~
1073458 .
(Found: C, 73.8; H, 5.8; N, 6.0; C14H13N02 requires! C,74.0; H,5.8; N, 6.2%).
(ii) Ethyl-3-(3-quinolyl)acrylate (51.68 g) was dissolved in ethanol (170 ml) and hydrogenated at 37 and a pressure of 50 p.s.i. using 10% Palladium on charcoal to give ethyl-3-(3-quinolyl)propionate.
(iii) Ethyl-3-(3-quinolyl)propionate (47.99 g) and ethyl formate (16.3 g) were added over a period of 3 hours to a stirred mixture of sodium wire (4.8 g) and dry ether (150 ml) cooled by an ice-bath. The mixture was stirred for 20 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (15.9 g) and ethanol (130 ml) and refluxed for 7 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acetic acid was added to pH 4. The mixture was filtered to give 5-(3-quinolylmethyl)-2-thiouracil, m.p. 281.6 (decomp.) (ex acetic acid-water).
(iv) A solution of 5-(3-quinolylmethyl)-2-thiouracil (17.51 g), methyl iodide (9.2 g) and sodium hydroxide (5.4 g) in water (200 ml) and ethanol (200 ml) was stirred at 75 for 1 hour, allowed to cool and acetic acid was added to pH 4 and the solid filtered off to give 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone, m.p. 215.5-218 (ex ethanol).
(v) An intimate mixture of 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone (2.1 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (1.3 g) was heated at 150-5 for 6 hours. The cooled mixture was triturated with hot water and treated with dilute ethanolic HCl to give 2-[2-(5-methyl-4-imidazolyl-methylthio)ethylamino~-5-(3-quinolylmethyl)-4-pyrimidone trihydrochloride, m.p. 184-9 (ex ethanol-water).
_33-10~34S8 EXAMPLE 25 1 ;
An intimate mixture of 5-(3-quinolylmethyl)-2-methylthio-4-pyrimidone (2.0 g) and 2--(2-thiazolylmethylthio)ethylamine (1~2 g) was heated at 145 for 4 hours. After cooling the residue was triturated with hot water and treated with dilute ethanolic HCl to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(3-quinolylmethy~ ~-pyrimidone trihydrochloride, m.p. I~.
202-205 (ex ethanol-water). _ ,. ,~
- EXAMPLE 26 ;
L
(i) A mixture of pyridine-3-carboxaldebyde (48 g), ethyl -~ ~
acetoacetate (52 g)~aqueous piperidine acetate (40%,4.8 g) _;
and 5% palladium on charcoal catalyst (50% wet, 2.48 g) was -~
hydrogenated at 100 p.s.i. and 30 for 22 hours. The mixture was diluted with ether, and filtered, and the filtrate was ;
evaporated and distilled under reduced pressure to give ethyl 2-(3-pyridylmethyl)acetoacetate (b.p. 146/1 mmHg). This ester was refluxed with thourea and sodium ethoxide in ethanol, and the mixture was s~bsequently acidified to give 5-(3-pyridylmethyl)-6-methyl-2-thiouracil m.p. 328-331.
~ii) Treatment of 5-(3-pyridylmethyl)-6-methyl-2-thiouracil with methyl iodide and sodium ethoxide in ethanol at 0 followed by acidification gave 2-methylthio-5-(3-pyridyl-methy)-6-methyl-4-pyrimidone m.p. 208-211.
(iii) Fusion of 2-methylthio-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone at 160-170 with (a)2-(2-thiazolylmethylthio)ethylamine (b)2-(3-bromo-2-pyridylmethylthio)ethylamine gave (a) 2-L~-(2-thiazolylmethylthio)ethylamino~-5-(3- .
pyridylmethyl]-6-methyl-4-pyrimidone, m.p. 118-121.
(b) 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone m.p. 159-162.
10'~34~8 (c) ~reatment of 2-methylthio-5-(3-pyridylmethyl)-
6-methyl-4-pyrimidone with 2-(5-methyl-4-imidazolyl-methylthio)ethylamine in refluxing pyridine for 25 hours, followed by evaporation of the mixture and chromatographic purification of the residue on silica gel (eluting with chloroform/methanol 5~
gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone m.p. 128-131. L
(i) 2-(6-Methyl-3-pyridyl)acrylic acid, m.p. 213-215.5 was r ~-prepared by condensing 6-methylpyridine-2-carboxaldehyde with ~ -malonic acid in pyridine with piperidine catalyst, and was converted into the corresponding ethyl ester m.p. 36-37 which ;
was reduced with hydrogen and palladium-on-charcoal catalyst to give ethyl 3-(6-methyl-3-pyridyl)propionate (oil).
