Pyrazole derivatives

Corbau, Romuald Gaston; Mowbray, Charles Eric; Perros, Manoussos; Stupple, Paul Anthony; Wood, Anthony;

This invention relates to the use of pyrazole derivatives of the formula ##STR1## and pharmaceutically acceptable salts and solvates thereof, in the manufacture of a reverse transcriptase inhibitor or modulator, to certain novel such pyrazole derivatives and to processes for the preparation of and compositions containing such novel derivatives.

This invention relates to the use of pyrazole derivatives in the manufacture of a reverse transcriptase inhibitor or modulator, to certain novel such pyrazole derivatives and to processes for the preparation of and compositions containing such novel derivatives.

The present pyrazole derivatives bind to the enzyme reverse transcriptase and are modulators, especially inhibitors thereof. Reverse transcriptase is implicated in the infectious lifecycle of HIV, and compounds which interfere with the function of this enzyme have shown utility in the treatment of conditions including AIDS. There is a constant need to provide new and better modulators, especially inhibitors, of HIV reverse transcriptase since the virus is able to mutate, becoming resistant to their effects.

The present pyrazole derivatives are useful in the treatment of a variety of disorders including those in which reverse transcriptase is implicated. Disorders of interest include those caused by Human Immunodificiency Virus (HIV) and genetically related retroviruses, such as Acquired Immune Deficiency Syndrome (AIDS).

European Patent Application EP 0 786 455 A1 discloses a class of imidazole compounds which inhibit the growth of HIV. A class of N-phenylpyrazoles which act as reverse transcriptase inhibitors are disclosed in J. Med. Chem., 2000, 43, 1034. Antiviral activity is ascribed to a class of N-(hydroxyethyl)pyrazole derivatives in U.S. Pat. No. 3,303,200.

According to the present invention there is provided the use of a compound of the formula ##STR2##

or a pharmaceutically acceptable salt or solvate thereof, wherein

either (i) R.sup.1 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl, benzyl, halo, --CN, --OR.sup.7,

--OR.sup.8, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 --NR.sup.5, --NR.sup.5 COR.sup.5,

NR.sup.5 --CO--(C.sub.1 -C.sub.6 alkylene)--OR.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.8, said C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, --CN,

--OR.sup.5, --OR.sup.8, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.8 R.sup.9,

--NR.sup.5 COR.sup.5, --NR.sup.5 COR.sup.6, --NR.sup.5 COR.sup.8, --SO.sub.2 NR.sup.5 R.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.6, and

R.sup.2 is H or --Y--Z,

or, (ii) R.sup.1 and R.sup.2, when taken together, represent unbranched C.sub.3 -C.sub.4 alkylene, optionally wherein one methylene group of said C.sub.3 -C.sub.4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R.sup.5 or R.sup.8 ;

Y is a direct bond or C.sub.1 -C.sub.3 alkylene;

Z is R.sup.10 or, where Y is C.sub.1 -C.sub.3 alkylene, Z is --NR.sup.5 COR.sup.10, --NR.sup.5 CONR.sup.5 R.sup.10,

--NR.sup.5 CONR.sup.5 COR.sup.10 or --NR.sup.5 SO.sub.2 R.sup.10 ;

R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl, benzyl, --CN, halo, --OR.sup.7, --CO.sub.2 R.sup.5,

--CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5,

--NR.sup.5 SO.sub.2 R.sup.7 or R.sup.6, said C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, --CN, --OR.sup.5, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5,

--NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5, --SO.sub.2 NR.sup.5 R.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.6 ;

R.sup.4 is phenyl or pyridyl, each being optionally substituted by R.sup.6, halo, --CN, C.sub.1 -C.sub.6 alkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, C.sub.3 -C.sub.7 cycloalkyl or C.sub.1 -C.sub.6 alkoxy;

each R.sup.5 is independently either H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, phenyl or benzyl, or, when two such groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.7 cycloalkyl and said piperazinyl and homopiperazinyl being optionally substituted on the nitrogen atom not taken together with the two R.sup.5 groups to form the ring by --COR.sup.7 or --SO.sub.2 R.sup.7 ;

R.sup.6 is a four to six-membered, aromatic, partially unsaturated or saturated heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by --OR.sup.5, --NR.sup.5 R.sup.5, --CN, oxo, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, --COR.sup.7 or halo;

R.sup.7 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, phenyl or benzyl;

R.sup.8 is C.sub.1 -C.sub.6 alkyl substituted by phenyl, phenoxy, pyridyl or pyrimidinyl, said phenyl, phenoxy, pyridyl and pyrimidinyl being optionally substituted by halo,

--CN, --CONR.sup.5 R.sup.5, --SO.sub.2 NR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --(C.sub.1 -C.sub.6 alkylene)--NR.sup.5 R.sup.5, C.sub.1 -C.sub.6 alkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, C.sub.3 -C.sub.7 cycloalkyl or C.sub.1 -C.sub.6 alkoxy;

R.sup.9 is H, C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.7 cycloalkyl, said C.sub.1 -C.sub.6 alkyl and C.sub.3 -C.sub.7 cycloalkyl being optionally substituted by --OR.sup.5, --NR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5, --CONR.sup.5 R.sup.5 or R.sup.6 ;

R.sup.10 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl, benzyl or C-linked R.sup.6, said C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, --OR.sup.5, --OR.sup.12, --CN, --CO.sub.2 R.sup.7, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5,

--C(.dbd.NR.sup.5)NR.sup.5 OR.sup.5, --CONR.sup.5 NR.sup.5 R.sup.5, --OCONR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 R.sup.12, --NR.sup.5 COR.sup.5,

--NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 COCONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7, --SO.sub.2 NR.sup.5 R.sup.5 or R.sup.6 ;

X is --CH.sub.2 --, --CHR.sup.11 --, --CO--, --S--, --SO-- or --SO.sub.2 --;

R.sup.11 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl or C.sub.1 -C.sub.6 alkoxy; and

R.sup.12 is C.sub.1 -C.sub.6 alkyl substituted by R.sup.6, --OR.sup.5, --CONR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5 or --NR.sup.5 R.sup.5 ;

in the manufacture of (a) a reverse transcriptase inhibitor or modulator or (b) a medicament for the treatment of a human immunodeficiency viral (HIV), or genetically related retroviral, infection or a resulting acquired immunodeficiency syndrome (AIDS).

