Title: Pyrimidine-2-sulphides and their S-oxides for use in medicine and methods of use therefor, pharmaceutical compositions containing them, processes for their preparation and per se novel sulphides and S-oxides

We claim:

1. A pharmaceutical composition for combating abnormal cell proliferation comprising as active ingredient an effective amount of a compound of the formula: ##STR12## wherein X represents a halogen atom; n is 0, 1 or 2; R¹ and R², which may be the same or different, each represents a hydrogen atom or a C₁-4 alkyl group, an amido group, a mono- or di-C₁-4 alkylamido group, a carboxyl group or a group of the formula --COOR^a in which R^a represents a C₁-8 alkyl, C₂-8 alkenyl or C₂-8 alkynyl group, a C₃-8 cycloalkyl or C₃-8 cycloalkenyl group, an aralkyl, aralkenyl or aralkynyl group with up to 4 carbon atoms in the aliphatic moiety, which moiety may be saturated or unsaturated, and up to 10 carbon atoms in the aryl moiety or a C₆-10 aryl group, the aryl moiety or group being optionally substituted by a C₁-4 alkyl group; and

R³ represents a C₁-8 alkyl, C₂-8 alkenyl or C₂-8 alkynyl group, a C₃-8 cycloalkyl group, a C₃-8 cycloalkenyl group, the group Het, wherein Het is a 3-7 membered heterocyclic ring having one or two heteroatoms selected from oxygen, nitrogen or sulphur and optionally carrying one or more C₁-4 alkyl or C₆-10 aryl groups; a Het substituted C₁-8 alkyl, C₂-8 alkenyl or C₂-8 alkynyl group, an aralkyl, aralkenyl or aralkynyl group with up to 4 carbon atoms in the aliphatic moiety which moiety may be saturated or unsaturated and up to 10 carbon atoms in the aryl moiety or a C₆-10 aryl group, the aryl moiety or group being optionally substituted by a C₁-4 alkyl group, said moieties or groups being optionally substituted by one or more substituents selected from halogen atoms and oxo, nitro, hydroxy, mercapto, Het as herein defined, --OR^b, --COOR^b, --SR^b, R^b SO--, R^b SO₂ --, wherein R^b is as defined for R^a or Het and is optionally substituted by one or more substituents selected from halogen, oxo, amino, hydroxy, mercapto, Het as herein defined, --OR^a, --COOR^a, --SR^a, R^a SO--, or R^a SO₂ --; C₁-8 alkanoylamino, di(C₁-8 alkyl)phosphonate and amino groups of the formula ##STR13## in which R^c and R^d, which may be the same or different, each represents a hydrogen atom or a C₁-4 alkyl, C₆-10 aralkyl or C₆-10 aryl group, the aryl moiety or group being optionally substituted by a C₁-4 alkyl group or R^c and R^d together with the nitrogen atom therebetween represents a perhydroazocinyl group; with the proviso that R³ is other than a 1-alkyl-5-nitro-imidazolyl-2-alkyl grop when n is 0 or, where an acidic or basic group is present, a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient.

2. The composition of claim 1, wherein R₃ represents a group Het', wherein Het' is a 3-7 membered heterocyclic ring having one or two heteroatoms selected from oxygen, nitrogen or sulphur, optionally carrying one or two substituents selected from halogen atoms, oxo or nitro groups; a C₁-4 alkyl group optionally carrying halogen, Het', Het'O--, C₆-10 aryloxy, halosubstituted C₆-10 aryloxy or di(C₁-4 alkyl) phosphonate; a C₂-4 alkenyl group optionally carrying oxo, Het' or C₆-10 aryl; a C₆-10 aryl group optionally carrying a C₁-4 alkyl substituent; or an aralkyl group with up to four carbon atoms in the alkyl moiety and up to ten carbon atoms in the aryl moiety.

3. The composition of claim 1, wherein R₃ is a C₁-4 alkyl group optionally carrying halogen, a C₂-4 alkenyl group optionally carrying oxo or phenyl, a phenyl group optionally carrying a C₁-4 alkyl group, a benzyl group or a methyl group carrying Het", -O-Het" or phenoxy optionally substituted by chlorine; wherein Het" is a 5- or 6-membered heterocyclic ring having one or two hetero atoms selected from oxygen, nitrogen or sulphur optionally carrying one or two substituents selected from chlorine atoms or oxo groups.

