Pyrimidine derivatives as selective inhibitors of COX-2

Details Pyrimidine derivatives as selective inhibitors of COX-2 Pyrimidine derivatives as selective inhibitors of COX-2

2002-07-31

2004-08-24

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S330000, C544S331000, C544S332000

Reexamination Certificate

active

06780870

ABSTRACT:

This invention relates to pyrimidine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
The enzyme cyclooxygenase (COX) has recently been discovered to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. Prostaglandins generated by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is largely responsible for the important physiological functions such as maintenance of gastrointestinal integrity and renal blood flow. In contrast the inducible form, COX-2, is believed to be largely responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inflammatory agents, hormones, growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1. We have now found a novel group of compounds which are both potent and selective inhibitors of COX-2.
DETAILED DESCRIPTION OF THE INVENTION
The invention thus provides the compounds of formula (I)
and pharmaceutically acceptable derivatives thereof, in which:
R
1
and R
2
are independently selected from H, or C
1-6
alkyl;
R
3
is C
1-6
alkyl or NH
2
;
R
4
is H or C
1-6
alkyl;
A is a 5- or 6-membered aryl, or a 5- or 6-membered aryl substituted by one or more R
5
;
R
5
is halogen, C
1-6
alkyl, C
1-6
alkyl substituted by one or more F, C
1-6
alkoxy, C
1-6
alkoxy substitued by one or more F, SO
2
NH
2
or SO
2
C
1-6
alkyl; and
n is 1 to 4.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds. Of particular interest as such derivatives are compounds modified at the benzenesulphonamide function to provide metabolically labile benzenesulphonamides. Acylated benzenesulphonamide derivatives are of especial interest.
It will be appreciated by those skilled in the art that the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position.
It will be further appreciated by those skilled in the art that benzenesulphonamide derivatives of formula (I) may be useful as intermediates in the preparation of compounds of formula (I), or as pharmaceutically acceptable derivatives of formula (I), or both.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
Suitable pharmaceutically acceptable salts include: acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates; and alkali metal salts, formed from addition of alkali metal bases, such as alkali metal hydroxides, e.g. sodium salts.
The term halogen is used to represent fluorine, chlorine, bromine or iodine.
The term ‘alkyl’ as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
The term 5-membered aryl means an aryl selected from the following:
The term 6-membered aryl means aryl selected from:
It will be appreciated by those skilled in the art that when R
1
and R
2
in formula (I) are different the corresponding compounds contain at least one chiral centre, by virtue of the asymmetric carbon atom defined thereby, and that such compounds exist in the form of a pair of optical isomers (i.e. enantiomers).
It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
In one aspect of the invention R
1
and R
2
are independently selected from H or methyl. In another aspect R
1
and R
2
are both H.
In another aspect of the invention R
3
is C
1-6
alkyl, such as C
1-3
alkyl (e.g. methyl).
In another aspect of the invention, R
4
is H or C
1-3
alkyl, such as methyl.
In another aspect of the invention A is selected from
and A is unsubstituted or substituted by one or two R
5
(e.g. one R
5
).
In another aspect of the invention A is selected from
In another aspect of the invention R
5
is halogen (e.g. F), C
1-3
alkyl (e.g. methyl), C
1-3
alkyl substituted by one to three F (e.g. CF
3
), C
1-3
alkoxy (e.g. methoxy), C
1-3
alkoxy substituted by one to three F (e.g. OCHF
2
or OCF
3
), or SONH
2
.
In another aspect of the invention R
5
is halogen (e.g. F) or C
1-6
alkoxy, such as C
1-3
alkoxy (e.g. methoxy).
In another aspect of the invention n is 1 to 3 (e.g. 1).
It is to be understood that the invention covers all combinations of particular aspects of the invention as described hereinabove.
Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R
1
and R
2
are independently selected from H or methyl; R
3
is C
1-6
alkyl, such as C
1-3
alkyl (e.g. methyl); R
4
is H or C
1-3
alkyl, such as methyl; A is selected from
and is unsubstituted or substituted by one or two R
5
(e.g. one R
5
); R
5
is halogen (e.g. F), C
1-3
alkyl (e.g. methyl), C
1-3
alkyl substituted by one to three F (e.g. CF
3
), C
1-3
alkoxy (e.g. methoxy), C
1-3
alkoxy substituted by one to three F (e.g. OCHF
2
or OCF
3
), or SONH
2
; and n is 1 to 3 (e.g. 1).
Within the invention there is provided another group of compounds of formula (I) (group B) wherein: R
1
and R
2
are independently selected from H or methyl; R
3
is C
1-6
alkyl, such as C
1-3
alkyl (e.g. methyl); R
4
is H or C
1-3
alkyl, such as methyl; A is selected from
R
5
is halogen (e.g. F), C
1-3
alkyl (e.g. methyl), C
1-3
alkyl substituted by one to three F (e.g. CF
3
), C
1-3
alkoxy (e.g. methoxy), C
1-3
alkoxy substituted by one to three F (e.g. OCHF
2
or OCF
3
), or SONH
2
; and n is 1 to 3 (e.g. 1).
Within the invention there is provided another group of compounds of formula (I) (group C) wherein: R
1
and R
2
are independently selected from H or methyl; R
3
is C
1-6
alkyl, such as C
1-3
alkyl (e.g. methyl); R
4
is H or C
1-3
alkyl, such as methyl; A is selected from
R
5
is halogen (e.g. F) or C
1-6
alkoxy, such as C
1-3
alkoxy (e.g. methoxy); and n is 1 to 3 (e.g. 1).
In another aspect of the invention, R
1
and R
2
in the compounds of groups A, B and C are both H.
In another aspect the invention provides the following compounds:
4-[4-(methylsulfonyl)phenyl]-N-(pyridin-4-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;
4-[4-(methylsulfonyl)phenyl]-N-(pyridin-3-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;
4-[4-(methylsulfonyl)phenyl]-N-(pyridin-2-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;
4-[4-(methylsulfonyl)phenyl]-N-(phenylmethyl)-6-(trifluoromethyl)-2-pyrimidinamine;
N-(4-methoxybenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine;
N-(4-fluorobenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine;
and pharmaceutically acceptable derivatives thereof.
Compounds of the invention are potent and selective inhibitors of COX-2. This activity is illustrated by their ability to selectively inhibit COX-2 over COX-1.
In view of their selective

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