(ii) Treatment of ethyl 3-(6-methyl-3-pyridyl)propionate with sodium and ethyl formate according to the procedure of Example l(i) gave 5-(6-methyl-3-pyridylmethyl)-2-thiouracil m.p. -240-241 which was converted into 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone m.p. 197-198.5 by the procedure of ExampIe l(ii).
(iii) Treatment of 5-(6-methyl-3-pyridylmethyl-2-methylthio-4-pyrimidone with (a) 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (b) 2-(2-thiazolylmethylthio)ethylamine (c) 2-(3-bromo-2-pyridylmethylthio)ethylamine .
(d) 4-(5-methyl-4-imidazolyl)butylamine (e) 4-(3-methoxy-2-pyridyl)butylamine (f) 4-(3-chloro-2-pyridyl)butylamine (g) 4-(2-pyridyl a butylamine (h) 4-(3-ethoxy-2-pyridyl)butylamine ~ . .
.. ~ . . . . _ `-" iO73458 according to the general procedure of Example l(iii) gave (a) 2-L2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydro- - -chloride m.p. 210-214.
(b) 2-~2-(2-thiazolylmethylthio)ethylamino~-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p.
187-190.
(c) 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino~-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 193-196.
(d) 2-~4-(5-methyl-4-imidazolyl)butylamino~-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p.
189-190.
(e) 2-~4-(3-methoxy-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p.
209-210.
(f) 2-[4-(3-chloro-2-pyridyl)butylamino~-5-(6-methyl-3-3-pyridylmethyl)-4-pyrimidone isolated as the free base m.p. 132-133.
(g) 2-~4-(2-pyridyl)butylamino3-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone isolated as the free base m.p. 166.5-157.5.
(h) 2-t4-~3-ethoxy-2-pyridyl)butylamino7-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone isolated as the free base m.p. 104-105.
0~3~58 :
.
EXAMPLE 28 .
(i)A mixture of ethyl formate (111 g) and 2-butanone ~
(108 g) was added dropwise to a stirred mixture of sodium _ hydride in oil (50% w/w, 72 g) and the mixture was allowed to stand overnight. Ether (800 ml) was added and the solid (101 g) was filtered off. Cyanoacetamide (69.5 g), piperidine -acetate (prepared by adding piperidine to acetic acid (7 ml) and water (18 ml) until the mixture was basic) and water (400 ml) .
were added to this solid and the mixture was heated under reflux for 2 hours and allowed to cool. The mixture was acidified with acetic acid and the solid which precipitated out was recrystallised from aqueous ethanol to give 3-cyano-5,6- ;
- dimethyl-2-hydroxypyridine (43.5 g). .
(ii) An-intimate mixture of 3-cyano-5,6-dimethyl-2-hydroxy-_ pyridine (42 g) and phosphorus pentachloride (81 g) was heated - at 140-160 for 2 hours. Phosphoryl chloride was removed by -distillation under reduced pressure and ice-water (500 g) was :~
added to the residue. The mixture was adjusted-to pH 7 with :
aqueous sodium hydroxide and extracted with ether. The ether extracts were evaporated to an oil which was crystallised _ from petroleum ether (~.p. 60-80) to give 2-chloro-3-cyano-5,6-dimethylpyridine (25.3 g) m.p. 83-87.
(iii) A mixture of 2-chloro-3-cyano-5,6-dimethylpyridine (21.5 g) .
semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol (475 ml) was hydrogenated at 50 p.s.i.
at 50 using Raney nickel catalyst (5 g). The mixture was added to water (750 ml) and was filtered. The solid uas filtered and suspended in water (130 ml) and concentrated hydro-chloric acid (70 ml) was added and the mixture was heated at 100 for 1 hour, formalin (40% w/w, 120 ml) was added and the _ mixture was heated at 100 for a ~urther ~ hour and was allowed to cool.- Sodium acetate (95 g) and water ~250 ml) were added and the mixture was extracted with ether and the extracts were washed with 5% aqueous potassium carbonate and evaporated to gi~e 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (13.24 g, ~
60%) m.p. 69-70. _ 0'~3458 (iv)A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (}6,85 g), ma~onic acid (11.45 g) piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and eva~orated to an oil. -This oil was dissolved in 2N sodium hydroxide solution and was extracted with chloroform (discarded). The aqueous phase was -acidified with hydrochloric acid and was extracted~with chloro- :
form. The chloroform extracts were washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%) m.p. 150-158. This acid was esterified usin~ ethanol and sulphuric acid to give the ethyl ester m.p. 85-88.