The present invention also provides a novel compound of the formula ##STR3##

or a pharmaceutically acceptable salt or solvate thereof, wherein

either (i) R.sup.1 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl, benzyl, halo, --CN, --OR.sup.7, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5, --NR.sup.5 CO--(C.sub.1 -C.sub.6 alkylene)-OR.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.6, said C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, --CN, --OR.sup.5, --OR.sup.8, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.8 R.sup.9, --NR.sup.5 COR.sup.5, --NR.sup.5 COR.sup.6, --NR.sup.5 COR.sup.8, --SO.sub.2 NR.sup.5 R.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.6 and

R.sup.2 is --Y--Z,

or, R.sup.1 and R.sup.2, when taken together, represent unbranched C.sub.3 -C.sub.4 alkylene, optionally wherein one methylene group of said C.sub.3 -C.sub.4 alkylene is replaced by an oxygen atom or a nitrogen atom, said nitrogen atom being optionally substituted by R.sup.5 or R.sup.8,

and R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl, benzyl, --CN, halo, --OR.sup.7, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 NR.sup.7 or R.sup.6, said C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl and benzyl being optionally substituted by halo, --CN, --OR.sup.5, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5, --SO.sub.2 NR.sup.5 R.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.6,

or (ii) R.sup.1 and R.sup.3 are each independently C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl or halo-(C.sub.1 -C.sub.6 alkyl), and R.sup.2 is H,

provided that

(a) for definition (i), R.sup.1 and R.sup.3 are not both H,

(b) for definition (i), R.sup.1 and R.sup.3 are not both optionally substituted phenyl, as defined therein,

(c) for definition (i), when R.sup.1 and R.sup.3 are both methyl, R.sup.2 is not phenyl or methyl, and

(d) for definition (ii), R.sup.1 and R.sup.3 are not both methyl;

Y is a direct bond or C.sub.1 -C.sub.3 alkylene;

Z is R.sup.10 or, where Y is C.sub.1 -C.sub.3 alkylene, Z is --NR.sup.5 COR.sup.10, --NR.sup.5 CONR.sup.5 R.sup.10,

--NR.sup.5 CONR.sup.5 COR.sup.10 or --NR.sup.5 SO.sub.2 R.sup.10 ;

R.sup.4 is phenyl or pyridyl, each substituted by at least one substituent selected from halo, --CN, C.sub.1 -C.sub.6 alkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, C.sub.3 -C.sub.7 cycloalkyl and C.sub.1 -C.sub.6 alkoxy;

each R.sup.5 is independently either H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, phenyl or benzyl, or, when two such groups are attached to the same nitrogen atom, those two groups taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl and morpholinyl being optionally substituted by C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.7 cycloalkyl and said piperazinyl and homopiperazinyl being optionally substituted on the nitrogen atom not taken together with the two R.sup.5 groups to form the ring by --COR.sup.7 or --SO.sub.2 R.sup.7 ;

R.sup.6 is a four to six-membered, aromatic, partially unsaturated or saturated heterocyclic group containing (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or 1 sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by --OR.sup.5, --NR.sup.5 R.sup.5, --CN, oxo, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, --COR.sup.7 or halo;

R.sup.7 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, phenyl or benzyl;

R.sup.8 is C.sub.1 -C.sub.6 alkyl substituted by phenyl, pyridyl or pyrimidinyl, said phenyl, pyridyl and pyrimidinyl being optionally substituted by halo, --CN, --CONR.sup.5 R.sup.5, --SO.sub.2 NR.sup.5 R.sup.5,

--NR.sup.5 SO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --(C.sub.1 -C.sub.6 alkylene)-NR.sup.5 R.sup.5, C.sub.1 -C.sub.6 alkyl, flouro-(C.sub.1 -C.sub.6)-alkyl, C.sub.3 -C.sub.7 cycloalkyl or C.sub.1 -C.sub.6 alkoxy;

R.sup.9 is H, C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.7 cycloalkyl, said C.sub.1 -C.sub.6 alkyl and C.sub.3 -C.sub.7 cycloalkyl being optionally substituted by --OR.sup.5, --NR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5, --CONR.sup.5 R.sup.5 or R.sup.6 ;

R.sup.10 is (a) benzyl or C-linked R.sup.6, said benzyl being optionally substituted by halo, --OR.sup.5, --OR.sup.12, --CN, --CO.sub.2 R.sup.7, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --C(.dbd.NR.sup.5)NR.sup.5 OR.sup.5, --CONR.sup.5 NR.sup.5 R.sup.5, --CONR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 R.sup.12, --NR.sup.5 COR.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 COCONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7, --SO.sub.2 NR.sup.5 R.sup.5 or R.sup.6, or (b) when R.sup.1 and R.sup.3 are each independently C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl or halo-(C.sub.1 -C.sub.6 alkyl), R.sup.10 is phenyl, C.sub.1 -C.sub.6 alkyl or C.sub.3 -C.sub.7 cycloalkyl each being optionally substituted by halo, --OR.sup.5, --OR.sup.12, --CN, --CO.sub.2 R.sup.7, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --C(.dbd.NR.sup.5)NR.sup.5 OR.sup.5, --CONR.sup.5 NR.sup.5 R.sup.5, --OCONR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 R.sup.12, --NR.sup.5 COR.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 COCONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7, --SO.sub.2 NR.sup.5 R.sup.5 or R.sup.6 ;

X is --CH.sub.2 --, --CHR.sup.11 --, --CO--, --S--, --SO-- or --SO.sub.2 --;

R.sup.11 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl or C.sub.1 -C.sub.6 alkoxy; and

R.sup.12 is C.sub.1 -C.sub.6 alkyl substituted by R.sup.6, --OR.sup.5, --CONR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5 or --NR.sup.5 R.sup.5.

In the above definitions, halo means fluoro, chloro, bromo or iodo. Unless otherwise stated, alkyl, alkenyl, alkynyl, alkylene and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkenyl include ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methylpropen-1-yl or 2-methylpropen-3-yl. Examples of alkynyl include ethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-buten-1-yl. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene and 1,3-propylene. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. `C-linked` used in the definition of R.sup.10 means that the R.sup.10 substituent is attached through a ring carbon atom. Where R.sup.1 and R.sup.2 are taken together, they form, along with the nitrogen atom and the carbon atom of the pyrazole ring to which they are attached, a 5- or 6-membered ring.

The pharmaceutically acceptable salts of the compounds of the formula (I) and the compounds of the formula (Ib) include the acid addition and the base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, para-toluenesulphonate and pamoate salts.

Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.

For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977.

The pharmaceutically acceptable solvates of the compounds of the formula (I) and the compounds of the formula (Ib), and the salts thereof, include the hydrates thereof.

Also included within the present scope of the compounds of the formula (I) and the compounds of the formula (Ib) are polymorphs thereof.

A compound of the formula (I) or a compound of the formula (Ib) may contain one or more asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) and the compounds of the formula (Ib) together with, where appropriate, the individual tautomers thereof, and mixtures thereof.

Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or high performance liquid chromatography (HPLC) of a stereoisomeric mixture of a compound of the formula (I) or a compound of the formula (Ib) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) or a compound of the formula (Ib) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by HPLC of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

Preferred individual compounds according to the invention include the Examples below.

