JP3167700B1 - 2,3-Diaryl-pyrazolo [1,5-B] pyridazine derivatives, their preparation and their use as cyclooxygenase 2 (COX-2) inhibitors - Google Patents

Abstract

The present invention provides a compound of formula (I) Wherein R ⁰ is halogen, C _1-6 alkyl, C _1-6
Alkoxy, C _1-6 substituted by one or more fluorine atoms
Alkoxy, or O (CH ₂ ) _n NR ⁴ R ⁵ ;
R ¹ and ^{R 2} are independently _{H, C 1-6} alkyl, _{C 1-6} alkyl substituted with 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 alkylsulfonyl, one or more fluorine atoms substituted _{C 1-6 alkoxy, O (CH 2) n CO} 2 C
_{1-6 alkyl, O (CH 2) n SC} 1-6 alkyl,
Selected from (CH ₂ ) _n NR ⁴ R ⁵ , (CH ₂ ) _n SC _1-6 alkyl or C (O) NR ⁴ R ⁵ (provided that
When R ⁰ is in the 4-position and is halogen, at least ^one of R ¹ and R ² is C _1-6 alkylsulfonyl, C _1-6 alkoxy substituted with 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 The present invention provides a compound represented by｝ wherein n is 1 to 4 and a pharmaceutically acceptable derivative thereof, which forms a 4- to 8-membered saturated ring together with the nitrogen atom to which it is bonded. The compounds of formula (I) are effective and selective inhibitors of COX-2 and are used in the treatment of pain, fever and inflammation of various conditions and diseases.

Description

[Detailed description of the invention]

The present invention relates to pyrazolo[1,5-b]pyridazine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in medicine.

Recently, the enzyme cyclooxygenase (CO
X) was discovered to exist in two isoforms COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzymes, while COX-2 is rapidly and readily induced by several agents, including mitogens, endotoxins, hormones, cytokines and growth factors. . Prostaglandins produced by the action of COX have both physiological and pathological roles. COX-1 is generally believed to be responsible for important physiological functions such as maintenance of gastrointestinal integrity and renal blood flow. In contrast, the inducible form of COX-2 is thought to be responsible for the pathological effects of prostaglandins when rapid induction of the enzyme occurs in response to substances such as inflammatory agents, hormones, growth factors and cytokines. be done. Therefore, selective inhibitors of COX-2 would have anti-inflammatory, antipyretic and analgesic properties without the potential side effects associated with inhibition of COX-1. The inventors have now discovered a novel class of compounds that are effective and selective inhibitors of COX-2.

Accordingly, the present invention provides a compound of formula (I)

[Chemical 7] {wherein R ⁰ is halogen, C _1-6 alkyl, C _1-6
alkoxy, _C1-6 substituted with one or more fluorine atoms
^alkoxy , or O ⁽ _CH2 ) _nNR4R5 ;
R ¹ and R ² are independently H, C _1-6 alkyl, C _1-6 alkyl substituted with one or more fluorine atoms, C _1-6
alkoxy, C _1-6 hydroxyalkyl, SC _1-6
Alkyl, C(O)H, C(O) _{Ci_6alkyl} , C
_{1-6alkylsulfonyl} , _C1-6alkoxy substituted with one or more _fluorine atoms, O( _CH2 ) _nCO2C
1-6 alkyl, O( _CH2 ) _{nSC 1-6} alkyl,
( _CH2 ⁾ _{nNR4R5 ,} ⁽ _CH2 ) _nSC1-6alkyl or ^C (O) ^NR4R5 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 alkylsulfonyl, C _1-6 alkoxy substituted with one or more fluorine atoms, O(CH ₂ ) _{nCO2Ci - 6alkyl} , O
( _CH2 ⁾ _{nSC1-6alkyl ,} ( _CH2 ) _nNR4
^R5 , or ( _CH2 ) _nSC1-6alkyl , _C
(O) ^NR4R5 ); ^R3 is _C1-6alkyl ^or _NH2 ; ^R4 and ^R5 are independently selected from H, or _C1-6alkyl ; forms a 4-8 membered saturated ring with the bonding nitrogen atom; and n is 1-4} and pharmaceutically acceptable derivatives thereof.

A pharmaceutically acceptable derivative is any pharmaceutically acceptable salt, solvate or ester of a compound of formula (I), or a salt or solvate of such an ester, or a Any other compound capable of providing (directly or indirectly) a compound of formula (I) or an effective metabolite or residue thereof upon administration is meant.

For pharmaceutical uses, the salts mentioned above are physiologically acceptable salts, but other salts may find use, for example, in the preparation of the compounds of formula (I) and their physiologically acceptable salts. Let's think.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably formed with inorganic acids such as hydrochloride, bromide and salt. There are hydrides and sulfates.

Halogen is used to represent fluorine, chlorine, bromine or iodine. "Alkyl" as a group or part of a group refers to straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n
-butyl, s-butyl, or t-butyl groups.

Preferably, R ⁰ is in the 3 or 4 position of the phenyl ring as defined in formula (I). Preferably, R ¹ is in 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 with one or more fluorine atoms, or O(CH ₂ ) _1-3 N
^{R4R5 .} More preferably, R ⁰ is F, C
_1-3 alkoxy, or C _1-3 alkoxy substituted with one or more fluorine atoms.

Preferably, R ¹ is C _1-4 alkylsulfonyl, C _1-4 alkoxy substituted with one or more fluorine atoms, O(CH ₂ ) _1-3 CO ₂ C _1-4 alkyl,
O _{(CH2)1-3SC1-4alkyl , ( CH2} )
_1-3NR4R5 , ( _CH2 ⁾ _{1-3SC1-4alkyl} ^{or C} (O) ^NR4R5 , or ^R0 is _{C1-6alkyl , C1-6alkoxy} , or O(C
H ₂ ) _n NR ⁴ R ⁵ may be H;
More preferably, R ¹ is C _1-4 alkylsulfonyl, C _1-4 alkoxy substituted with one or more fluorine atoms, or R ⁰ is C _1-6 alkyl, C
_1-6 alkoxy, C substituted with one or more fluorine atoms
_1-6 alkoxy, ^or may be H when O( _CH2 ) _nNR4R5 ^.

Preferably ^R2 is H. Preferably ^R3 is methyl or _NH2 .

Preferably R ⁴ and R ⁵ are independently C
are _1-3 alkyl, or form a 5-6 membered saturated ring with the nitrogen atom to which they are attached. Preferably n is 1-3, more preferably n is 1 or 2.

In the present invention, R ⁰ is F, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkoxy substituted with one or more fluorine atoms, or O(CH ₂ ) _n NR ⁴
is R ⁵ ; R ¹ is C _1-4 alkylsulfonyl, C _1-4 alkoxy substituted with one or more fluorine atoms, O
_{( CH2} ) _{nCO2C1-4alkyl} , O _{( CH2} ) _n
SC1-4alkyl , ⁽ _CH2 ) _nNR4R5 , ( ^CH
₂ ) _n SC _1-4 alkyl or C(O)NR ⁴ R ⁵ or R ⁰ is C _1-3 alkyl, C _1-3 alkoxy, C _1-3 substituted with one or more fluorine atoms alkoxy, or may be H when O( _CH2 ) _nNR4R5 ; ^R2 is ^H ; ^R3 is methyl or _NH2 ; ^R4 and ^R5 _are independently _{C1 -3}
is alkyl or forms a 5- to 6-membered saturated ring with the nitrogen atom to which they are attached; and n is 1
There is provided one group of compounds of formula (I) (Group A), which are ~3.