(v)Ethyl 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylate (32.7 g) in ethanol (500 ml) was hydrogenated at 25-30 and 50 p.s.i.
using palladium-on-charcoal catalyst (5%, 3 g). The mixture ~:
was filtered and the filtrate evaporated to an oil which was partitioned between chloroform and 2N hydrochloric acid. The aqueous phase was made basic with aqueous sodium hydroxide, extracted with chloroform and the chloroform extracts evaporated to give ethyl 3-(5,6-dimethyl-3-pyridyl)propionate (21.8 g, 80%) as an oil. .
(vi) Reaction of ethyl 3-(5,6-dimethyl-3-pyridyl) propionate .
with ethyl formate and sodium hydride in dimethoxyethane -according to the general procedure of Example 24(iii) gave 3-(5,6-dimethyl-3-pyridyl)-2-formylpropionate m.p. 148-149, 6uccessive treatment of this ester with thiourea and ~ methyl iodide according to the general procedure of Example lti)(ii) gave 5-(5,6-dimethyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone and reaction of this compound with 2-(3-bromo-2-pyridylmethylthio)ethylamine at 140 for 6 hours ~ave ¦~
2- ~-(3-bromo-2-pyridylmethylthio)ethyl~amino7-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone m p. 105-107.
-38- _ ~i) A mixture of 2-methoxy-5-cyanopyrid$ne (61.26 g), semi-carbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1300 ml) and water (400 ml) was hydrogenated at 50 p.s.i. using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 ml~ water (1000 ml) was added and the mixture was allowed to stand at 0 overnight. The mixture was filtered and the solid was washed with water and dissolved in 10% hydrochloric acid (1000 ml). Formaldehyde solution (36% w/v, 450 ml) was added and the mixture was warmed for 15 minutes, allowed to cool and was added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether (3 x 500 ml) and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50%) m.p. 48-49.
(ii) A mixture of 6-methoxypyridine-3-carboxaldehyde 2.34 g), monoethyl malonate (4.51 g), pyridine (12 ml) and piperidine (6 drops) was heated under reflux for 5 hours and was evaporated to an oil. This oil was partitioned between ether and dilute aqueous ammonia. The ether layer was washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methoxy-3-pyridyl)acrylate (2.8 g, 79%) m.p. 49-52.
(iii) Ethyl 3-(6-methoxy-3-pyridyl)acrylate (32.33 g) in ethanol (160 ml) was hydrogenated at 50 p.s.i. at 40 using palladium-on-charcoal catalyst (5%, 0.2 g). The mixture was filtered and the filtrate was evaporated to give ethyl 3-(6-methoxy-3-pyridyl)propionate (32.7 g) as an oil.
~ . . . ~ .
07~58 ~iv) A mixture of ethyl 3-(6-methoxy-3-pyridyl)propionate (32.74 g) and ethyl formate (17.22 g) was added dropwise over ~
1~ hours to a stirred suspension of sodium hydride in oil r (50%, 9.38 g) in 1,2-dimethoxyethane (50 ml) cooled to -2, ¦~
allowed to stand overnight at room temperature and was poured L
on to ice. The mixture was extracted with ether (discarded), and the aqueous phase was adjusted to pH 5 with 2N sulphuric r acid. An oil was precipitated and crystallised on standing to give ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (25.9 g, D
70%) m.p. 91.5-94. A sample recrystallised from aqueous -ethanol had m.p. 93-94. ~-Successive treatment of this ester with thiourea and methyl iodide according to the general procedure of Example l(i)(ii) gives 5-(6-methoxy-3-pyridylmethyl)-2-methylthio-4-pyrimidone and reaction of this compound at 140 for 6 hours with (a) 2-(5-methyl-4-imidazolylmethylthio)ethylamine (b) 2-(2-thiazolylmethylthio)ethylamine .
gives (a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 205-209, - (b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone m.p. 95-97.