Particularly preferred individual compounds according to the invention include

2-{4-[(3,5-dichlorophenyl)sulfanyl]-3,5-dimethyl-1H-pyrazol-1-yl}ethanol;

2-[4-[(3,5-dichlorophenyl)sulfanyl]-3-ethyl-5-(hydroxymethyl)-1H-pyrazol-1- yl]ethanol; and

2-{4-[(3,5-dichlorophenyl)sulfanyl]-3,5-diethyl-1H-pyrazol-1-yl}ethanol.

The following preferred features of the invention relate both to compounds of the formula (I) and compounds of the formula (Ib).

Preferably, R.sup.1 is C.sub.1 -C.sub.6 alkyl, --OR.sup.7, --CO.sub.2 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 CO--(C.sub.1 -C.sub.6 alkylene)-OR.sup.5 or R.sup.6, said C.sub.1 -C.sub.6 alkyl being optionally substituted by halo, --CN, --OR.sup.5, --OR.sup.8, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.8 R.sup.9, --NR.sup.5 COR.sup.5, --NR.sup.5 COR.sup.6, --NR.sup.5 COR.sup.8, --SO.sub.2 NR.sup.5 R.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.6.

Preferably, R.sup.1 is C.sub.1 -C.sub.6 alkyl, --OR.sup.7, --CO.sub.2 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 CO--(C.sub.1 -C.sub.6 alkylene)-OR.sup.5 or R.sup.6, said C.sub.1 -C.sub.6 alkyl being optionally substituted by halo or --OR.sup.5.

Preferably, R.sup.1 is C.sub.1 -C.sub.3 alkyl, --OCH.sub.3, --CO.sub.2 (C.sub.1 -C.sub.2 alkyl), --NHCO.sub.2 (C.sub.1 -C.sub.2 alkyl), --NH.sub.2, --N(CH.sub.3).sub.2, --NHCOCH.sub.2 OCH.sub.3 or furanyl, said C.sub.1 -C.sub.3 alkyl being optionally substituted by fluoro or --OH.

Preferably, R.sup.1 is methyl, ethyl, prop-2-yl, hydroxymethyl, trifluoromethyl, --OCH.sub.3, --CO.sub.2 CH.sub.2 CH.sub.3, --NHCO.sub.2 CH.sub.2 CH.sub.3, --NH.sub.2, --N(CH.sub.3).sub.2, --NHCOCH.sub.2 OCH.sub.3 or furan-2-yl.

Preferably, R.sup.1 is ethyl.

Preferably, R.sup.1 is methyl, ethyl, trifluoromethyl or --CH.sub.2 NHCH.sub.2 (4-cyanophenyl).

Preferably, R.sup.2 is H, C.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CO--(C.sub.1 -C.sub.6 alkyl), --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CONR.sup.5 --(C.sub.1 -C.sub.6 alkyl), --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CONR.sup.5 CO-(phenyl), --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 SO.sub.2 (C-linked R.sup.6), --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CO(C-linked R.sup.6), --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CO-(phenyl), each C.sub.1 -C.sub.6 alkyl and phenyl being optionally substituted by halo, --OR.sup.5, --OR.sup.12, --CN, --CO.sub.2 R.sup.7, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --C(.dbd.NR.sup.5)NR.sup.5 OR.sup.5, --CONR.sup.5 NR.sup.5 R.sup.5, --OCONR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 R.sup.12, --NR.sup.5 COR.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 COCONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7, --SO.sub.2 NR.sup.5 R.sup.5 or R.sup.6.

Preferably, R.sup.2 is H, C.sub.1 -C.sub.6 alkyl, --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CO--(C.sub.1 -C.sub.6 alkyl), --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CONR.sup.5 --(C.sub.1 -C.sub.6 alkyl), --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CONR.sup.5 CO-(phenyl),

--(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 SO.sub.2 R.sup.6, --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 COR.sup.6, --(C.sub.1 -C.sub.3 alkylene)-NR.sup.5 CO-(phenyl), each C.sub.1 -C.sub.6 alkyl and phenyl being optionally substituted by halo, --OR.sup.5, --CN, --CO.sub.2 R.sup.7, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --OCONR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 COCONR.sup.5 R.sup.5 or R.sup.6.

Preferably, R.sup.2 is H, C.sub.1 -C.sub.3 alkyl, --(C.sub.1 -C.sub.2 alkylene)-NHCO--(C.sub.1 -C.sub.3 alkyl), --(C.sub.1 -C.sub.2 alkylene)-NHCONH--(C.sub.1 -C.sub.3 alkyl), --(C.sub.1 -C.sub.2 alkylene)-NHCONHCO-(phenyl), --(C.sub.1 -C.sub.2 alkylene)-NHSO.sub.2 R.sup.6, --(C.sub.1 -C.sub.2 alkylene)-NHCOR.sup.6, --(C.sub.1 -C.sub.2 alkylene)-NHCO-(phenyl), each C.sub.1 -C.sub.3 alkyl and phenyl being optionally substituted by fluoro, --OH, --O(C.sub.1 -C.sub.6 alkyl), --CN, --CO.sub.2 (C.sub.1 -C.sub.6 alkyl), --CONH.sub.2, --OCONH.sub.2, --OCONHCO.sub.2 Ph, --NH.sub.2, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --NHCONH.sub.2, --NHCOCONH.sub.2 or R.sup.6.

Preferably, R.sup.2 is H, --CH.sub.2 OH, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 CH.sub.2 OH, --CH.sub.2 OCONH.sub.2, --CH.sub.2 CH.sub.2 OCONH.sub.2, --CH.sub.2 OCONHCO.sub.2 Ph, --CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 CONH.sub.2, --CH.sub.2 CH.sub.2 NH.sub.2, --CH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2, --CH.sub.2 CH.sub.2 NHCOCHF.sub.2, --CH.sub.2 CH.sub.2 NHCOCH.sub.2 CN, --CH.sub.2 CH.sub.2 NHCOCH.sub.2 N(CH.sub.3).sub.2, --CH.sub.2 CH.sub.2 NHCOCH.sub.2 OCH.sub.3, --CH.sub.2 CH.sub.2 NHCOCH.sub.2 OH, --CH.sub.2 CH.sub.2 NHCOCH.sub.2 OCH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 NHCOCH.sub.2 NHCONH.sub.2, --CH.sub.2 CH.sub.2 NHCOCONH.sub.2, --CH.sub.2 CH.sub.2 NHCONHCH.sub.2 CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 NHCONHCOPh, --CH.sub.2 CH.sub.2 NHCONHCO(2,6-difluorophenyl), --CH.sub.2 CH.sub.2 NHSO.sub.2 (2,4-dihydroxypyrimidin-5-yl), --CH.sub.2 CH.sub.2 NHSO.sub.2 (1-methylimidazol4-yl), --CH.sub.2 CH.sub.2 NHCO(tetrahydrofuran-2-yl), --CH.sub.2 CH.sub.2 NHCO(1,5-dimethylpyrazol-3-yl), --CH.sub.2 CH.sub.2 NHCOCH.sub.2 (tetrazol-1-yl), --CH.sub.2 CH.sub.2 NHCOPh, --CH.sub.2 CH.sub.2 NHCO(pyridin-2-yl), --CH.sub.2 CH.sub.2 NHCO(pyrimidin-2-yl), --CH.sub.2 CH.sub.2 NHCO(2-fluorophenyl), --CH.sub.2 CH.sub.2 NHCO(3-hydroxyphenyl), --CH.sub.2 CH.sub.2 NHCO(3-hydroxypyridazin-6-yl), --CH.sub.2 CH.sub.2 NHCO(2-hydroxypyridin-6-yl), --CH.sub.2 CH.sub.2 NHCO(2-oxo-2H-pyran-5-yl) or --CH.sub.2 CH.sub.2 NHCO(1,2,3-thiadiazol-4-yl).