4. The composition of claim 1, wherein R₃ is a C₁-4 alkyl group optionally carrying iodine or chlorine, a C₂-4 alkenyl group substituted by an oxo or phenyl group, a phenyl group, tolyl group, a benzyl group or a methyl group carrying Het" or --O--Het", wherein Het" is a 5- or 6-membered heterocyclic ring having one or two hetero atoms selected from oxygen, nitrogen or sulphur optionally carrying one or two substituents selected from chlorine atoms or oxo groups.

5. The composition of claim 2, wherein R¹ and R² are the same or different and are hydrogen or methyl and n is 2.

6. The composition of claim 3, wherein R¹ and R² are the same or different and are hydrogen or methyl and n is 2.

7. The composition of claim 4, wherein R¹ and R² are the same or different and are hydrogen or methyl and n is 2.

8. A composition as claimed in claim 1 which comprises as active ingredient a compound of formula I wherein R¹ and R² each represent a hydrogen atom.

9. A composition as claimed in claim 1 which comprises as active ingredient a compound of formula I wherein n is 2.

10. A composition as claimed in claim 1 which comprises as active ingredient:

2-methylsulfonyl-5-chloropyrimidine,

2-(chloromethyl)sulfonyl-5-chloropyrimidine,

2-styrylsulfonyl-5-chloropyrimidine,

2-benzylsulfonyl-5-chloropyrimidine,

2-(3-Oxobuten-1-yl)sulfonyl-5-chloropyrimidine,

2-(iodomethyl)sulfonyl-5-chloropyrimidine,

2-benzylsulfonyl-5-bromopyrimidine,

2-(5-chloropyrimidine-2-oxymethyl)sulfonyl-5-chloropyrimidine or

2-benzylsulfinyl-5-chloropyrimidine.

11. A composition as claimed in claim 1 wherein R^a is C₁-4 alkyl.

12. A composition as claimed in claim 1 wherein R³ is methyl, chloromethyl, iodomethyl, acetyl substituted methyl, ethyl, or vinyl; phenyl, thienyl or a methyl group substituted with a 5-halopyrimidin-2-oxy group and R¹ and R² are hydrogen.

13. A compound which is:

2-(chloromethyl)sulfonyl-5-chloropyrimidine,

2-(3-oxobuten-1-yl)sulfonyl-5-chloropyrimidine,

3-(iodomethyl)sulfonyl-5-chloropyrimidine or

2-(5-chloropyrimidine-2-oxymethyl)sulfonyl-5-chloropyrimidine.

Other info:


Inventors: Benneche, Tore (Oslo, NO)
Gacek, Mikkel J. (Oslo, NO)
Undheim, Kjell (Oslo, NO)

Application Number: 06/223760
Filing Date: 1981-01-09
Publication_date: 1983-12-27
Assignee: NYEGAARD & CO AS (NO)

Primary Class(es): 514/274 514/252.140, 514/885, 514/210.200, 514/212.080, 544/3
Other Classes: C07C233/07; C07D239/38; C07D239/40; C07F9/6512; C07H17/02; C07C233/00; C07D239/00; C07F9/00; C07H17/00; C07D239/38; A61K31/505
US Patent Ref:

2876224	March, 1959	Grant et al.	544/316	Basic esters of substituted pyrimidine-4-carboxylic acids and their preparation
3112316	November, 1963	Westphal et al.	544/317
4248618	February, 1981	Serban et al.	544/318	Derivatives of (pyrimidyloxy)phenoxy-alkanecarboxylic acid and herbicidal compositions thereof

Other Refs: EP0001187EP0015124DE2455582DE2820032GB1561290

March, 1979	2-phenoxy-pyrimidines and their use as pesticides.
September, 1980	PARASITICIDAL HETEROCYCLIC ETHER DERIVATIVES, PROCESSES FOR THE MANUFACTURE THEREOF AND COMPOSITIONS
May, 1976
November, 1978
February, 1980

Other References: Budesinsky et al., Coll. Czech. Chem. Commun., vol. 30, pp. 3895-3901, (1965).
Budesinsky et al., Coll. Czech. Chem. Commun., vol. 37, pp. 1721-1733, (1972).
Brown et al., J. Chem. Soc., 1971, pp. 250-256.
Krchnak et al., Coll. Czech. Chem. Commun., vol. 40, pp. 1384-1389, (1975).

Primary Examiner: Lee, Mary C.
Assistant Examiner:
Attorney: Bacon & Thomas