(i) Sodium (20.8 g) was dissolved in methanol (285 ml), a solution of 2-chloro-4-cyanopyridine (115.53 g) in methanol/-dioxan (1:1, 850 ml) was added and the mixture was boiled under reflux for 2~ hours and was allowed to cool. The mixture was filtered and the volume of the filtrate was reduced by _ evaporation to 200 ml and water (400 ml) was added. The solid which precipitated out was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%) m.p. 93-95.5, . . , ioq34s8 (ii) A mixture of 2-methoxy-4-cyanopyridine (57.2 g~, semi-carbazide hydrochloride (71.25 g~, sodium acetate (69.86 g), ethanol (1200 ml) and water (370 ml) was hydrogenated at 50 p.s.i. using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 450 ml, water (900 ml) was added and the mixture was allowed to stand at 0 overnight. The mixture was filtered and the solid was washed with water and was dissolved in 10% hydrochloric acid (950 ml). Formaldehyde solution (36% w/v, 420 ml) was added and the mixture was warmed for 30 minutes, allowed to cool and was added to a solution of sodium acetate (280 g) in water (840 ml). The mixture was extracted with ether (3 x 500 ml) and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 2-methoxypyridine-15 4-carboxaldehyde (20.53 g, 35%) m.p. 33-5. A sample recrys-tallised from petroleum ether had m.p. 33-36.
(iii) Substitution of 2-methoxypyridine-4-carboxaldehyde for 6-methoxypyridine-3-carboxaldehyde in the general procedure of Example 29(ii-iv) gave ethyl 2-formyl(2-methoxy-4-pyridyl) propionate as an oil.
Successive treatment of this ester with thiourea and methyl iodide according to the general procedure of Example 1 (i)(ii) gives 5-(2-methoxy-4-pyridylmethyl)-2-methylthio-4-pyrimidone and reaction of this compound at 140 for 6 hours with a) 2-(5-methyl-4-imidazolylmethylthio)ethylamine b) 2-(2-thiazolylmethylthio)ethylamine gives a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p.
b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p. 105.5-106.5.
,~ . - : ~ . ,.: . ,
gave 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone m.p. 128-131. L
(i) 2-(6-Methyl-3-pyridyl)acrylic acid, m.p. 213-215.5 was r ~-prepared by condensing 6-methylpyridine-2-carboxaldehyde with ~ -malonic acid in pyridine with piperidine catalyst, and was converted into the corresponding ethyl ester m.p. 36-37 which ;
was reduced with hydrogen and palladium-on-charcoal catalyst to give ethyl 3-(6-methyl-3-pyridyl)propionate (oil).
(ii) Treatment of ethyl 3-(6-methyl-3-pyridyl)propionate with sodium and ethyl formate according to the procedure of Example l(i) gave 5-(6-methyl-3-pyridylmethyl)-2-thiouracil m.p. -240-241 which was converted into 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone m.p. 197-198.5 by the procedure of ExampIe l(ii).
(iii) Treatment of 5-(6-methyl-3-pyridylmethyl-2-methylthio-4-pyrimidone with (a) 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (b) 2-(2-thiazolylmethylthio)ethylamine (c) 2-(3-bromo-2-pyridylmethylthio)ethylamine .
(d) 4-(5-methyl-4-imidazolyl)butylamine (e) 4-(3-methoxy-2-pyridyl)butylamine (f) 4-(3-chloro-2-pyridyl)butylamine (g) 4-(2-pyridyl a butylamine (h) 4-(3-ethoxy-2-pyridyl)butylamine ~ . .
.. ~ . . . . _ `-" iO73458 according to the general procedure of Example l(iii) gave (a) 2-L2-(5-methyl-4-imidazolylmethylthio)ethylamino~-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydro- - -chloride m.p. 210-214.
(b) 2-~2-(2-thiazolylmethylthio)ethylamino~-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p.
187-190.
(c) 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino~-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 193-196.
(d) 2-~4-(5-methyl-4-imidazolyl)butylamino~-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p.
189-190.
(e) 2-~4-(3-methoxy-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p.
209-210.
(f) 2-[4-(3-chloro-2-pyridyl)butylamino~-5-(6-methyl-3-3-pyridylmethyl)-4-pyrimidone isolated as the free base m.p. 132-133.
(g) 2-~4-(2-pyridyl)butylamino3-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone isolated as the free base m.p. 166.5-157.5.
(h) 2-t4-~3-ethoxy-2-pyridyl)butylamino7-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone isolated as the free base m.p. 104-105.