Preferably, R.sup.2 is H, methyl, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 NH.sub.2, --CH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2, --CH.sub.2 CN, --CH.sub.2 CH.sub.2 OCH.sub.3, --CH.sub.2 CONH.sub.2, --CH.sub.2 CH.sub.2 NHCOCH.sub.2 OCH.sub.3 or azetidin-3-yl.

Preferably, R.sup.2 is --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 NH.sub.2, --CH.sub.2 CN or azetidin-3-yl.

Preferably, R.sup.3 is C.sub.1 -C.sub.6 alkyl, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7 or --NR.sup.5 R.sup.5, said C.sub.1 -C.sub.6 alkyl being optionally substituted by halo, --CN, --OR.sup.5, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 COR.sup.5, --SO.sub.2 NR.sup.5 R.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.6.

Preferably, R.sup.3 is C.sub.1 -C.sub.6 alkyl, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.5 or --NR.sup.5 R.sup.5, said C.sub.1 -C.sub.6 alkyl being optionally substituted by halo, --CN or --OR.sup.5.

Preferably, R.sup.3 is C.sub.1 -C.sub.3 alkyl, --CO.sub.2 (C.sub.1 -C.sub.2 alkyl), --CONH.sub.2, --NHCO.sub.2 (C.sub.1 -C.sub.4 alkyl), --N(CH.sub.3).sub.2 or --NH.sub.2, said C.sub.1 -C.sub.3 alkyl being optionally substituted by halo, --CN or --OH.

Preferably, R.sup.3 is methyl, ethyl, prop-2-yl, hydroxymethyl, cyanomethyl, trifluoromethyl, --CO.sub.2 CH.sub.2 CH.sub.3, --CONH.sub.2, --NHCO.sub.2 C(CH.sub.3).sub.3, --N(CH.sub.3).sub.2 or --NH.sub.2.

Preferably, R.sup.3 is methyl, ethyl, prop-2-yl or trifluoromethyl.

Preferably, R.sup.3 is ethyl.

Preferably, X is --CH.sub.2 --, --CHR.sup.11 --, --CO--, --S-- or --SO.sub.2 --.

Preferably, X is --CH.sub.2 --, --CH(OCH.sub.3)--, --CO--, --S-- or --SO.sub.2 --.

Preferably, X is --CH.sub.2 -- or --S--.

Preferably, R.sup.6 is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morphoninyl, piperazinyl, diazepinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl or pyrazinyl each being optionally substituted by --OR.sup.5, --NR.sup.5 R.sup.5, --CN, oxo, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, --COR.sup.7 or halo.

Preferably, R.sup.6 is furan-2-yl, 2,4-dihydroxypyrimidinyl, 1-methylimidazolyl, tetrahydrofuranyl, 1,5-dimethylpyrazolyl, tetrazolyl, pyridinyl, pyrimidinyl, 3-hydroxypyridazinyl, 2-hydroxypyridinyl, 2-oxo-2H-pyranyl or 1,2,3-thiadiazolyl.

Preferably, R.sup.6 is 2,4-dihydroxypyrimidinyl, 1-methylimidazolyl, tetrahydrofuranyl, 1,5-dimethylpyrazolyl, tetrazolyl, pyridinyl, pyrimidinyl, 3-hydroxypyridazinyl, 2-hydroxypyridinyl, 2-oxo-2H-pyranyl or 1,2,3-thiadiazolyl.

Preferably, R.sup.10 is C.sub.1 -C.sub.6 alkyl, phenyl, or C-linked R.sup.6, said C.sub.1 -C.sub.6 alkyl and phenyl being optionally substituted by halo, --OR.sup.5, --OR.sup.12, --CN, --CO.sub.2 R.sup.7, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --C(.dbd.NR.sup.5)NR.sup.5 OR.sup.5, --CONR.sup.5 NR.sup.5 R.sup.5, --OCONR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 R.sup.12, --NR.sup.5 COR.sup.5, --NR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 COCONR.sup.5 R.sup.5, --NR.sup.5 SO.sub.2 R.sup.7, --SO.sub.2 NR.sup.5 R.sup.5 or R.sup.6.

Preferably, R.sup.10 is C.sub.1 -C.sub.6 alkyl, phenyl, or C-linked R.sup.6, said C.sub.1 -C.sub.6 alkyl and phenyl being optionally substituted by halo, --OR.sup.5, --CN, --CO.sub.2 R.sup.7, --CONR.sup.5 R.sup.5, --OCONR.sup.5 R.sup.5, --OCONR.sup.5 CO.sub.2 R.sup.7, --NR.sup.5 R.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 COCONR.sup.5 R.sup.5 or R.sup.6.

Preferably, R.sup.10 is C.sub.1 -C.sub.3 alkyl, phenyl, or R.sup.6, said C.sub.1 -C.sub.3 alkyl and phenyl being optionally substituted by fluoro, --OH, --O(C.sub.1 -C.sub.6 alkyl), --CN, --CO.sub.2 (C.sub.1 -C.sub.6 alkyl), --CONH.sub.2, --OCONH.sub.2, --OCONHCO.sub.2 Ph, --NH.sub.2, --N(C.sub.1 -C.sub.6 alkyl).sub.2, --NHCONH.sub.2, --NHCOCONH.sub.2 or R.sup.6.

