Process for the preparation of pyrazolopyridine derivatives

Details Process for the preparation of pyrazolopyridine derivatives Process for the preparation of pyrazolopyridine derivatives

2002-06-14

2004-10-12

Bernhardt, Emily (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S236000, C568S031000

Reexamination Certificate

active

06803463

ABSTRACT:

CROSS-REFERENCES TO RELATED APPLICATIONS
This application is a Rule 371 Application of PCT Application No. EP00/13001, filed Dec. 20, 2000, which claims priority to GB Application Serial No. 9930358.8, filed Dec. 22, 1999.
This invention relates to a process for the preparation of pyrazolopyridazine derivatives and to intermediates for use therein.
Pyrazolopyridazine derivatives 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;
are disclosed in international patent application publication no. WO99/12930, incorporated herein by reference.
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.
The compounds of formula (I) are potent and selective inhibitors of COX-2. They 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.
Several processes for the preparation of the compounds of formula (I) are disclosed in WO99/12930.
The present invention provides a particularly advantageous process of preparing compounds of formula (I), not hitherto specifically disclosed, which comprises oxidation of a corresponding dihydro-pyrazolopyridazine.
Accordingly, in a first aspect, the instant invention provides a process for the preparation of a compound of formula (I) which comprises oxidising under conventional conditions a compound of formula (II)
wherein R
0
to R
3
are as defined for formula (I).
Conveniently the oxidation is effected in a solvent, such as a halogenated alkane (e.g. dichloromethane); at ambient to elevated temperature, such as from 20° C. to reflux (e.g. at about 25° C.); and in the presence of a catalyst, such as activated carbon, or a transition metal catalyst (e.g. palladium on activated carbon). Alternatively, the catalyst may be replaced by an oxidising agent, such as a source of oxygen (e.g. air), or iodine.
The process according to the invention is surprisingly advantageous, being easy to carry out and proceeding in good yield.
As will be appreciated by those skilled in the art, the preparation of pharmaceutically acceptable derivatives of formula (I) may conveniently be effected by a process which comprises oxidising under conventional conditions a corresponding derivative of formula (II).
In another aspect the invention provides a process for preparing a compound of formula (I) where R
0
is at the 3- or 4-position of the phenyl ring, as defined in formula (I).
In another aspect the invention provides a process for preparing a compound of formula (I) where R
1
is at the 6-position of the pyridazine ring, as defined in formula (I).
In another aspect the invention provides a process for preparing a compound of formula (I) where 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
; or, more preferably, R
0
is F, C
1-3
alkoxy or C
1-3
alkoxy substituted by one or more fluorine atoms.
In another aspect the invention provides a process for preparing a compound of formula (I) where 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; or, 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.
In another aspect the invention provides a process for preparing a compound of formula (I) where R
2
is H.
In another aspect the invention provides a process for preparing a compound of formula (I) where R
3
is methyl or NH
2
.
In another aspect the invention provides a process for preparing a compound of formula (I) where 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.
In another aspect the invention provides a process for preparing a compound of formula (I) where n is 1-3, more preferably 1 or 2.
In another aspect the invention provides a process for preparing 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
1-4
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.
In another aspect the invention provides a process for preparing 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.
In another aspect the invention provides a process for preparing a compound of formula (I) within group (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
.
In another aspect the invention provides a process for preparing

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