In Group A, R ⁰ is F, methyl, C _1-2 alkoxy, OCHF ₂ , or O(CH ₂ ) _n NR ⁴ R
⁵ ; R ¹ is methylsulfonyl, OCHF ₂ , O
_{( CH2} ) _{nCO2C1-4alkyl} , O _{( CH2} ) _n
SCH3 , ⁽ _{CH2 ) nNR4R5} , ( _CH2 ) ^nSC
H ₃ or C(O)NR ⁴ R ⁵ or R
may be H when ⁰ is methyl, _C1-2alkoxy , _OCHF2 , or O( _CH2 ) _nN ( _CH3 ) ₂ ; ^R2 is H; ^R3 is methyl or _NH2
and R ⁴ and R ⁵ are both methyl, or form a 5-6 membered saturated ring with the nitrogen atom to which they are attached; and n is 1-2. There is provided another group of compounds (Group A1) of

In Group A, R ⁰ is F, C _1-3 alkoxy, or C _1-3 alkoxy substituted with one or more fluorine atoms; R ¹ is C _1-4 alkylsulfonyl;
C _1-4 alkoxy substituted with one or more fluorine atoms, or even H when R ⁰ is C _1-3 alkoxy or C _1-3 alkoxy substituted with one or more fluorine atoms A further group of compounds (group A2), well; ^R2 is H; ^R3 is methyl or _NH2
is provided.

In groups A, A1 and A2, R ⁰ is preferably in the 3 or 4 position of the phenyl ring and R ² is preferably in the 6 position of the pyridazine ring.

The present invention provides all isomers of the compounds of formula (I) and pharmaceutically acceptable compounds thereof, including all geometric isomers, tautomers and optical isomers and mixtures thereof (eg racemic mixtures). It is understood to include derivatives of

A particularly preferred compound of the invention is: 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.

The compounds of the invention are potent and selective inhibitors of COX-2. This activity is demonstrated by its ability to selectively inhibit COX-2 over COX-1.

In view of its COX-2 selective inhibitory activity,
The compounds of the invention are for use in human or veterinary medicine;
It is of particular interest in the treatment of pain (both chronic and acute), fever and inflammation in various conditions and diseases. Such symptoms and diseases are well known in the art and include symptoms associated with influenza or other viral infections such as rheumatic fever, the common cold; back and neck pain; headaches; toothaches; sprains and strains; inflammation; neuralgia; synovitis; arthritis, including rheumatoid arthritis;
osteoarthritis, including osteoarthritis; gout and ankylosing spondylitis; tendonitis; bursitis; skin-related diseases such as psoriasis, eczema, burns and dermatitis; Those generated from

The compounds of this invention are also useful in treating other conditions mediated by selective inhibition of COX-2.

For example, because the compounds of the present invention inhibit cellular and neoplastic transformation and metastatic cancer growth, they are believed to be useful in the treatment of certain cancer diseases, such as colon cancer.

The compounds of the present invention also prevent neuronal damage by inhibiting the generation of neuronal free radicals (and hence oxidative stress), thus preventing stroke; epilepsy and epileptic seizures (grand mal, petit mal; myoclonic). It is thought to be useful in the treatment of epilepsy and partial seizures.

The compounds of the present invention also inhibit prostanoid-induced smooth muscle contraction and are therefore believed to be useful in the treatment of dysmenorrhoea and premature labor.

The compounds of the invention inhibit inflammatory progression and
hence asthma, allergic rhinitis, and respiratory disorder syndromes; gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis; and vascular diseases, migraines, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, type I diabetes, myasthenia gravis,
multiple sclerosis, sarcoidosis, nephrotic syndrome,
It is believed to be useful in treating inflammation in diseases such as Behcet's syndrome, polymyositis, gingivitis, conjunctivitis, and myocardial ischemia.

The compounds of the present invention are also believed to be useful in the treatment of ocular diseases such as retinitis, retinopathy, uveitis, and acute injury to ocular tissue.

The compounds of the present invention are also useful in dementia, especially degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia (multiple infarcts). and dementia associated with intracranial area occupancy injuries, trauma, infections and related diseases (including HIV infection), metabolism, toxins, anoxia, vitamin deficiencies; and aging. It is believed to be useful in the treatment of associated mild intellectual disability, particularly age-related memory impairment.

According to a further aspect of the invention we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.

In accordance with another aspect of the present invention, we have discovered compounds of formula (I) or pharmaceutically acceptable compounds thereof for use in the treatment of conditions mediated by selective inhibition of COX-2. Provide derivatives.

According to a further aspect of the invention, we comprise administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof,
A method of treating a human or animal subject having a condition mediated by selective inhibition of COX-2 is provided.

In accordance with another aspect of the present invention, the inventors have discovered compounds of formula (I ) or a pharmaceutically acceptable derivative thereof. According to a further aspect of the invention, the inventors have disclosed a human with an inflammatory disease comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof. or provide a method of treating an animal subject.

[0032] Unless otherwise specified, it is to be understood that references to treatment include both treatment of commonly identified symptoms and prophylactic treatment.

Advantageously, the compounds of the present invention may be used with one or more other therapeutic agents. Examples of drugs suitable for adjunctive therapy include analgesics such as glycine antagonists, sodium channel inhibitors (e.g. lamotrigine), substrate P antagonists (e.g. _NK1 antagonists), acetaminophen, or phenacetin; matrix metalloprotease inhibitors; nitric oxide synthase (NOS) inhibitors (e.g. iNOS or nNOS inhibitors); tumor necrosis factor alpha release or action inhibitors; antibody therapy (e.g. monoclonal antibody therapy); stimulants including caffeine _;
antagonists; proton pump inhibitors such as omeprazole; antacids such as aluminum or magnesium hydroxide; antiflatulent agents such as simethicone;
decongestants such as phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levorotatory desoxyephedrine; codeine, hydrocodone, carmiphene, carbetapentane, or dextramethorphan diuretics; or sedating or non-sedating antihistamines. The present invention provides a compound of formula (I) or one of its pharmaceutically acceptable derivatives.
It is understood to encompass use in combination with other therapeutic agents as described above.

The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. provide. Such compositions may be conveniently mixed with one or more physiologically acceptable carriers or excipients and provided for normal use.

The compounds of formula (I) and their pharmaceutically acceptable derivatives may be formulated for administration by any suitable method. They may be formulated for administration eg topically or by inhalation, or more preferably for oral, transdermal or parenteral administration. The pharmaceutical composition will be in a form to provide sustained release of the compound of formula (I) and its pharmaceutically acceptable derivatives.

For oral administration, the pharmaceutical composition may be formulated with acceptable excipients such as tablets (including sublingual tablets), capsules, powders, solutions, syrups or suspensions prepared in a conventional manner. It may take the form of a liquid.

For transdermal administration, the pharmaceutical compositions may be presented in the form of transdermal patches such as transdermal iontophoretic patches.

For parenteral administration, the pharmaceutical composition may be given by injection or continuous infusion (eg intravenously, intravascularly or subcutaneously). The compositions may take such forms as suspensions, drenches or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending agents, stabilizers and/or dispersing agents. For administration by injection these may be in unit dose form or in multiple dose form preferably with an added preservative.

Alternatively, for parenteral administration, the active ingredient may be reconstituted with a suitable vehicle and powdered.

[0040] The compounds of the present invention may also be formulated as depot preparations. Such long acting formulations may be administered by injection (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (eg, as emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, eg, sparingly soluble salts.

As noted above, the compounds of the present invention may be used in combination with other therapeutic agents. Accordingly, in a further aspect the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof and an additional therapeutic agent.

Said combination may conveniently be provided for use in the form of a pharmaceutical formulation, and thus a pharmaceutical formulation comprising said combination and a pharmaceutically acceptable carrier or excipient is the subject of the present invention. Including further aspects. Each component of such formulations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent effective against the same medical condition, the dose of each compound is the same as when that compound is used alone. different. Appropriate doses will be readily appreciated by those skilled in the art.

Proposed daily doses of the compounds of formula (I) for human treatment range from 0.05 mg/kg to 100 mg/kg.
0.01 mg/kg to 500 mg/kg, such as 0.1 mg/kg to 50 mg/kg, may conveniently be administered in 1 to 4 doses. The precise dosage employed will depend on the age and medical condition of the recipient and route of administration. Thus, for systemic administration, for example 0.25 mg/k
A daily dose of g to 10 mg/kg would be suitable.

The compounds of formula (I) and their pharmaceutically acceptable derivatives may be prepared by any method known in the art for the preparation of compounds of analogous structure.