Preferably, R.sup.10 is --CH.sub.2 OH, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 CH.sub.2 OH, --CH.sub.2 OCONH.sub.2, --H.sub.2 CH.sub.2 OCONH.sub.2, --CH.sub.2 OCONHCO.sub.2 Ph, --CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 CONH.sub.2, --CH.sub.2 CH.sub.2 NH.sub.2, --CH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2, --CHF.sub.2, --CH.sub.2 CN, --.sub.2 N(CH.sub.3).sub.2, --CH.sub.2 OCH.sub.3, --CH.sub.2 OH, --CH.sub.2 OCH.sub.2 CH.sub.3, CH.sub.2 NHCONH.sub.2, --CH.sub.2 CH.sub.2 CH.sub.3, phenyl, 2,6-difluorophenyl, 2,4-dihydroxypyrimidin-5-yl, 1-methylimidazol-4-yl, tetrahydrofuran-2-yl, 1,5-dimethylpyrazol-3-yl, --CH.sub.2 (tetrazol-1-yl), pyridin-2-yl, pyrimidin-2-yl, 2-fluorophenyl, 3-hydroxyphenyl, 3-hydroxypyridazin-6-yl, 2-hydroxypyridin-6-yl, 2-oxo-2H-pyran-5-yl or 1,2,3-thiadiazol-4-yl.

Preferably, R.sup.10 is methyl, --CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 CH.sub.2 OH, --CH.sub.2 CH.sub.2 NH.sub.2,

--CH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2, --CH.sub.2 CN, --CH.sub.2 CH.sub.2 OCH.sub.3, --CH.sub.2 CONH.sub.2, --CH.sub.2 CH.sub.2 NHCOCH.sub.2 OCH.sub.3 or azetidin-3-yl.

The following preferred features of the invention relate to compounds of the formula (I).

Preferably, R.sup.4 is phenyl optionally substituted by R.sup.6, halo, --CN, C.sub.1 -C.sub.6 alkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, C.sub.3 -C.sub.7 cycloalkyl or C.sub.1 -C.sub.6 alkoxy.

Preferably, R.sup.4 is phenyl substituted by halo, --CN or C.sub.1 -C.sub.3 alkyl.

Preferably, R.sup.4 is phenyl substituted by fluoro, chloro, bromo, --CN, or methyl.

Preferably, R.sup.4 is 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 3,5-dichlorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 3,5-dicyanophenyl, 3,5-dibromophenyl or 3,5-dimethylphenyl.

Preferably, R.sup.4 is (i) phenyl substituted at the 3 position by fluoro, chloro, methyl or cyano or (ii) phenyl substituted at the 3 and 5 positions by two substituents independently chosen from fluoro, chloro, methyl and cyano.

The following preferred features of the invention relate to compounds of the formula (Ib).

Preferably, R.sup.4 is phenyl substituted by at least one substituent selected from halo, --CN, C.sub.1 -C.sub.6 alkyl, fluoro-(C.sub.1 -C.sub.6)-alkyl, C.sub.3 -C.sub.7 cycloalkyl and C.sub.1 -C.sub.6 alkoxy.

Preferably, R.sup.4 is phenyl substituted by at least one substituent selected from halo, --CN and C.sub.1 -C.sub.3 alkyl.

Preferably, R.sup.4 is phenyl substituted by at least one substituent selected from fluoro, chloro, bromo, --CN and methyl.

Preferably, R.sup.4 is 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 3,5-dichlorophenyl, 2,6-difluorophenyl, 3,5-difluorophenyl, 3,5-dicyanophenyl, 3,5-dibromophenyl or 3,5-dimethylphenyl.

Preferably, R.sup.4 is (i) phenyl substituted at the 3 position by fluoro, chloro, methyl or cyano or (ii) phenyl substituted at the 3 and 5 positions by two substituents independently chosen from fluoro, chloro, methyl and cyano.

All of the compounds of the formula (I) and the compounds of the formula (Ib) can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section, or by similar methods thereto. The present invention also encompasses any one or more of these processes for preparing the compounds of formula (Ib).

In the following general methods, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X are as previously defined for a compound of the formula (Ib) or a compound of the formula (I) unless otherwise stated.

Compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 and R.sup.3 are each either H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl, benzyl, --CO.sub.2 R.sup.5, --CONR.sup.5 R.sup.5, or C-linked R.sup.6, optionally substituted where allowed, may be prepared by the reaction of a compound of the formula ##STR4##

with a compound of the formula

H.sub.2 NNHR.sup.2 (III),

or a salt or hydrate thereof, optionally in the presence of an acid or a base, the base preferably being a tertiary amine base such as triethylamine and the acid preferably being acetic acid. In a typical procedure, a solution of the compound of the formula (II) in a suitable solvent, such as ethanol, is treated with the compound of the formula (III), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux.

Functional equivalents of compounds of the formula (II) may also be used in this reaction. These include compounds of the formula (IV) or (V), in which L.sup.1 and L.sup.2, respectively, are each suitable leaving groups, preferably --N(C.sub.1 -C.sub.6 alkyl).sub.2, most preferably --N(CH.sub.3).sub.2. ##STR5##

Thus, a compound of the formula (Ib) or a compound of the formula (I) may be prepared by the condensation of a compound of the formula (IV) or (V) with a compound of the formula (III), or a salt or hydrate thereof, optionally in the presence of an acid or a base, the base preferably being a tertiary amine base such as triethylamine and the acid preferably being acetic acid. In a typical procedure, a solution of the compound of the formula (IV) or (V) in a suitable solvent, such as acetic acid, is treated with the compound of the formula (III), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux. Compounds of the formula (IV) or (V) are particularly suitable for the synthesis of compounds of the formula (Ib) or compounds of the formula (I) in which R.sup.1 or R.sup.3, respectively, is H.

Compounds of the formula (IV) in which R.sup.1 is H and L.sup.1 is dimethylamino may be prepared by the reaction of a compound of the formula (VI) with dimethylformamide dimethylacetal at an elevated temperature, preferably at about 100.degree. C. Compounds of the formula (V) in which R.sup.3 is H and L.sup.2 is dimethylamino may be prepared by the reaction of a compound of the formula (VII) under the same conditions. Other compounds of the formula (IV) or (V) in which L.sup.1 or L.sup.2 is dimethylamino may be prepared analogously.

Compounds of the formula (VI) are either commercially available or may be prepared ##STR6##

by methods well know in the art. For example, where X is S, compounds of the formula (VI) may be prepared by the reaction of a compound of the formula

R.sup.3 COCH.sub.2 Br (VIII)

with a compound of the formula

R.sup.4 SH (IX).

In a typical procedure a solution of a compound of the formula (VIII) in a suitable solvent, such as acetone, is treated with a compound of the formula (IX), optionally treated with a base, such as potassium carbonate and optionally treated with a catalyst such as sodium iodide or tetrabutylammonium iodide. The reaction is preferably performed at room temperature.

Compounds of the formula (VII) are either commercially available or may be prepared from a compound of the formula

R.sup.1 COCH.sub.2 Br (X)

and a compound of the formula (IX) in the same way that a compound of the formula (VI) may be prepared from a compound of the formula (VIII).