0~3~58 :
.
EXAMPLE 28 .
(i)A mixture of ethyl formate (111 g) and 2-butanone ~
(108 g) was added dropwise to a stirred mixture of sodium _ hydride in oil (50% w/w, 72 g) and the mixture was allowed to stand overnight. Ether (800 ml) was added and the solid (101 g) was filtered off. Cyanoacetamide (69.5 g), piperidine -acetate (prepared by adding piperidine to acetic acid (7 ml) and water (18 ml) until the mixture was basic) and water (400 ml) .
were added to this solid and the mixture was heated under reflux for 2 hours and allowed to cool. The mixture was acidified with acetic acid and the solid which precipitated out was recrystallised from aqueous ethanol to give 3-cyano-5,6- ;
- dimethyl-2-hydroxypyridine (43.5 g). .
(ii) An-intimate mixture of 3-cyano-5,6-dimethyl-2-hydroxy-_ pyridine (42 g) and phosphorus pentachloride (81 g) was heated - at 140-160 for 2 hours. Phosphoryl chloride was removed by -distillation under reduced pressure and ice-water (500 g) was :~
added to the residue. The mixture was adjusted-to pH 7 with :
aqueous sodium hydroxide and extracted with ether. The ether extracts were evaporated to an oil which was crystallised _ from petroleum ether (~.p. 60-80) to give 2-chloro-3-cyano-5,6-dimethylpyridine (25.3 g) m.p. 83-87.
(iii) A mixture of 2-chloro-3-cyano-5,6-dimethylpyridine (21.5 g) .
semicarbazide hydrochloride (24.0 g), sodium acetate (42.3 g), water (225 ml) and methanol (475 ml) was hydrogenated at 50 p.s.i.
at 50 using Raney nickel catalyst (5 g). The mixture was added to water (750 ml) and was filtered. The solid uas filtered and suspended in water (130 ml) and concentrated hydro-chloric acid (70 ml) was added and the mixture was heated at 100 for 1 hour, formalin (40% w/w, 120 ml) was added and the _ mixture was heated at 100 for a ~urther ~ hour and was allowed to cool.- Sodium acetate (95 g) and water ~250 ml) were added and the mixture was extracted with ether and the extracts were washed with 5% aqueous potassium carbonate and evaporated to gi~e 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (13.24 g, ~
60%) m.p. 69-70. _ 0'~3458 (iv)A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (}6,85 g), ma~onic acid (11.45 g) piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and eva~orated to an oil. -This oil was dissolved in 2N sodium hydroxide solution and was extracted with chloroform (discarded). The aqueous phase was -acidified with hydrochloric acid and was extracted~with chloro- :
form. The chloroform extracts were washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%) m.p. 150-158. This acid was esterified usin~ ethanol and sulphuric acid to give the ethyl ester m.p. 85-88.
(v)Ethyl 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylate (32.7 g) in ethanol (500 ml) was hydrogenated at 25-30 and 50 p.s.i.
using palladium-on-charcoal catalyst (5%, 3 g). The mixture ~:
was filtered and the filtrate evaporated to an oil which was partitioned between chloroform and 2N hydrochloric acid. The aqueous phase was made basic with aqueous sodium hydroxide, extracted with chloroform and the chloroform extracts evaporated to give ethyl 3-(5,6-dimethyl-3-pyridyl)propionate (21.8 g, 80%) as an oil. .
(vi) Reaction of ethyl 3-(5,6-dimethyl-3-pyridyl) propionate .
with ethyl formate and sodium hydride in dimethoxyethane -according to the general procedure of Example 24(iii) gave 3-(5,6-dimethyl-3-pyridyl)-2-formylpropionate m.p. 148-149, 6uccessive treatment of this ester with thiourea and ~ methyl iodide according to the general procedure of Example lti)(ii) gave 5-(5,6-dimethyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone and reaction of this compound with 2-(3-bromo-2-pyridylmethylthio)ethylamine at 140 for 6 hours ~ave ¦~
2- ~-(3-bromo-2-pyridylmethylthio)ethyl~amino7-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone m p. 105-107.