Suitable methods for preparing compounds of formula (I) and their pharmaceutically acceptable derivatives are described below.
In the formulas below, R ⁰ -R ⁵ and n are as defined in formula (I) above unless otherwise specified; Hal is B
is halogen such as r or I; X ^- is a counterion such as I ^- ; alkyl is as defined above.

Thus, according to the first step (A), the compound of formula (I) is converted to the formula (II)

[Chemical 8] A compound of or a protected derivative thereof of formula (II
I)

[Chemical 3] with a boronic acid or a suitable derivative thereof in the presence of a suitable transition metal catalyst. Suitable derivatives of formula (III) include R.
Miyaura et al., J. Org. Chem., 1995, 60, 7508-7510
and boronate esters such as those described in . Conveniently, the reaction is carried out in a solvent such as an ether (eg 1,2 dimethoxyethane) in the presence of a base such as an inorganic base (eg sodium carbonate) with a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0). is done using

According to another step (B), formula (I)
wherein R ³ is C _1-6 alkyl is a compound of formula (IV)

[Chemical 9] or a protected derivative thereof under normal conditions. Conveniently, this oxidation is carried out with potassium peroxomonosulfate (Oxone™
and the reaction is carried out in a solvent such as aqueous alcohol (eg aqueous methanol) between −78° C. and ambient temperature.

According to another step (C), formula (I)
wherein R ¹ is C _1-6 alkylsulfonyl is a compound of formula (V)

[Chemical 5] or a protected derivative thereof under normal conditions. Conveniently, this oxidation is carried out as described for step (B) immediately above.

According to another step (D), formula (I)
(wherein R ¹ is C _1-6 alkoxy substituted with one or more fluorine atoms) is represented by formula (VI)

[Chemical 6] or a protected derivative thereof with a halofluoroalkane under conventional conditions. Conveniently, the reaction is carried out in a solvent such as a polar solvent (e.g. N,N-dimethylformamide) in the presence of a strong base such as an inorganic hydride (e.g. sodium hydride) at about ambient temperature and further to the desired formula ( It is carried out using the appropriate bromofluoroalkane to give the compound of I).

According to another step (E), formula (I)
can be prepared by interconversion using another compound of formula (I) as a precursor. The following technique shows a suitable interconversion. A compound of formula (I) (wherein R ¹ or R ² represents C _1-6 alkyl substituted with one or more fluorine atoms) can be converted to a suitable compound of formula (I) (wherein R ¹ or ^R2 represents _C1-6 hydroxyalkyl, C(O)H or C(O) _C1-6 alkyl) by treatment with a suitable fluorine source. Suitable fluorine sources include, for example, diethylaminosulfatrifluoride. Conveniently the reaction is carried out in the presence of a solvent such as a halogenated hydrocarbon (e.g. dichloromethane) at a low temperature such as -78[deg.]C.

Compounds of formula (I) (wherein R ¹ or R ²
represents C(O)H) can be prepared by oxidation from the corresponding compound of formula (I) wherein R ¹ or R ² represents CH ₂ OH. Suitable oxidizing agents include
An example is manganese tetroxide. Conveniently, this oxidation is carried out at elevated temperature (eg reflux) in the presence of a solvent such as a halogenated hydrocarbon (eg chloroform).

Compounds of formula (I) (wherein R ¹ or R ²
represents a C _1-6 hydroxyalkyl, and the hydroxyl group is attached to the carbon attached to the pyridazine ring), a compound of formula (I) (wherein R ¹ or R ² represents the corresponding aldehyde or ketone) It can be produced by reduction. Suitable reducing agents include hydrogenating reducing agents such as diisobutylaluminum hydride. Conveniently, this reduction is carried out with a halogenated hydrocarbon (e.g. dichloromethane)
at temperatures as low as −78° C. in the presence of solvents such as

As will be appreciated by those skilled in the art, at any step in the synthesis of compounds of formula (I) one or more sensitive groups within the molecule must be protected against undesirable side reactions. considered necessary or desirable.

Another step (F) for preparing compounds of formula (I) thus comprises deprotecting the protected derivatives of compounds of formula (I).

Protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. For example, Theodora W. Greene and Peter, who also describe methods for removing such groups.
'Protective Groups in Organic Syn' by GM Wuts
thesis', Second Edition, (John Wiley and Sons, 1991).

Compounds of formula (II) are represented by formula (VII)

[Chemical 10] can be produced by halogenating the compound of by a conventional method.

Thus, the ester of formula (VI) is first treated, for example, with a strong base (eg sodium hydroxide) in the presence of a solvent (eg ethanol) at elevated temperature to give
It is hydrolyzed to its corresponding acid. The corresponding acid is then treated with a halogenating agent, conveniently at ambient temperature and in a solvent (eg a chlorinated hydrocarbon) under conditions under which the acid undergoes both halogenation and decarboxylation reactions.
Conveniently, the halogenating agent is a strong acid (e.g. hydrobromic acid in acetic acid) or a brominating agent such as bromine in the presence of N-bromosuccinimide and the corresponding compound of formula (II) (wherein Hal is bromine).

Esters of formula (VII) are represented by formula (VIII)

[Chemical 11] The compound of formula (IX)

[Chemical 12] can be prepared by reacting with an aminopyridazinium complex of . Conveniently, the reaction is carried out at ambient temperature in the presence of a base such as potassium carbonate and a solvent such as N,N-dimethylformamide.

The boronic acids of formula (III) are either known compounds or can be prepared by methods in the literature, such as those described in EPA Publication No. 533,268.

Compounds of formulas (IV), (V) and (VI) may be prepared by methods analogous to those described for the preparation of compounds of formula (I) from compounds of formula (II).

Compounds of formula (VIII) are known compounds or are described for example by DH Wadsworth et al, J Org C
hem, (1987), 52(16), 3662-8 and J. Morris and D.
It can be prepared by literature methods such as those described in G. Wishka, Synthesis (1994), (1), 43-6.

Compounds of formula (IX) are known compounds or may be described, for example, by Y Kobayashi et al, Chem Pharm Bu
ll, (1971), 19(10), 2106-15; T. Tsuchiya, J. Kurit
a and K. Takayama; Chem Pharm. Bull, 28(9) 2676-268
1 (1980) and K Novitskii et al, Khim Geterotskil
It may be prepared by literature methods such as those described in Soedin, 1970 2, 57-62.

It will be appreciated that certain of the above intermediates are novel compounds and that all novel intermediates herein form further aspects of the invention. Compounds of formula (II) are key intermediates and represent a special aspect of the invention.

Conveniently, the compounds of the invention are isolated in the free base form after work-up. Pharmaceutically acceptable acid addition salts of compounds of the invention may be prepared using conventional methods.

Solvates (eg hydrates) of the compounds of the present invention are formed during the course of one of the above process steps.

The following examples illustrate the invention.
It is not intended to limit the invention in any way. All temperatures are in °C. Merc for flash column chromatography
It was done with k9385 silica. Thin layer chromatography (Tlc) was performed on silica plates. NMR is B
A Rucker 250 MHz spectrometer was used. Chemical shifts are given in δppm with tetramethylsilane as internal chemical shift reference. The following abbreviations: Me=methyl,
We use s=singlet, d=doublet, t=triplet and m=multiplet.