Compounds of the formula (II) may be prepared using the route shown in Scheme 1 in which L.sup.3 is a suitable leaving group, preferably chloro. ##STR7##

In Scheme 1, compounds of the formula (II) in which X is --CH.sub.2 -- may be prepared by the reduction of a compound of the formula (XI) with a suitable reducing agent such as (a) hydrogen in the presence of a palladium catalyst, (b) diphenylsilane in the presence of a palladium catalyst and a zinc salt or (c) triethylsilane in the presence of an acid such as trifluoroacetic acid. In a typical procedure, a solution of the compound of the formula (XI) in a suitable solvent, such as ethanol or a mixture of ethanol and ethyl acetate, under a hydrogen atmosphere, is treated with 5% w/w palladium on barium sulphate. In another typical procedure, a solution of the compound of the formula (XI) in a suitable solvent, such as dichloromethane, is treated with diphenylsilane, tetrakis(triphenylphosphine)palladium (0) and zinc chloride. In a further typical example, a solution of the compound of the formula (XI) in a suitable solvent, such as dichloromethane, is treated with triethylsilane and trifluoroacetic acid.

Compounds of the formula (XI) may be prepared by the condensation of a compound of the formula (XII) with a compound of the formula

R.sup.4 CHO (XV),

or a functional equivalent thereof, such as an acetal, optionally in the presence of a suitable catalyst, such as a mixture of acetic acid and piperidine In a typical procedure, a solution of the compound of the formula (XII) in a suitable solvent such as toluene is treated with a compound of the formula (XV), acetic acid and piperidine and heated at a temperature of from room temperature to the reflux temperature of the solvent. Preferably, the reaction mixture is heated under reflux using a Dean-Stark apparatus. Compounds of the formula (XI), prepared in this way, in which R.sup.1 and R.sup.3 are different, are usually formed as a mixture of stereoisomers. Such a mixture may be used directly in subsequent transformations or separated into its individual stereoisomers which may then be used separately.

Alternatively, compounds of the formula (II) in which X is --CH.sub.2 -- may be prepared by the reaction of a compound of the formula (XII) with a compound of the formula

R.sup.4 CH.sub.2 L.sup.6 (XXVIII)

in which L.sup.6 is a suitable leaving group, preferably is chloro, bromo, iodo or para-toluenesulphonate, in the presence of a suitable base. In a typical procedure, a solution of the compound of the formula (XII) in a suitable solvent, such as 2-butanone, tetrahydrofuran, acetonitrile or diethylether, is treated with a base, such as sodium ethoxide, sodium hydride or sodium carbonate, and the compound of the formula (XXVIII), optionally with heating. A preferred combination is 2-butanone as the solvent and sodium hydride as the base.

Compounds of the formula (XII) and compounds of the formula (XXVIII) are either commercially available or are easily prepared by methods well known to the skilled person.

Compounds of the formula (II) in which X is --CHR.sup.10 -- (other than where R.sup.10 is C.sub.1 -C.sub.6 alkoxy--see below for the preparation of these compounds) may be prepared by the reduction of a compound of the formula (XIII) with a suitable reducing agent such as (a) hydrogen in the presence of a palladium catalyst, (b) diphenylsilane in the presence of a palladium catalyst and a zinc salt or (c) triethylsilane in the presence of an acid such as trifluoroacetic acid. In a typical procedure, a solution of the compound of the formula (XIII) in a suitable solvent, such as ethanol or a mixture of ethanol and ethyl acetate, under a hydrogen atmosphere, is treated with 5% w/w palladium on barium sulphate. In another typical procedure, a solution of the compound of the formula (XIII) in a suitable solvent, such as dichloromethane, is treated with diphenylsilane, tetrakis(triphenylphosphine)palladium (0) and zinc chloride. In a further typical example, a solution of the compound of the formula (XIII) in a suitable solvent, such as dichloromethane, is treated with triethylsilane and trifluoroacetic acid.

Compounds of the formula (XIII) may be prepared by the condensation of a compound of the formula (XII) with a compound of the formula

R.sup.4 COR.sup.10 (XVI),

or a functional equivalent thereof, such as a ketal, optionally in the presence of a suitable catalyst, such as a mixture of acetic acid and piperidine. In a typical procedure, a solution of the compound of the formula (XII) in a suitable solvent such as toluene is treated with a compound of the formula (XVI), acetic acid and piperidine and heated at a temperature of from room temperature to the reflux temperature of the solvent. Preferably, the reaction mixture is heated under reflux using a Dean-Stark apparatus. Compounds of the formula (XIII), prepared in this way, in which R.sup.1 and R.sup.3 are different, are usually formed as a mixture of stereoisomers. Such a mixture may be used directly in subsequent transformations or separated into its individual stereoisomers which may then be used separately.

Compounds of the formula (II) in which X is --S-- may be prepared by the reaction of a compound of the formula (XIV) with a compound of the formula (IX). In a typical procedure a solution of a compound of the formula (XIV) in a suitable solvent, such as acetone, is treated with a compound of the formula (IX), optionally treated with a base, such as potassium carbonate and optionally treated with a catalyst such as sodium iodide or tetrabutylammonium iodide. The reaction is preferably performed at room temperature.

Compounds of the formula (XIV) may be prepared by the reaction of a compound of the formula (XII) with a suitable activating agent, e.g. in the case where L.sup.3 is chloro, with a chlorinating agent such as sulphuryl chloride. In a typical procedure, where L.sup.3 is chloro, the compound of the formula (XII) is treated with sulphuryl chloride, optionally in the presence of a suitable solvent such as dichloromethane.

Compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 or R.sup.3 is --OR.sup.7 may be prepared using the route shown in Scheme 2 in which R.sup.a is C.sub.1 -C.sub.6 alkyl and L.sup.4 is a suitable leaving group, preferably trifluoromethanesulphonate. ##STR8##

In Scheme 2, compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 is --OR.sup.7 may be prepared by the reaction of a compound of the formula (XVII) with an alcohol of the formula

R.sup.7 OH (XXV)

in the presence of a suitable catalyst, preferably a palladium catalyst, and carbon monoxide. In a typical procedure a mixture of the compound of the formula (XVII), a suitable palladium catalyst such as 1,1'-bis(diphenylphosphino)ferrocenepalladium(II)chloride, the alcohol of the formula (XXV) and, optionally, a suitable solvent such as N,N-dimethylformamide is heated, preferably to about 50.degree. C., under an atmosphere of carbon monoxide, preferably at a pressure of 345 kPa.

Compounds of the formula (XVII) may be prepared by the derivatisation of a compound of the formula (XVIII). In the case where L.sup.4 is trifluoromethanesulphonate a suitable derivatising agent is phenyltriflamide. In a typical procedure, where L.sup.4 is trifluoromethanesulphonate, a solution of the compound of the formula (XVIII) and a suitable base, preferably a trialkylamine base such as triethylamine, in a suitable solvent such as dichloromethane is treated with phenyltriflamide.

