Pyrazolopyridines

Details Pyrazolopyridines Pyrazolopyridines

2001-08-30

2002-12-24

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S121000

Reexamination Certificate

active

06498166

ABSTRACT:

CROSS-REFERENCES TO RELATED APPLICATIONS
This application is a Rule 371 Application of PCT Application No. EP99/10263, filed Dec. 22, 1999, which claims priority to GB Application Serial No. 9904506.4, filed Feb. 27, 1999 and GB Application Serial No. 9920904.1, filed Sep. 3, 1999.
This invention relates to pyrazolo[1,5-a]pyridine 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 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 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
0
and R
1
are independently selected from H, halogen, C
1-6
alkyl, C
1-6
alkoxy, or C
1-6
alkoxy substituted by one or more fluorine atoms;
R
2
is halogen, CN, CONR
4
R
5
, CO
2
H, CO
2
C
1-6
alkyl, or NHSO
2
R
4
;
R
3
is C
1-6
alkyl or NH
2
; and
R
4
and R
5
are independently selected from H, C
1-6
alkyl, phenyl, phenyl substituted by one or more atoms or groups (selected from halogen, C
1-6
alkyl, C
1-6
alkoxy, or C
1-6
alkoxy substituted by one or more fluorine atoms), or together with the nitrogen atom to which they are attached form a saturated 4 to 8 membered ring.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester, 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. Examples of such benzenesulphonamide derivatives include:
N-alkylcarbonylbenzenesulphonamides;
N-alkoxyalkylcarbonylbenzenesulphonamides;
N-alkoxycarbonylbenzenesulphonamides;
N-arylcarbonylbenzenesulphonamides;
N-alkoxycarbonylalkylcarbonylbenzenesulphonamides;
N-carboxylalkylcarbonylbenzenesulphonamides;
N-alkylcarbonyloxyalkylcarbonylbenzenesulphonamides;
N-alkylaminoalkylcarbonylbenzenesulphonamides; and
N-dialkylaminoalkylcarbonylbenzenesulphonamides.
With reference to such benzenesulphonamide derivatives, and by way of example only, alkyl may be C
1-6
alkyl or C
1-6
alkyl substituted by one or more halogen (e.g. chlorine) atoms; alkoxy may be C
1-6
alkoxy or C
1-6
alkoxy substituted by one or more halogen (e.g. chlorine) atoms; and aryl may be phenyl or substituted phenyl.
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 of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
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.
In one aspect of the invention R
0
is at the 3- or 4-position of the phenyl ring, as defined in formula (I).
In another aspect of the invention R
2
is at the 6-position of the pyrazolopyridine ring, as defined in formula (I).
In another aspect of the invention R
0
and R
1
are independently H, halogen or C
1-4
alkoxy.
In another aspect of the invention R
2
is CN or halogen.
In another aspect of the invention R
3
is C
1-3
alkyl or NH
2
.
Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R
0
and R
1
are independently H, halogen or C
1-4
alkoxy; R
2
is CN or halogen; and R
3
is C
1-3
alkyl or NH
2
.
Within group A, there is provided a further group of compounds (group A1) wherein: R
0
is F; R
1
is H; R
2
is CN or Br; and R
3
is methyl or NH
2
.
Within group A, there is provided a further group of compounds (group A2) wherein: R
0
is F; R
1
is H; R
2
is CN, Br or Cl; and R
3
is methyl or NH
2
.
Within groups A, A1 and A2 there are provided further groups of compounds wherein R
0
is at the 3- or 4-position (preferably the 4-position) of the phenyl ring and R
2
is at the 6-position of the pyrazolopyridine ring, as defined in formula (I).
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 the invention provides the compounds:
4-[6-cyano-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide;
2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]pyrazolo[1,5-a]pyridine-6-carbonitrile;
4-[6-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide;
6-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]pyrazolo[1,5-a]pyridine;
and pharmaceutically acceptable derivatives thereof.
In another aspect the invention provides the compounds:
4-[6-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide;
4-[6-chloro-2-(4-ethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide;
4-[6-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide;
4-[6-chloro-2-phenyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide;
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 COX-2 inhibitory activity, the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment of the pain (both chronic and acute), fever and inflammation of a variety of conditions and diseases mediated by selective inhibition of COX-2. Such conditions and diseases are well known in the art and include rheumatic fever; symptoms ass

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