Example 1 6-Difluoromethoxy-2-(4-fluoro-phenyl
le)-3-(4-methanesulfonyl-phenyl)-pyra
Zoro[1,5-b]pyridazine (i) 6-methoxy-2-(4-fluoro-phenyl-
pyrazolo[1,5-b]pyridazine-3-carboxylic acid
3-(4-fluorophenyl)-prop-2-ionic acid methyl ester (3.36 g) and 1-amino-3-methoxy-pyridazin-1-ium mesitylenesulfonate ¹ (6.5 g) in acetonitrile (125 ml). 141
9g), 1,8-diazabicyclo [5.4.
0]undec-7-ene (3.39 ml) was added and the mixture was stirred at ambient temperature for 48 hours. The reaction was vented for the first two hours. The mixture was concentrated in vacuo, dissolved in ethyl acetate (150ml), washed with water (3x25ml), dried ( _MgSO4 ), filtered and evaporated in vacuo to give the title compound as a brown solid (4. 77
g). ^1H NMR ( _CDCl3 ): 8.4 (d, 1H, J = 10Hz) 7.85-7.90 (m, 2H)
7.1-7.2(m, 2H) 6.9-7.0(d, 1H, J=10Hz) 4.1(s, 3H)
3.9 (s,3H) MH ⁺ 302 Ref: ¹ T. Tsuchiya, J. Kurita and K. Takayama, Che
M. Pham. Bull. 28(9) 2676-2681 (1980)

(ii) 6-methoxy-2-(4-fluoro
rho-phenyl-pyrazolo[1,5-b]pyridazine-3
-carboxylic acid 6-methoxy-2-(4-fluoro-phenyl-pyrazolo[1,5-b]pyridazine-3-carboxylic acid methyl ester (4.469 g), 2N sodium hydroxide (5
0 ml) and methanol (90 ml) was heated to reflux for 2 hours. The cooled solution was added to 2N hydrochloric acid (200m
l) and the title compound was isolated as a solid by filtration (3.639g). ^1H NMR (DMSO- _d6 ): 12.8 (br. s, 1H) 8.4 (d, 1H, J = 10H
z) 7.8-7.9(m, 2H) 7.21-7.32(m, 2H) 7.15-7.2(d, 1H,
J=10Hz) 4.0(s, 3H) MH ⁺ 288

(iii) 2-(4-fluoro-phenyl
le)-3-(4-methanesulfonyl-phenyl)-6-
Methoxy-pyrazolo[1,5-b]pyridazine 6-Methoxy- in dimethylformamide (10 ml)
2-(4-fluoro-phenyl-pyrazolo[1,5-
b] A mixture of pyridazine-3-carboxylic acid (869 mg) and sodium bicarbonate (756 mg) was treated with N-bromosuccinimide (587 mg) and stirred at ambient temperature for 1 hour, then water (50 ml) was added and ethyl acetate (3
x 50 ml), dried ( _MgSO4 ) and evaporated in vacuo. The resulting brown solid (1.612 g) was dissolved in 1,2 dimethoxyethane (20 ml). 2N
sodium carbonate aqueous solution (10 m) was mixed with 4-(methanesulfonyl)phenylboronic acid (660 mg) and tetrakis(triphenylphosphine) palladium (0) (100
mg) and the mixture was heated to reflux for 20 hours.
The reaction was taken up in water (50 ml) with dichloromethane (3x
100 ml). The combined organic extracts were dried ( _MgSO4 ) and evaporated in vacuo to a brown solid (1.1
16g) which was purified by flash column chromatography on silica eluting with cyclohexane/ethyl acetate (4:1 then 2:1) to give the title compound as a yellow solid (390mg). Tlc, _SiO2 , Rf 0.3 (1:1 cyclohexane/ethyl acetate), detection UV MH ⁺ 398

(iv) 2-(4-fluoro-phenyl)
-3-(4-methanesulfonyl-phenyl)-pyrazolo
[1,5-b]pyridazin-6-ol 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-methoxy-pyrazolo[1,
5-b] A mixture of pyridazine (321 mg) and pyridazine hydrochloride (1.4 g) was placed in a closed container (Reactivia
l ^TM ) at 200° C. for 3 hours. The cooled reaction was taken in water (20ml) and ethyl acetate (3x30ml
l). The combined organic extracts are dried (MgS
O ₄ ), filtration and evaporation in vacuo gave a solid which was triturated with diethyl ether to give the title compound as a solid (1.19mg). Tlc, _SiO2 , Rf 0.07 (1:2 cyclohexane/ethyl acetate), detection UV MH ⁺ 384

(v) 6-difluoromethoxy-2-(4)
-fluoro-phenyl)-3-(4-methanesulfonyl
-phenyl)-pyrazolo[1,5-b]pyridazine 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b] in anhydrous dimethylformamide (5 ml) A solution of pyridazin-6-ol (0.2 g) was added to sodium hydride (0.046).
g, 60% dispersion in mineral oil) and after foaming ceased, a bromodifluoromethane gas stream was bubbled through the mixture for 30 minutes at ambient temperature. The reaction mixture was then poured into water (50m) and extracted with ethyl acetate (50ml), the organic extracts washed with water (3x50ml), dried and concentrated in vacuo. Purification of the residue by chromatography gave the title compound as a white solid (0.17 g). MH ⁺ = 434 ^1H NMR ( _CDCl3 ): 8.05-8.0 (d, J = 10HZ, 2H) 8.0-7.95
(d, J=10HZ, 1H) 7.6-7.5(m, 4H) 7.8-7.2(t, J=70HZ,
1H) 7.1-7.05(t, J=11HZ, 2H) 6.9-6.85(d, J=10HZ, 1
H) 3.15(s, 3H) Tlc, _SiO2 , Rf 0.35 (ethyl acetate/cyclohexane (1:1))

Example 2 3-(4-methanesulfonyl-phenyl)-2-(4-
Methoxy-phenyl)-pyrazolo[1,5-b]pyrida
Dine (i) 2-(4-methoxy-phenyl)-pyrazolo
[1,5-b]pyridazine-3-carboxylic acid methyl ester
Methyl 3-(4-methoxy-phenyl)-prop-2-ionic acid ¹ (14.46 g, 76 m) in teracetonitrile
M) and 1-aminopyridazinium iodide ² (2 eq) was added diazabicyclo[5,4,0]undec-7-ene (22.76 ml, 2 eq) dropwise under nitrogen and stirred for 6 hours. Purification by chromatography on silica gel, eluting with toluene then toluene:ethyl acetate (9:1) gave the title compound as a brown solid (2.76g). MH ⁺ = 284 ^1H NMR ( _CDCl3 ) δ 3.87 (3H, s) 3.9 (3H, s) 7.0 (2H, d,
J=9Hz) 7.25(1H, dd, J=9&4Hz) 7.90(2H, d, J=9Hz) 8.
45(1H, dd, J=4 & 2Hz) 8.55(1H, dd, J=9 & 2Hz) Ref: ¹ J. Morris and DG Wishka, Synthesis (199
4), (1), 43-6 Ref: ² kobayashi et al Chem. Pharm. Bullz (1971), 1
9 (10), 2106-15

(ii) 3-(4-methanesulfonyl-f
phenyl)-2-(4-methoxy-phenyl)-pyrazolo
2-(4-Methoxy-phenyl)-pyrazolo[ 1,5 -b]pyridazine-3-carboxylic acid methyl ester (2.76 g) and sodium hydroxide in [1,5-b]pyridazine ethanol (30 ml). A mixture of aqueous solution (2N, 30 ml) was refluxed under nitrogen for 2 hours. The cooled mixture was acidified with hydrochloric acid (2N) and the resulting white solid (2.53g) was isolated by filtration. This solid was dissolved in DMF and sodium bicarbonate (2.67 g, 3.3 eq) was added portionwise followed by N-bromosuccinimide (1.88 g, 1.1 eq). After stirring for 1 hour under nitrogen, water was added and extracted with ethyl acetate (2 x 25 ml). The dried organic phase was concentrated and the residue dissolved in DME (60 ml). Aqueous sodium carbonate (2N, 15ml) was added followed by 4-methanesulfonyl-phenylboronic acid (3.12g) and tetrakis(triphenylphosphine)palladium(0) (250mg). The mixture was heated to reflux under nitrogen for 18 hours, cooled, poured into water and extracted with ethyl acetate (2 x 25 ml). The combined organic phases were dried and concentrated on silica gel. toluene: ethyl acetate (8:
Concentration by chromatography on silica gel eluting with 1) gave the title compound as an off-white solid (3.58g). MH ⁺ 380 ¹ H NMR (DMSO) δ 3.25(3H, s) 3.75(3H, s) 6.95(2H, d,
J=8.5Hz) 7.25(1H, dd, J=9 & 5Hz) 7.45(2H, d,J=8.5H
z) 7.60(2H, d, J=8Hz) 7.9(2H, d, J=8.5Hz) 8.15(1H,
dd, J=9 & 2Hz) 8.49(1H, dd, J=5 & 2Hz)