Compounds of the formula (XVIII) may be prepared by the reaction of a compound of the formula (XIX) with a compound of the formula (III), or a salt or hydrate thereof, optionally in the presence of an acid or a base, the base preferably being a tertiary amine base such as triethylamine and the acid preferably being acetic acid. In a typical procedure, a solution of the compound of the formula (XIX) in a suitable solvent, such as ethanol, is treated with the compound of the formula (III), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux.

Compounds of the formula (XIX) may be prepared by the derivatisation of a compound of the formula (XX) in the same way that compounds of the formula (II) may be prepared by the derivatisation of a compound of the formula (XII) as described above.

Compounds of the formula (XX) are either commercially available or are readily prepared by methods well known to the skilled person.

In Scheme 2, compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.3 is --OR.sup.7 may be prepared from a compound of the formula (XXIV) in the same way that a compound of the formula (I) or a compound of the formula (Ib) in which R.sup.1 is --OR.sup.7 is prepared from a compound of the formula (XX), as described above, mutatis mutandis.

The skilled man will appreciate that compounds of the formula (XVIII) and compounds of the formula (XXII) may exist in one of several tautomeric forms.

Alternatively, compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 or R.sup.3 is --OR.sup.7 may be prepared from compounds of the formula (XVIII) or (XXII), respectively, by reaction with a compound of the formula (XXV) under dehydrating conditions, e.g. using the Mitsunobu reaction. In a typical procedure, a solution of the compound of the formula (XVIII) or (XXII) in a suitable solvent, such as tetrahydrofuran is treated with a dialkylazodicarboxylate, preferably diethylazodicarboxylate, a triarylphosphine, preferably triphenylphosphine and a compound of the formula (XXV).

Alternatively, compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 or R.sup.3 is --OR.sup.7 may be prepared from compounds of the formula (XVIII) or (XXII), respectively, by reaction with a compound of the formula

R.sup.7 L.sup.7 (XXIX)

in which L.sup.7 is a suitable leaving group, preferably halo, optionally in the presence of a suitable base. In a typical procedure, a solution of the compound of the formula (XVIII) or the compound of the formula (XXII) in a suitable solvent, such as tetrahydrofuran, dimethylformamide or ethanol, is treated with a base, such as sodium ethoxide or sodium carbonate, and the compound of the formula (XXIX), optionally with heating.

Compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 or R.sup.3 is halo may be prepared by the reaction, respectively, of a compound of the formula (XVIII) or a compound of the formula (XXII) with a suitable halogenating agent. In a typical procedure, the compound of the formula (XVIII) or (XXII) is treated with POCl.sub.3, optionally in the presence of a suitable solvent such as dimethylformamide, to give a compound of the formula (Ib) or a compound of the formula (I) in which R.sup.1 or R.sup.3, respectively, is chloro.

Compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 or R.sup.3 is --OCONR.sup.5 R.sup.5 may be prepared by the reaction, respectively, of a compound of the formula (XVIII) or a compound of the formula (XXII) with a compound of the formula

R.sup.5 R.sup.5 NCOL.sup.5 (XXVI)

in which L.sup.5 is a suitable leaving group, preferably chloro, or, in the case where one of the R.sup.5 groups is H, with a compound of the formula

R.sup.5 N.dbd.C.dbd.O (XXVII).

Compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 or R.sup.3 is --NH.sub.2 may be prepared by the route shown in Scheme 3. ##STR9##

In Scheme 3, compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 is --NH.sub.2 may be prepared by the reaction of a compound of the formula (XXX) with a compound of the formula (III), or a salt or hydrate thereof, optionally in the presence of an acid or a base, the base preferably being a tertiary amine base such as triethylamine and the acid preferably being acetic acid. In a typical procedure, a solution of the compound of the formula (XXX) in a suitable solvent, such as ethanol, is treated with the compound of the formula (III), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux.

Compounds of the formula (XXX) may be prepared from a compound of the formula (XXXI) in the same way that compounds of the formula (II) may be prepared from a compound of the formula (XII) as described above.

Compounds of the formula (XXXI) are either commercially available or readily prepared by methods well known to the skilled person.

In Scheme 3, compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.3 is --NH.sub.2 may be prepared from a compound of the formula (XXXIII) in the same way that compounds of the formula (Ib) and compounds of the formula (I) in which R.sup.1 is NH.sub.2 may be prepared from compounds of the formula (XXXI), mutatis mutandis.

Compounds of the formula (Ib) and compounds of the formula (I) in which X is --CO-- or --CHR.sup.10 -- and R.sup.10 is C.sub.1 -C.sub.6 alkoxy may be prepared by the route shown in Scheme 4 in which R.sup.b is C.sub.1 -C.sub.6 alkyl. ##STR10##

In Scheme 4, compounds of the formula (Ib) and compounds of the formula (I) in which X is --CO-- (i.e. compounds of the formula (Ic)) may be prepared by the oxidation of a compound of the formula (XXXIV). In a typical procedure, a solution of a compound of the formula (XXXIV) in a suitable solvent, such as dichloromethane, is treated with N-methylmorpholine-N-oxide and tetra-n-propylammonium perruthenate.sup.(VII).

Compounds of the formula (Ib) and compounds of the formula (I) in which X is --CHR.sup.10 -- and R.sup.10 is C.sub.1 -C.sub.6 alkoxy (i.e. compounds of the formula (Id)) may be prepared by the alkylation of a compound of the formula (XXXIV). In a typical procedure, a solution of a compound of the formula (XXXIV) in a suitable solvent, such as N,N-dimethylformamide, is treated with a base, such as sodium hydride, and a compound of the formula

R.sup.b L.sup.8 (XXXVIII)

wherein R.sup.b is C.sub.1 -C.sub.6 alkyl and L.sup.8 is a suitable leaving group, preferably chloro, bromo or iodo.

Compounds of the formula (XXXIV) may be prepared by the reaction of a compound of the formula (XXXV) with a suitable metal or organometallic reagent to form an organometallic intermediate which is reacted with a compound of the formula (XV). A preferred metal is magnesium. In a typical procedure, a solution of the compound of the formula (XXXV) in a suitable solvent, such as tetrahydrofuran, is treated with an alkylmagnesium chloride, e.g. iso-propylmagnesium chloride, preferably with cooling in an ice bath, and a compound of the formula (XV) is added.