-38- _ ~i) A mixture of 2-methoxy-5-cyanopyrid$ne (61.26 g), semi-carbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1300 ml) and water (400 ml) was hydrogenated at 50 p.s.i. using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 500 ml~ water (1000 ml) was added and the mixture was allowed to stand at 0 overnight. The mixture was filtered and the solid was washed with water and dissolved in 10% hydrochloric acid (1000 ml). Formaldehyde solution (36% w/v, 450 ml) was added and the mixture was warmed for 15 minutes, allowed to cool and was added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether (3 x 500 ml) and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 6-methoxypyridine-3-carboxaldehyde (31.5 g, 50%) m.p. 48-49.
(ii) A mixture of 6-methoxypyridine-3-carboxaldehyde 2.34 g), monoethyl malonate (4.51 g), pyridine (12 ml) and piperidine (6 drops) was heated under reflux for 5 hours and was evaporated to an oil. This oil was partitioned between ether and dilute aqueous ammonia. The ether layer was washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methoxy-3-pyridyl)acrylate (2.8 g, 79%) m.p. 49-52.
(iii) Ethyl 3-(6-methoxy-3-pyridyl)acrylate (32.33 g) in ethanol (160 ml) was hydrogenated at 50 p.s.i. at 40 using palladium-on-charcoal catalyst (5%, 0.2 g). The mixture was filtered and the filtrate was evaporated to give ethyl 3-(6-methoxy-3-pyridyl)propionate (32.7 g) as an oil.
~ . . . ~ .
07~58 ~iv) A mixture of ethyl 3-(6-methoxy-3-pyridyl)propionate (32.74 g) and ethyl formate (17.22 g) was added dropwise over ~
1~ hours to a stirred suspension of sodium hydride in oil r (50%, 9.38 g) in 1,2-dimethoxyethane (50 ml) cooled to -2, ¦~
allowed to stand overnight at room temperature and was poured L
on to ice. The mixture was extracted with ether (discarded), and the aqueous phase was adjusted to pH 5 with 2N sulphuric r acid. An oil was precipitated and crystallised on standing to give ethyl 2-formyl-3-(6-methoxy-3-pyridyl)propionate (25.9 g, D
70%) m.p. 91.5-94. A sample recrystallised from aqueous -ethanol had m.p. 93-94. ~-Successive treatment of this ester with thiourea and methyl iodide according to the general procedure of Example l(i)(ii) gives 5-(6-methoxy-3-pyridylmethyl)-2-methylthio-4-pyrimidone and reaction of this compound at 140 for 6 hours with (a) 2-(5-methyl-4-imidazolylmethylthio)ethylamine (b) 2-(2-thiazolylmethylthio)ethylamine .
gives (a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone trihydrochloride m.p. 205-209, - (b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone m.p. 95-97.
(i) Sodium (20.8 g) was dissolved in methanol (285 ml), a solution of 2-chloro-4-cyanopyridine (115.53 g) in methanol/-dioxan (1:1, 850 ml) was added and the mixture was boiled under reflux for 2~ hours and was allowed to cool. The mixture was filtered and the volume of the filtrate was reduced by _ evaporation to 200 ml and water (400 ml) was added. The solid which precipitated out was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%) m.p. 93-95.5, . . , ioq34s8 (ii) A mixture of 2-methoxy-4-cyanopyridine (57.2 g~, semi-carbazide hydrochloride (71.25 g~, sodium acetate (69.86 g), ethanol (1200 ml) and water (370 ml) was hydrogenated at 50 p.s.i. using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 450 ml, water (900 ml) was added and the mixture was allowed to stand at 0 overnight. The mixture was filtered and the solid was washed with water and was dissolved in 10% hydrochloric acid (950 ml). Formaldehyde solution (36% w/v, 420 ml) was added and the mixture was warmed for 30 minutes, allowed to cool and was added to a solution of sodium acetate (280 g) in water (840 ml). The mixture was extracted with ether (3 x 500 ml) and the combined extracts were successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 2-methoxypyridine-15 4-carboxaldehyde (20.53 g, 35%) m.p. 33-5. A sample recrys-tallised from petroleum ether had m.p. 33-36.
(iii) Substitution of 2-methoxypyridine-4-carboxaldehyde for 6-methoxypyridine-3-carboxaldehyde in the general procedure of Example 29(ii-iv) gave ethyl 2-formyl(2-methoxy-4-pyridyl) propionate as an oil.
Successive treatment of this ester with thiourea and methyl iodide according to the general procedure of Example 1 (i)(ii) gives 5-(2-methoxy-4-pyridylmethyl)-2-methylthio-4-pyrimidone and reaction of this compound at 140 for 6 hours with a) 2-(5-methyl-4-imidazolylmethylthio)ethylamine b) 2-(2-thiazolylmethylthio)ethylamine gives a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p.
b) 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p. 105.5-106.5.