Example 3 2-(4-ethoxy-phenyl)-3-(4-methans
Rulfonyl-phenyl)-pyrazolo[1,5-b]pyrida
Dine (i) 4-[3-(4-methanesulfonyl-phenyl)
- pyrazolo[1,5-b]pyridazin-3-yl]-f
To 3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine (3.58 _g ) in CH2Cl2 at _-70 °C, tribromide Boron (1M solution _{in CH2Cl2} , 2.1 eq) was added. The mixture was stirred for 10 minutes, then warmed to 0° C. and stirred at 0° C. overnight. The reaction mixture was made alkaline with potassium carbonate, then acidified with hydrochloric acid (2M), poured into water and treated with CH ₂ Cl ₂ . Extracted. The organic phase was dried, filtered and concentrated to give the title compound as a yellow solid (1.87g). MH ⁺ 366 ¹ H NMR (DMSO) δ 3.30 (3H, s) 6.80 (2H, d, J=8.5Hz) 7.3
0(1H, dd, J=9 & 5Hz) 7.35(2H, d, J=8.5Hz) 7.60(2H,
d, J=8Hz) 8.0(2H, d, J=8.5Hz) 8.20(1H, dd, J=9 &
2Hz) 8.55(1H, dd, J=5 & 2Hz) 9.75(1H,s)

(ii) 2-(4-ethoxy-phenyl)
-3-(4-methanesulfonyl-phenyl)-pyrazolo
[1,5-b]pyridazine 4-[3-(4-Methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-2-yl]-phenol (663 mg, 1.5 mL) in acetonitrile (30 mL).
82), iodoethane (1 eq) and potassium carbonate (2 eq) were heated to reflux under nitrogen for 18 hours. The cooled reaction mixture was washed with water (30 ml) and ethyl acetate (30 ml).
The liquid was separated with The organic phase was collected, dried and purified by chromatography to give the title compound as an opalescent foam (547mg). MH ⁺ 394 ¹ H NMR (DMSO) δ 1.45 (3H, t, J=7Hz) 3.10 (3H, s) 4.1
(2H, q, J=7Hz) 6.87(2H, d, J=9Hz) 7.08(1H, dd, J=9
& 5Hz) 7.55(4H, t, J=9Hz) 7.92(1H, dd,J=9&2Hz)
7.95(2H, d, J=9Hz) 8.20(1H, dd,J=9 & 2Hz) 8.32(1H,
dd, J=5 & 2Hz)

Example 4 2-(4-Fluoro-phenyl)-6-methanesulfonyl
R-3-(4-methanesulfonyl-phenyl)-pyrazo
ro[1,5-b]pyridazine (i) 2-(4-fluoro-phenyl)-6-methyls
Rufanyl-pyrazolo[1,5-b]pyridazine-3-
To carboxylic acid methyl ester TFA (25 ml) was added solid t-butoxycarbonyl-
O-mesitylenesulfonylhydroxylamine ¹ (7.
8g) was added portionwise with stirring over 10 minutes, then stirred for a further 20 minutes. Place the solution on ice (~2
00 ml) and left until the ice melts. The resulting white solid was collected by filtration, washed with water and treated with DME (100
ml). The solution was dried over 4A molecular sieves for 1.5 hours, then filtered to give 3-methylthio-pyridazine ² (2.5 mL) in dichloromethane (35 mL).
6g) and the reaction was stirred at room temperature for 20 hours. Filtration of the intermediate salt yielded pale brown crystals (3.8
7g), suspended in acetonitrile (100ml) and methyl 3-(4-fluoro-phenyl)-prop-2-ionic acid (2.02g) added. 1,8-diazabicyclo[5,4,0]undec-7-ene (2.
1 ml) was added dropwise and the reaction was stirred at room temperature for 20 hours.
The resulting crystalline precipitate was collected by filtration, washed and dried (770mg). Concentration of the filtrate gave a second crop (430 mg). The residue was partitioned between water and ethyl acetate (100 ml each), and the aqueous layer was washed with ethyl acetate (20 ml).
extracted with The combined organics were washed with water, brine and dried. Removal of solvent gave a brown oil,
This was purified by flash chromatography on silica (300 g) eluting with cyclohexane/ethyl acetate (3:1) to give a further amount of product (247 m
g) was obtained. The three groups were combined to give the title compound as a pale brown solid (1.45g). MH ⁺ 318 ¹ H NMR (CDCl ₃ ) δ 2.70 (3H, s) 3.88 (3H, s) 7.08-7.18
(3H, m) 7.84(2H, m) 8.31(1H, d, J=10Hz) Ref: ¹ K Novitskii et al, khim Geterotskil Soedin,
1970 2, 57-62 Ref: ² Barlin GB, Brown, WV, J Chem Soc (196
8), (12), 1435-45

(ii) 2-(4-fluoro-phenyl)
-3-(4-methanesulfonyl-phenyl)-6-methyl
Rusulfanyl-pyrazolo[1,5-b]pyridazine 2-(4-Fluoro-phenyl)-6-(methylthio)-pyrazolo[1,5-b] in methanol (40 ml)
pyridazine-3-carboxylic acid methyl ester (1.45
g) A mixture of potassium carbonate (690 mg) and water (14 ml) was stirred and heated to reflux under nitrogen for 20 hours. The solvent was removed and the resulting solid was partitioned between ethyl acetate (50ml) and water (250ml). The aqueous layer was acidified to pH 1 (2M HCl) and the solid collected by filtration (1.0 g,
MH ⁺ 304). A mixture of solid (1.0 g) sodium bicarbonate (557 mg) and NBS (594 mg) was stirred at room temperature for 4 hours. The reaction was poured into water (150ml) and extracted with ethyl acetate (3x50ml). The combined extracts were washed with water (50ml), brine (20ml), dried and concentrated. The resulting solid (1.015
g, MH ⁺ 338,340), 4-(methanesulfonyl)phenylboronic acid (902 mg), sodium carbonate (740 mg) and tetrakis(triphenylphosphine)palladium(0) (175 mg) were stirred and DM
E (30 mls) and water (15 ml) under nitrogen for 4
It was heated under reflux for 8 hours. The reaction was poured into water and extracted with ethyl acetate (3 x 50ml). The combined extracts were dried and solvent removed to give a brown solid. This was purified on silica (300g) eluting with cyclohexaneethylacetone (1:1) to give the title compound as a yellow solid (0.713g). MH ⁺ 414 ¹ HNMRδ(DMSO) 2.65(3H, s) 3.28(3H, s) 7.20-7.30(3
H, m) 7.55(2H, m) 7.62(4H, d, J=8.5Hz) 7.95-8.05(3
H, m)

(iii) 2-(4-fluoro-phenyl
le)-6-methanesulfonyl-3-(4-methanesulfonyl
2-(4-Fluoro -phenyl)-3-(4-methanesulfonyl-phenyl)-6- in Nyl-phenyl)-pyrazolo[1,5-b]pyridazine MeOH (5 ml)
A suspension of (methylthio)-pyrazolo[1,5-b]pyridazine (60mg 0.145) and water (2ml) was stirred with oxone (196mg 0.32) for 20 hours. The resulting solution was poured into water (50ml) and extracted with chloroform (3x20ml). The combined extracts were dried to remove solvent. Crystallization of the residue from methanol gave the title compound as a white solid (60
mg). MH ⁺ 446 ^1H NMR (DMSO- _d6 ) δ 3.34(3H, s) 3.53(3H, s) 7.33(2H,
t, J=9Hz) 7.62(2H, m) 7.68(1H, d, J=8.5Hz) 8.04(1
H, d, J=10Hz) 8.52(1H, d, J=9Hz) TLC SiO _2Hexane :ethyl acetate (1:1) Rf0.24UV

