Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-13
2002-09-17
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S236000
Reexamination Certificate
active
06451794
ABSTRACT:
This application is a 371 application of PTC/EP98/05558, filed Sep. 3, 1998.
This invention relates to pyrazolo[1,5-b]pyridazine 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.
The invention thus provides the compounds of formula (I)
and pharmaceutically acceptable derivatives thereof in which:
R
0
is halogen, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkoxy substituted by one or more fluorine atoms, or O(CH
2
)
n
NR
4
R
5
;
R
1
and R
2
are independently selected from H, C
1-6
alkyl, C
1-6
alkyl substituted by one or more fluorine atoms, C
1-6
alkoxy, C
1-6
hydroxyalkyl, SC
1-6
alkyl, C(O)H, C(O)C
1-6
alkyl, C
1-6
alkylsulphonyl, C
1-6
alkoxy substituted by one or more fluorine atoms, O(CH
2
)
n
CO
2
C
1-6
alkyl, O(CH
2
)
n
SC
1-6
alkyl, (CH
2
)
n
NR
4
R
5
, (CH
2
)
n
SC
1-6
alkyl or C(O)NR
4
R
5
; with the proviso that when R
0
is at the 4-position and is halogen, at least one of R
1
and R
2
is C
1-6
alkylsulphonyl, C
1-6
alkoxy substituted by one or more fluorine atoms, O(CH
2
)
n
CO
2
C
1-6
alkyl, O(CH
2
)
n
SC
1-6
alkyl, (CH
2
)
n
NR
4
R
5
or (CH
2
)
n
SC
1-6
alkyl, C(O)NR
4
R
5
;
R
3
is C
1-6
alkyl or NH
2
;
R
4
and R
5
are independently selected from H, or C
1-6
alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring; and
n is 1-4.
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 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.
Preferably, R
0
is at the 3- or 4-position of the phenyl ring, as defined in formula (I).
Preferably, R
1
is at the 6-position of the pyridazine ring, as defined in formula (I).
Preferably, R
0
is F, C
1-3
alkyl, C
1-3
alkoxy, C
1-3
alkoxy substituted by one or more fluorine atoms, or O(CH
2
)
1-3
NR
4
R
5
. More preferably R
0
is F, C
1-3
alkoxy or C
1-3
alkoxy substituted by one or more fluorine atoms.
Preferably, R
1
is C
1-4
alkylsulphonyl, C
1-4
alkoxy substituted by one or more fluorine atoms, O(CH
2
)
1-3
CO
2
C
1-4
alkyl, O(CH
2
)
1-3
SC
1-4
alkyl, (CH
2
)
1-3
NR
4
R
5
, (CH
2
)
1-3
SC
1-4
alkyl or C(O)NR
4
R
5
or, when R
0
is C
1-6
alkyl, C
1-6
alkoxy, O(CH
2
)
n
NR
4
R
5
, may also be H. More preferably R
1
is C
1-4
alkylsulphonyl, C
1-4
alkoxy substituted by one or more fluorine atoms or, when R
0
is C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkoxy substituted by one or more fluorine atoms, or O(CH
2
)
n
NR
4
R
5
, may also be H.
Preferably, R
2
is H.
Preferably, R
3
is methyl or NH
2
.
Preferably R
4
and R
5
are independently C
1-3
alkyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring.
Preferably, n is 1-3, more preferably 1 or 2.
Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R
0
is F, C
1-3
alkyl, C
1-3
alkoxy, C
1-3
alkoxy substituted by one or more fluorine atoms, or O(CH
2
)
n
NR
4
R
5
; R
1
is C
1-6
alkylsulphonyl, C
1-4
alkoxy substituted by one or more fluorine atoms, O(CH
2
)
n
CO
2
C
1-4
alkyl, O(CH
2
)
n
SC
1-4
alkyl, (CH
2
)
n
NR
4
R
5
, (CH
2
)
n
SC
1-4
alkyl or C(O)NR
4
R
5
or, when R
0
is C
1-3
alkyl, C
1-3
alkoxy, C
1-3
alkoxy substituted by one or more fluorine atoms, or O(CH
2
)
n
NR
4
R
5
, may also be H; R
2
is H; R
3
is methyl or NH
2
; R
4
and R
5
are independently C
1-3
alkyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring; and n is 1-3.
Within group A, there is provided another group of compounds (group A1) wherein R
0
is F, methyl, C
1-2
alkoxy, OCHF
2
; or O(CH
2
)
n
NR
4
R
5
; R
1
is methylsulphonyl, OCHF
2
, O(CH
2
)
n
CO
2
C
1-4
alkyl, O(CH
2
)
n
SCH
3
, (CH
2
)
n
NR
4
R
5
, (CH
2
)
n
SCH
3
or C(O)NR
4
R
5
or, when R
0
is methyl, C
1-2
alkoxy, OCHF
2
, or O(CH
2
)
n
N(CH
3
)
2
, may also be H; R
2
is H; R
3
is methyl or NH
2
; R
4
and R
5
are both methyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring; and n is 1-2.
Within group A, there is provided a further group of compounds (group A2) wherein R
0
is F, C
1-3
alkoxy or C
1-3
alkoxy substituted by one or more fluorine atoms; R
1
is C
1-4
alkylsulphonyl, C
1-4
alkoxy substituted by one or more fluorine atoms or, when R
0
C
1-3
alkoxy or C
1-3
alkoxy substituted by one or more fluorine atoms, may also be H; R
2
is H; and R
3
is methyl or NH
2
.
Within groups A, A1 and A2, R
0
is preferably at the 3- or 4-position of the phenyl ring and R
2
is preferably at the 6-position of the pyridazine ring.
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).
Particularly preferred compounds of the invention are:
3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine;
6-difluoromethoxy-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
2-(4-fluoro-phenyl)-6-methanesulfonyl-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
2-(4-difluoromethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
4-[2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazin-3-yl]-benzenesulfonamide;
6-difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
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 condit
Beswick Paul John
Campbell Ian Baxter
Mathews Neil
Naylor Alan
Morgan Lorie Ann
Raymond Richard L.
Smithkline Beecham Corporation
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