,~ . - : ~ . ,.: . ,
Claims (29)
1. A process for the preparation of a compound of the formula:- wherein Het is 2- or 4- imidazolyl, 2- or 4- imidazolyl substituted by lower alkyl, halogen, trifluoromethyl or hydroxymethyl, 2-pyridyl, 2-pyridyl substituted by lower alkyl, lower alkoxy, halogen, amino or hydroxy, or 2-thiazolyl; Y is sulphur or methylene; Z is hydrogen or lower alkyl: W is methylene; p and q are such that their sum is 0 to 4; Het'is pyridyl, pyridyl substituted by lower alkyl or lower alkoxy, quinolyl, thienyl or thiazolyl; which comprises reacting an isocytosine of the formula:- where Z, W, p, q and Het' are as defined above and Q is lower alkylthio, benzylthio, halogen or other grouping which is conveniently displaced by an amine, with an amine of formula:-Het-CH2-Y-(CH2)2-NH2 wherein Het and Y are as defined above.
2, The process according to Claim 1 wherein Het is 2-or 4-imidazolyl, 2- or 4- imidazolyl substituted by lower alkyl or halogen, 2-pyridyl, 2-pyridyl substituted by lower alkyl, lower alkoxy, halogen, amino or hydroxy, or 2-thiazolyl,
3. The process according to Claims 1 or 2 wherein Q
is methylthio.
is methylthio.
4. The process according to Claims 1 or 2 wherein the reaction is carried out in a solvent such as pyridine.
5. A process for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone which comprises reacting 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine.
6. A process for producing 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone which comprises reacting 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone with 2-(2-thiazolylmethylthio)ethyl-amine.
7. A process for producing 2-{2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridyl-methyl)-4-pyrimidone which comprises reacting 5-(4-pyridyl-methyl)-2-methylthio-4-pyrimidone with 2-(3-bromo-2-pyridyl-methylthio)ethylamine.
8. A process for producing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thienylmethyl)-4-pyrimidone which comprises reacting 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)ethylamine.
9. A process for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone which comprises reacting 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone wlth 2-(5-methyl-4-imidazolylmethylthio)-ethylamine.
10. A process for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone which comprises reacting (5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine.
11. A process for preparing 2-[2-(3-bromo-2-pyridylmethylthio)-ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone which comprises reacting 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone with 2-(3-bromo-2-pyridylmethylthio)-ethylamine.
12. A process for preparing 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(2-thiazolemethyl)-4-pyrimidone which comprises reacting 5-[2-thiazolylmethyl)-2-methylthio-4-pyrimidone with 2-(5-methyl-4-imidazolylmethylthio)-ethylamine.
13. A process for preparing 2-[2-(2-thiazolylmethylthio)-ethylamino]-5-(3-pyridyl-methyl)-4-pyrimidone-which comprises reacting 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone with 2-(2-thiazolyl-methylthio)-ethylamine.
14. A process for preparing 2-[2-(3-bromo-2-pyridylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone which comprises reacting 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone with 2-(3-bromo-2-pyridylmethylthio)ethylamine.
15. A compound of the formula:
wherein Het is 2- or 4- imidazolyl, 2- or 4-imidazolyl substituted by lower alkyl, halogen, trifluoromethyl or hydroxymethyl, 2-pyridyl, 2-pyridyl substituted by lower alkyl, lower alkoxy, halogen, amino or hydroxy, or 2-thiazolyl; Y is sulphur or methylene; Z is hydrogen or lower alkyl; W is methylene; p and q are such that their sum is 0 to 4; Het' is pyridyl, pyridyl substituted by lower alkyl or lower alkoxy, quinolyl, thienyl or thiazolyl; or the pharmaceutioally acceptable salts thereof whenever prepared or produced by the process of Claim 1 or by any obvious chemical equivalent thereof.
wherein Het is 2- or 4- imidazolyl, 2- or 4-imidazolyl substituted by lower alkyl, halogen, trifluoromethyl or hydroxymethyl, 2-pyridyl, 2-pyridyl substituted by lower alkyl, lower alkoxy, halogen, amino or hydroxy, or 2-thiazolyl; Y is sulphur or methylene; Z is hydrogen or lower alkyl; W is methylene; p and q are such that their sum is 0 to 4; Het' is pyridyl, pyridyl substituted by lower alkyl or lower alkoxy, quinolyl, thienyl or thiazolyl; or the pharmaceutioally acceptable salts thereof whenever prepared or produced by the process of Claim 1 or by any obvious chemical equivalent thereof.
16. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 5 or any obvious chemical equivalent thereof.
17. 2-[2-(2-Thiazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 6 or any obvious chemical equivalent tbereof.
18. 2-[2-(3-Bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 7 or any obvious chemical equivalent thereof.
19. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thienylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 8 or any obvious chemical equivalent thereof.
20. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 9 or any obvious chemical equivalent thereof.
21. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 10 or any obvious chemical equivalent thereof.
22. 2-[2-(3-Bromo-2-pyridylmethylthio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 11 or any obvious chemical equivalent thereof.
23. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-thiazolylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 12 or by any obvious chemical equivalent thereof.
24. 2-[2-(2-Thiazolylmethylthio)ethylamino]-5-(3-pyridyl-methyl)-4-pyrimidone whenever prepared or produced by the process of Claim 13 or any obvious chemical equivalent thereof.
25. 2-[2-(3-Bromo-2-pyridylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 14 or any obvious chemical equivalent thereof.
Claims Supported By The Supplementary Disclosure
Claims Supported By The Supplementary Disclosure
26. The process for producing 2-[4-(5-methyl-4-imidazolyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone which comprises reacting 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone with 4-(5-methyl-4-imidazolyl)butyl-amine.
27. The process for producing 2-[4-(3-methoxy-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone which comprises reacting 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone with 4-(3-methoxy-2-pyridyl)butyl-amine.
28. 2-[4-(5-Methyl-4-imidazolyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone whenever prepared or produced by the process of Claim 26 or any obvious chemical equivalent thereof.
29. 2-[4-(3-Methoxy-2-pyridyl)butylamino]-5-(3-pyridyl-methyl)-4-pyrinidone whenever prepared or produced by the process of Claim 27 or any obvious chemical equivalent thereof.
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| BE (1) | BE849810A (en) |
| BG (1) | BG29722A3 (en) |
| CA (1) | CA1073458A (en) |
| CH (1) | CH631981A5 (en) |
| CS (1) | CS203995B2 (en) |
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| 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 |
| IL56265A (en) * | 1977-12-28 | 1982-08-31 | Om Lab Sa | Process for preparing imidazolyl methylthio guanidine derivatives and a novel intermediate therefor |
| IN151188B (en) * | 1978-02-13 | 1983-03-05 | Smith Kline French Lab | |
| US4539207A (en) * | 1978-02-13 | 1985-09-03 | Smith Kline & French Laboratories Limited | Pyrimidine compounds |
| AU527202B2 (en) * | 1978-04-11 | 1983-02-24 | Smith Kline & French Laboratories Limited | 2-aminopyrimidones |
| ZA792607B (en) * | 1978-05-30 | 1980-07-30 | Smith Kline French Lab | Nitro compounds |
| ZA793392B (en) * | 1978-07-15 | 1980-08-27 | Smith Kline French Lab | Isoureas and isothioureas |
| US4374836A (en) | 1978-10-16 | 1983-02-22 | Imperial Chemical Industries Ltd. | Antisecretory heterocyclic derivatives, process for their manufacture and pharmaceutical compositions containing them |
| US4309435A (en) | 1978-10-16 | 1982-01-05 | Imperial Chemical Industries Ltd. | Antisecretory guanidine derivatives 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 |
| US4255428A (en) | 1979-03-24 | 1981-03-10 | Smith Kline & French Laboratories Limited | 5-(Hydroxypyridylalkyl)-4-pyrimidones |
| JPS55133379A (en) * | 1979-04-05 | 1980-10-17 | Smith Kline French Lab | Pyrimidone compound |
| EP0017680B1 (en) * | 1979-04-11 | 1982-04-21 | Smith Kline & French Laboratories Limited | Pyrimidone derivatives, process for preparing them and pharmaceutical compositions containing them |
| 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 |
| US6417366B2 (en) * | 1999-06-24 | 2002-07-09 | Abbott Laboratories | Preparation of quinoline-substituted carbonate and carbamate derivatives |
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| IN146736B (en) * | 1975-10-02 | 1979-08-25 | Smith Kline French Lab |
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