Example 5 2-(4-difluoromethoxy-phenyl)-3-(4
-methanesulfonyl-phenyl)-pyrazolo[1,5-
b]pyridazine 4-[3- in anhydrous dimethylformamide (5 ml)
(4-methanesulfonyl-phenyl)-pyrazolo[1,
5-b]pyridazin-2-yl]-phenol (200
mg, 0.55 mmol) was added sodium hydride (48 mg, 60% dispersion in oil, 1.2 mmol). Bromodifluoromethane gas was slowly bubbled through the solution for 20 min, then CH ₂ Cl ₂ (30 ml).
diluted with After post-treatment with water, CH ₂ C as eluent
l ₂ : Chromatography on silica gel with ethyl acetate (3:1) and CH ₂ Cl ₂ as eluent:
Chromatography with ethyl acetate (10:1) gave the title compound as a white solid (63m
g, 28%). MH ⁺ 416 NMR (CDCl ₃ ) δ 8.38 (1H, dd, J = 4Hz) 8.01 (2H, d, J = 8.5
Hz) 7.94(1H, dd, J=9 & 2Hz) 7.65(2H, d, J=8.5Hz)
7.57(2H, d, J=8Hz) 7.10(3H, m) 6.87-6.27(1H, t,J=
7.4Hz) 3.15(3H, s)

Example 6 4-[2-(4-ethoxy-phenyl)-pyrazolo
[1,5-b]pyridazin-3-yl]-benzenesulfur
phonamide (i) 2-(4-ethoxy-phenyl)-pyrazolo
[1,5-b]pyridazine-3-carboxylic acid methyl ester
Diazabicyclo [5,4,0] was added to a solution of methyl 3-(4-ethoxy-phenyl)prop-2-ionic acid (1.0 g) and 1-aminopyridazinium iodide ² (2.19 g) in teracetonitrile (10 ml). ] undec-7-ene (1.47 ml, 2 eq) was added dropwise under nitrogen and stirred for 5 hours. Concentration and water work-up gave the title compound as a sticky brown solid (1.2g). MH ⁺ 298

(ii) 2-(4-ethoxy-phenyl)
-pyrazolo[1,5-b]pyridazine-3-carboxylic acid 2-(4-ethoxy-phenyl)-pyrazolo[1,5-
b] pyridazine-3-carboxylic acid methyl ester (1.
2g), ethanol (10ml) and 2N sodium hydroxide (10ml) was heated to 80°C for 1.5 hours. The mixture was allowed to cool and acidified to pH 1 with 2N hydrochloric acid. Isolate the title compound as a brown solid by filtration (716 mg, 63%). MH ⁺ 284

(iii) 2-(4-ethoxy-phenyl
2-(4-ethoxy- phenyl)-3-iodo-pyrazolo[1,5-b]pyridazine DMF (8 ml)
- pyrazolo[1,5-b]pyridazine-3-carboxylic acid (710 mg), N-iodosuccinimide (678 m
g) and sodium bicarbonate (717 mg) was stirred for 4 hours. A further amount of N-iodosuccinimide (100 mg) was added and stirring continued for 2 hours. Aqueous workup gave a dark brown solid which was purified by SPE using dichloromethane as eluent. This gave the title compound (429 mg, 47%) as an orange-brown solid. MH ⁺ 366

(iv) 4-[2-(4-ethoxy-phene
nyl)-pyrazolo[1,5-b]pyridazin-3-y
4- iodobenzenesulfonamide (0.311 g), dipinacordiborane ¹ (0.279 g), potassium acetate (486 mg) and [1,1′-bis(1,1′-bis( A mixture of diphenylphosphino)-ferrocene]palladium(II) chloride complex with dichloromethane (1:1) (0.45 g) was heated at 80° C. for 2 hours under nitrogen. The cooled reaction mixture was concentrated in vacuo and the residue was suspended in 1,2 dimethoxyethane (10ml) and treated with 2N sodium carbonate (4ml) and tetrakis(triphenylphosphine)palladium(0) (20ml).
g) with 2-(4-ethoxy-phenyl)-3-iodo-pyrazolo[1,5-b]pyridazine (0.4 g)
was added and the mixture was heated to reflux under nitrogen for 18 hours. The cooled reaction mixture was poured into water (60ml) and the suspension was extracted with ethyl acetate (3x60ml). The organic extracts were combined _, dried ( _Na2SO4 ) and concentrated. Purify the residue by chromatography, eluting with dichloromethane/ethyl acetate (3:1) to give the title compound (0.116 g, 27%) as a yellow solid. MH ⁺ 395 NMR (CDCl ₃ ) δ 8.32 (1H, dd, J = 4 & 2Hz) 7.97 (2H, d, J
=8Hz) 7.89(1H, dd, J=9 & 2Hz) 7.54(4H, m) 7.04(1H,
dd, J=9 & 4Hz) 6.88(2H, d, J=9Hz) 1.43(3H, t,J=7H
z) Ref: ¹ R. Miyaura et al J. Org. Chem., 1995, 60, 75
08-7510.

Example 7 6-Difluoromethoxy-2-(3-fluoro-phenyl
le)-3-(4-methanesulfonyl-phenyl)-pyra
Zoro[1,5-b]pyridazine (i) 1-(2,2-dibromo-vinyl)-3-fluoro
Rho-benzene Stirred and chilled (ice/salt, 0° C.) anhydrous CH ₂ Cl ₂ (2
To a solution of carbon tetrabromide (48.82 g) in (00 ml) was added triphenylphosphine (77.1 g) portionwise over 3 minutes while keeping the temperature below 10°C. After the resulting orange suspension was stirred at 0°C for 1 hour, 3-fluorobenzaldehyde (7.8 ml) was added to it. After the addition is complete, the suspension is stirred at 0° C. for 1 hour,
It was then quenched by adding water (75 ml). The organic phase is separated, washed with brine (75 ml) and dried (N
_a2SO4 ) and evaporated to _dryness . The remaining gum was placed in cyclohexane (1 L) and stirred for 30 minutes. The organic phase was decanted and the residue dissolved in CH ₂ Cl ₂ in cyclohexane (1 L). Repeat this process two more times,
The combined organic phases were concentrated to 100 ml and passed through silica gel. Concentrate the filtrate to give the title compound (24 g, 100%) as a mobile yellow oil. MH ⁺ 280, MH ^- 279 NMR( _CDCl3 )δ7.05(1H, tm, J=9Hz) 7.3(3H, m) 7.45(1
H, s)

(ii) (3-fluoro-phenyl)-
Ropinonic acid methyl ester - 1 in anhydrous THF (350 ml) cooled to 78°C
To a stirred solution of -(2,2-dibromo-vinyl)-3-fluoro-benzene (23.8 g) was added n-butyllithium (2.2 eq, 1.6 M in hexanes) dropwise over 30 minutes. After the mixture was stirred at -78°C for an additional 30 minutes, methyl chloroformate (11.6 g, 9.0 g, 9.0 g) was added.
5 ml) was added and the resulting mixture was allowed to warm to 0° C. for 1 hour before adding 1:1 saturated aqueous sodium bicarbonate:
Diluted with ammonium chloride (100 ml) and extracted with ether (2 x 100 ml). The combined organic extracts were washed with brine (25 ml) and dried (Na ₂ S
O ₄ ) and evaporated to dryness to give the title compound as a brown oil (16.7 g, 100%). MH ^- 173 NMR ( _CDCl3 ) δ 7.4-7.1(4H, m) 3.85(3H, s, _CO2Me )

(iii) 2-(3-fluoro-phenyl
le)-6-methoxy-pyrazolo[1,5-b]pyridazide
(3- fluoro -phenyl)-propynoic acid methyl ester (2.67 g) and 1-amino-3-methoxy-pyridazin-1-ium in acetonitrile (80 ml) mesitylene sulfonate (4.89 g)
1,8-diazabicyclo[5,4,0]undec-7-ene (5 ml) was added to the stirred, cooled mixture of
The mixture was stirred at 0° C. for 1 hour and then at ambient temperature for 18 hours. The mixture was concentrated in vacuo and ethyl acetate (150m
l) and water (150 ml) were separated. The aqueous phase was separated and further extracted with ethyl acetate (2 x 100ml). The combined organic extracts were combined with water (2 x 50ml), brine (25ml
l), dried (MgSO ₄ ), filtered and evaporated in vacuo to give a solid which was triturated with anhydrous ether:petroleum ether (1:0.5) to give the title compound as a brown solid. was obtained (2.4 g, 53
%). MH ⁺ 302 ¹ H NMR (CDCl ₃ ) δ 12.8 (1H, brs) 8.4 (1H, d, J 10Hz)
7.7-7.6(2H, m) 7.42(1H, q, J8Hz) 7.15(1H, td, J=8
& 3Hz) 6.95(1H, d, J=10Hz) 4.1(3H, s) 3.88(3H, s)

(iv) 2-(3-fluoro-phenyl)
-6-methoxy-pyrazolo[1,5-b]pyridazine-
3-carboxylic acid 2-(3-fluoro- in absolute ethanol (50 ml)
Phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylic acid methyl ester (2.3 g)
2N sodium hydroxide (50 ml) was added to the solution of
The resulting mixture was heated to reflux for 3 hours. The cooled reaction mixture was slowly poured into a stirred solution of 2N hydrochloric acid (300ml). The resulting suspension was stirred at ambient temperature for 1 hour, then filtered and the filter cake was washed with water and dried under vacuum at 60° C. to give the title compound as an off-white solid (2.0 g, 91 %). MH ⁺ 288 ¹ H NMR (DMSO) 8.45(1H, J=10Hz) 7.67(2H, m) 7.5(1H,
q, J=7Hz) 7.3(1H, td, J=7 & 2Hz) 7.21(1H, d, J=10
Hz) 4.0 (3H, s)

(v) 3-bromo-2-(3-fluoro-
phenyl)-6-methoxy-pyrazolo[1,5-b]py
To a stirred solution of 2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine-3-carboxylic acid (2.0 g) in lidazine anhydrous DMF (20 ml) was added n-bromosuccinimide ( 1.78 g) was added and the resulting solution was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (800 ml) and then water (10 x 100 ml).
l) and saturated brine (25 ml), dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a tan solid (2.1 g, 93%). MH ⁺ 323, MH ^- 321 ^1HNMR ( _CDCl3 ) 7.9(2H, m) 7.8(1H, d, J=10Hz) 7.45
(1H, m) 7.19(1H, td, J=8 & 2Hz) 6.78(1H, d, J=10H
z) 4.1(3H, s)

(vi) 6-difluoromethoxy-2-
(3-fluoro-phenyl)-pyrazolo[1,5-b]
Part of pyridazine 3-bromo-2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine (4
00 mg, 2.1 g total) were placed in individual reaction vials containing magnetic stir bars. Pyridine hydrochloride (10 equivalents) was added to each vial and the vials were sealed and heated at 200° C. for 3 hours. After allowing the vial to cool to 140° C., it was opened and the contents poured into ice/water. The resulting mixture was extracted with ethyl acetate (3 x 100 ml) and the combined organic extracts were washed with water (7 x 75 ml), dried ( _Na2SO4 ) and evaporated to give desbromophenol as a brown solid _. was obtained (1.0 g, MH ⁺ 230). Anhydrous D
Dissolved in MF (10 ml) and added sodium hydride (60% dispersion in mineral oil, 200 mg) portionwise. After stirring for 20 minutes at ambient temperature, the solution was placed in a small chilled autoclave and bromodifluoromethane (5 ml condensed at -30°C, xs) was added. The autoclave was then sealed, allowed to warm to ambient temperature and stirred for 36 hours. The resulting solution was diluted with ethyl acetate (200 ml), washed with water (10 x 20 ml) and dried ( _Na2S
O ₄ ) and the remaining gum was purified by flash column chromatography using cyclohexane:ethyl acetate (4:1) as eluent. This gave the title compound as a solid (652 mg, 60
%). MH ⁺ 280MH ⁻ 278 NMR (DMSO) 8.42 (1H, d, J = 10Hz) 7.85 (1H, d, J = 8Hz)
7.78(1H, t, J=70Hz) 7.55(1H, q, J=8Hz) 7.38(1H, s)
7.25(1H,m) 7.17(1H,d,J=10Hz)

(vii) 3-bromo-6-difluoromethyl
Toxy-2-(3-fluoro-phenyl)-pyrazolo
[1,5-b]pyridazine 6-difluoromethoxy- in anhydrous DMF (10 ml)
2-(3-fluoro-phenyl)-pyrazolo[1,5-
b] pyridazine (251 mg) and sodium bicarbonate (1
85 mg) of N-bromosuccinimide (195 mg).
mg) was added and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (300 ml), water (10 x 20 ml),
Wash with brine (20 ml) and dry (Na ₂ SO
₄ ) and concentrated to give the title compound as a solid (293 mg, 91%). MH ⁺ 359, MH ⁻ 356/357 NMR(DMSO)δ8.36(1H,d,J=10Hz) 7.88(1H,d,J=8Hz)
7.78(1H, t, J=70Hz, _OCHF2 ) 7.77(1H, dm, J=10Hz)
7.62 (1H, dt, J = 8 & 6Hz) 7.38 (1H, dt, J = 9 & 2Hz) 7.3
(1H, d, J=10Hz)

(viii) 6-difluoromethoxy-2
-(3-fluoro-phenyl)-3-(4-methanesulfur
phonyl-phenyl)-pyrazolo[1,5-b]pyridazide
To a stirred solution of 3-bromo-6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (286 mg) in dioxane DMF (20 ml ) was added 2N aqueous sodium carbonate (10 ml). was added. To this mixture was added 4-methanesulfonyl-phenylboronic acid (180 mg) and tetrakistriphenylphosphine palladium(0) (34 mg). The resulting mixture was stirred and heated to reflux for 18 hours. The cooled reaction mixture was diluted with ethyl acetate (300ml) and the organic solution was washed with water (10x30ml), brine (30ml) and
Drying and evaporation (Na ₂ SO ₄ ) gave a gum which was purified by flash column chromatography using chloroform:ethyl acetate (50:1 to 5:1) as eluent. Combine and concentrate the appropriate fractions to give the title compound as an off-white solid (132 mg, 37%). MH ⁺ 434 ¹ H NMR (CDCl ₃ ) δ 8.02 (1H, d, J = 9 Hz) 7.95 (2H, d, J = 1
0Hz) 7.58(1H, d, J=9Hz) 7.52(1H, t, J=70Hz) 7.32(3
H,m) 7.08(1H,m) 6.9(1H,d,J=9Hz) 3.15(3H,s)

Biological data cDNA for human COX-1 and human COX-2
In COS cells stably transfected with
Inhibitory activity against human COX-1 and COX-2 was evaluated. 24 hours prior to the experiment, C
OS cells were transferred from the 175 ^cm2 flasks in which they were grown onto 24-well cell culture plates. Incubation medium (heat-inactivated fetal bovine serum ( ¹⁰ % v/v), penicillin (10
0 IU/ml), streptomycin (100 μg/m
l) and Dulbecco's modified Eagle's medium (DMEM) supplemented with geneticin (600 μg/ml)) were removed. 10 ml of phosphate buffered saline (PB
S) was added to wash the cells. The PBS was discarded, then the cells were rinsed in 10 ml trypsin for 20 seconds, after which the trypsin was removed and the flask was placed in an incubator (37°C) for 1-2 minutes until the cells detached from the flask. Flasks were then removed from the incubator and cells were resuspended in 10 ml of fresh incubation medium. The contents of the flask are transferred to a 250 ml sterile container and then the volume of incubation medium is increased to 100 ml.
ml. Pipette 1 ml of cell suspension 4 x 24
into each well of a well cell culture plate. then
The plate was placed in an incubator (37° C., 95% air/5% CO ₂ ) overnight. If more than one flask of cells was required, the cells of individual flasks were combined before distribution into 24-well plates.

After overnight incubation, the incubation medium was completely removed from the 24-well cell culture plates and replaced with 250 μl of fresh DMEM (37° C.). Test compounds were made 250x the required test concentration in DMSO and added to the wells in a volume of 1 μl. The plate was then swirled to mix gently and then placed in an incubator (37° C., 95% air/5% CO ₂ ) for 1 hour. After the incubation period, 10
μl of arachidonic acid (750 μM) was added to give a final arachidonic acid concentration of 30 μM. Plates were then incubated for an additional 15 minutes, after which incubation medium was harvested from each well of the plate and stored at -20°C prior to detection of prostaglandin _E2 (PGE2) levels using an enzyme immunoassay. The inhibitory potency of a test compound is defined as the concentration of compound required to inhibit PGE2 release from cells by 50%, _IC50
expressed as a value. The selectivity ratio of COX-1 inhibition to COX-2 was calculated by comparing each _IC50 value.

With respect to the compounds of the invention, the following COX-
_IC50 values for inhibition of 2 and COX-1 were obtained.

[Table 1]

──────────────────────────────────────────────────── ─── Continuation of the front page (51) ^Int.Cl. 19/02 19/02 19/06 19/06 25/06 25/06 25/16 25/16 25/28 25/28 27/02 27/02 27/16 27/16 29/00 29/00 35/ 00 35/00 (73) Patentee 397009934 Glaxo Wellcome House, Berkeley Avenue Greenford, Middles ex UB60NN, Great Britain (72) Inventor Ian, Campbell Stevenage, Gunnels, Hertfordshire, England; wood, low De Glaxo, Wellcome, PLC (72) Inventor Neil, Matthews, Stevenage, Gunnels, Wood, Lord Glaxo, Wellcome, PLC (72) Inventor, Hertfordshire, UK Alan, Naylor, Hertford, UK Shah, Stevenage, Gunnels, Wood, Lord Glaxo, Wellcome, PLC (56) References WO 95/501 (WO, A1) WO 96/6840 (WO, A1) WO 96/21667 (WO , A1) International Publication 96/31509 (WO, A1) International Publication 96/41645 (WO, A1) Expert Opinion on Therapeutic Patents, Vol. 7, No. 1, 1997, pp 55-62 Expert Opinion on Therapeutic Patents, Vol. 8, No. 1, 1998, pp 21-29 (58) Researched field (Int. Cl. ⁷ , DB name) C07D 487/04 A61K 31/5025

Claims (15)

(57) [Claims] 1. A compound of formula (I) and a pharmaceutically acceptable derivative thereof. [Chemical 1] {wherein R ⁰ is halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy substituted with one or more fluorine atoms, or O(CH ₂ ) _n NR ⁴ R ⁵ ; R ¹ and R ² are independently H, C _1-6 alkyl, C _1-6 alkyl substituted with one or more fluorine atoms, C _1-6
alkoxy, C _1-6 hydroxyalkyl, SC _1-6
Alkyl, C(O)H, C(O) _{Ci_6alkyl} , C
_{1-6alkylsulfonyl} , _C1-6alkoxy substituted with one or more _fluorine atoms, O( _CH2 ) _nCO2C
1-6 alkyl, O( _CH2 ) _{nSC 1-6} alkyl,
⁽ _CH2 ⁾ _{nNR4R5 ,} ⁽ _CH2 ) _nSC1-6alkyl or C(O) ^NR4R5 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 alkylsulfonyl, C _1-6 alkoxy substituted with one or more fluorine atoms, O(CH ₂ ) _{nCO2Ci - 6alkyl} , O
( _CH2 ⁾ _{nSC1-6alkyl ,} ( _CH2 ) _nNR4
^R5 , or ( _CH2 ) _nSC1-6alkyl , _C
(O) ^NR4R5 ); ^R3 is _C1-6alkyl ^or _NH2 ; ^R4 and ^R5 are independently selected from H, or _C1-6alkyl ; forms a 4-8 membered saturated ring with the bonding nitrogen atom; and n is 1-4} 2. R ⁰ is F, C _1-3 alkyl, C _1-3
alkoxy, C _1-3 substituted with one or more fluorine atoms
^alkoxy , or O ⁽ _CH2 ) _nNR4R5 ;
R ¹ is C _1-4 alkylsulfonyl, C _1-4 alkoxy substituted with one or more fluorine atoms, O(CH ₂ ) _n C
_O2C1-4alkyl , O _{( CH2} ⁾ _nSC1-4alkyl ^, ( _{CH2 ) nNR4R5} , ( _CH2 ) _nSC
1-4alkyl or C(O) ^NR4R5 , or ^R0 is _C1-3alkyl , _C1-3alkoxy ^,
C _1-3 alkoxy substituted with one or more fluorine atoms,
or when O( _CH2 ) _nNR4R5 may be H; ^R2 is H; ^{R3 is} methyl ^or NH
is 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 2. The compound of claim 1, wherein: 3. R ⁰ is F, methyl, C _1-2 alkoxy, OCHF ₂ , or O(CH ₂ ) _n NR ⁴ R ⁵ ; R ¹ is methylsulfonyl, OCHF ₂ , O(C
_H2 ) _{nCO2Ci- 4alkyl ,} O( _CH2 ) _{nSC
H3 ,} ⁽ _CH2 ) _nNR4R5 , ( _CH2 ) ^nSC
H ₃ or C(O)NR ⁴ R ⁵ or R
may be H when ⁰ is methyl, _C1-2alkoxy , _OCHF2 , or O( _CH2 ) _nN ( _CH3 ) ₂ ; ^R2 is H; ^R3 is methyl or _NH2
^R4 and ^R5 are both methyl, or form a 5-6 membered saturated ring with the nitrogen atom to which they are attached; and n is 1-2, or 2. A compound according to 2 above. 4. R ⁰ is F, C _1-3 alkoxy, or C _1-3 alkoxy substituted with one or more fluorine atoms; R ¹ is C _1-4 alkylsulfonyl, one or more fluorine atoms; substituted C _1-4 alkoxy or H when R ⁰ is C _1-3 alkoxy or C _1-3 alkoxy substituted with one or more fluorine atoms
^R2 is H; ^R3 is methyl or _NH2 . 5. A compound according to any one of claims 1-4, wherein R ⁰ is in the 3 or 4 position of the phenyl ring. 6. A compound according to any one of claims 1 to 5, wherein ^R1 is in the 6-position of the pyridazine ring. 7. 2-(4-ethoxy-phenyl)-3-
(4-methanesulfonyl-phenyl)-pyrazolo[1,
5-b]pyridazine; 6-difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine; and pharmaceutically acceptable derivatives thereof . 8. A process for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof according to any one of claims 1 to 7, comprising formula (II) A compound of or a protected derivative thereof of formula (II
I) [Chemical 3] or a protected derivative thereof; and removing the protecting group and optionally converting the compound of formula (I) prepared by the above methods to a pharmaceutically acceptable derivative thereof. way to be. 9. A process for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof according to any one of claims 1 to 7, wherein R ³ represents C _1-4 alkyl to the formula (IV) or a protected derivative thereof with an oxidizing agent; and removing the protecting group and optionally converting the compound of formula (I) prepared by the above method to a pharmaceutically acceptable derivative thereof. a method comprising: 10. A process for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof according to any one of claims 1-7, wherein R ¹ is C _1-6 alkylsulfonyl In the case of formula (V) and removing the protecting group and optionally converting the compound of formula (I) prepared by the above method into a pharmaceutically acceptable derivative thereof. Method. 11. A process for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof according to any one of claims 1 to 7, wherein R ¹ is substituted with one or more fluorine atoms. is C _1-6 alkoxy, the formula (VI) or a protected derivative thereof with a halofluoroalkane; and removing the protecting group, optionally prepared by the method described above.
to a pharmaceutically acceptable derivative thereof. 12. A compound of formula (I) or a pharmaceutically acceptable derivative thereof according to any one of claims 1 to 7, in admixture with one or more physiologically acceptable carriers or excipients; A pharmaceutical composition comprising: 13. For use in human or veterinary medicine,
13. A pharmaceutical composition according to claim 12. 14. Use in the treatment of conditions mediated by selective inhibition of COX-2.
The pharmaceutical composition according to . 15. The pharmaceutical composition of claim 14, wherein the condition mediated by selective inhibition of COX-2 is pain (both chronic and acute), fever, or inflammatory disease.