Compounds of the formula (XXXV) may be prepared by the reaction of a compound of the formula (XXXVI) with a suitable base, preferably sodium hydride, and the addition of a compound of the formula

R.sup.2 L.sup.9 (XXXIX)

wherein L.sup.9 is a suitable leaving group, preferably a chloro, bromo, iodo or tosylate group. In a typical procedure, a solution of the compound of the formula (XXXVI) in a suitable solvent, such as N,N-dimethylformamide, is treated firstly with a suitable base, such as sodium hydride, and then with a compound of the formula (XXXIX). The reaction is then preferably heated, most preferably to 50.degree. C. If R.sup.2 contains a free --OH, --NH.sub.2, or --NH-- group then a protecting group is preferably employed to mask such functionality. Examples of suitable protecting groups will be apparent to the skilled person [see, for instance, `Protecting groups in Organic Synthesis (Second Edition)` by Theodora W. Green and Peter G. M. Wuts, 1991, John Wiley and Sons]. The protecting group may be removed immediately or carried through subsequent steps, as described above, and removed as a final step (see below).

Compounds of the formula (XXXVI) may be prepared by the reaction of a compound of the formula (XXXVII) with a suitable iodinating agent. In a typical procedure, a solution of the compound of the formula (XXXVII) in a suitable solvent, such as dichloromethane, is treated with the iodinating agent which is preferably N-iodosuccinimide.

Compounds of the formula (XXXVII) are either commercially available or are readily prepared by methods well known to the skilled man. Such compounds may, for instance, be prepared by analogy with the methods presented above, for example by the reaction of a diketone (XII) with a compound of the formula (III), or a salt or solvate thereof.

It will be appreciated by those skilled in the art that, in many cases, compounds of the formula (Ib) and compounds of the formula (I) may be converted, respectively, into other compounds of the formula (Ib) or compounds of the formula (I) by functional group transformations. For instance:

(a) Compounds of the formula (Ib)/(I) in which R.sup.2 is H may be converted into compounds of the formula (Ib)/(I) in which R.sup.2 is optionally substituted C.sub.1 -C.sub.6 alkyl by reaction with an appropriate alkylating agent. In a typical procedure, a solution of a compound of the formula (Ib)/(I) in which R.sup.2 is H in a suitable solvent such as ethanol or N,N-dimethylformamide is treated with an alkyl bromide and a base such as sodium ethoxide or sodium hydride and heated at a temperature of from room temperature to the reflux temperature of the solvent. A preferred combination is N,N-dimethylformamide as the solvent, sodium hydride as the base and room temperature as the temperature. Examples of specific alkylating agents include bromoacetonitrile, ethyl 4-chloroacetoacetate, ethyl bromoacetate, methyl bromoacetate and chloroethylamine hydrochloride. The use of further specific alkylating agents is illustrated by the Examples below.

(b) Compounds of the formula (Ib)/(I) in which R.sup.2 contains as ester functionality may be reduced with a suitable reducing agent, such as lithium aluminium hydride, to give corresponding compounds of the formula (Ib)/(I) in which R.sup.2 contains a hydroxy group. In a typical procedure, a solution of the compound of the formula (Ib)/(I), in which R.sup.2 contains an ester group, in a suitable solvent, such as diethyl ether, is treated with lithium aluminium hydride, preferably with cooling to a temperature of from -78.degree. C. to 0.degree. C.

(c) Compounds of the formula (Ib)/(I) in which R.sup.1 or R.sup.3 is --NH.sub.2, may be converted into compounds of the formula (Ib)/(I) in which R.sup.1 or R.sup.3, respectively, is --NHR.sup.c, where R.sup.c is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl or benzyl by a reductive amination with an appropriate aldehyde or ketone. In a typical reductive amination, the reaction will proceed in a suitable solvent such as dichloromethane, in the presence of a suitable reducing agent such as sodium triacetoxyborohydride and optionally in the presence of an acid such as acetic acid. A further reductive amination may be performed on a compound of the formula (Ib)/(I) in which R.sup.1 or R.sup.3 is --NHR.sup.c to give a compound of the formula (Ib)/(I) in which R.sup.1 or R.sup.3, respectively, is --NR.sup.c R.sup.c, where R.sup.c is as defined above and each R.sup.c may be the same or different.

(d) Compounds of the formula (Ib)/(I) in which R.sup.1 or R.sup.3 is --NHR.sup.5, may be converted into compounds of the formula (Ib)/(I) in which, respectively, R.sup.1 is --NR.sup.5 COR.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7 or --NR.sup.5 SO.sub.2 R.sup.7 or R.sup.3 is --NR.sup.5 COR.sup.5, --NR.sup.5 CONR.sup.5 R.sup.5, --NR.sup.5 CO.sub.2 R.sup.7 or --NR.sup.5 SO.sub.2 R.sup.7 by reaction with an appropriate acylating or sulphonylating agent in a suitable inert solvent, such as dichloromethane, optionally in the presence of a base, preferably a tertiary amine base such as triethylamine.

(e) compounds of the formula (Ib)/(I) in which R.sup.1 or R.sup.3 is --CO.sub.2 R.sup.5, wherein R.sup.5 is other than H, may be converted into compounds of the formula (Ib)/(I) in which R.sup.1 or R.sup.3, respectively, is --CO.sub.2 H by hydrolysis. Typically the reaction will be carried out in a suitable solvent, such as aqueous ethanol, or aqueous 1,4-dioxan and in the presence of a base such as sodium hydroxide. Such an acid may be converted to a primary amide by reaction with ammonia and a suitable coupling agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide. Such a primary amide may then be converted into a nitrile by dehydration with a suitable dehydrating agent, such as phosphoryl chloride.

(f) Compounds of the formula (Ib)/(I) in which R.sup.1 or R.sup.3 is --CO.sub.2 H, may be converted into compounds of the formula (Ib)(I) in which R.sup.1 or R.sup.3, respectively, is --NH.sub.2, by the Curtius rearrangement. In a typical procedure, the reaction is carried out in a suitable solvent, such as dichloromethane, in the presence of a reagent such as diphenylphosphoryl azide.

(g) Compounds of the formula (Ib)/(I) in which X is --S-- may be converted into compounds of the formula (Ib)/(I) in which X is --SO-- by reaction with a suitable oxidising agent, such as meta-chloroperoxybenzoic acid. The reaction is carried out in the presence of a suitable solvent such as dichloromethane.

(h) Compounds of the formula (Ib)/(I) in which X is --S-- may be converted into compounds of the formula (Ib)/(I) in which X is --SO.sub.2 -- by reaction with a suitable oxidising agent such as Oxone (trade mark), meta-chloroperoxybenzoic acid or hydrogen peroxide. In a typical procedure, a solution of the compound of the formula (Ib)/(I) in which X is --S-- in a suitable solvent, such as dichloromethane, is treated with meta-chloroperoxybenzoic acid.

(i) Compounds of the formula (Ib)/(I) in which R.sup.1, R.sup.2 or R.sup.3 contain a heterocycle of the formula R.sup.6 may be prepared by standard heterocycle-forming reactions well known to the skilled person (see, for example, Advanced Organic Chemistry, 3rd Edition, by Gerry March or Comprehensive Heterocyclic Chemistry, A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Volumes 1-11), either from another compound of the formula (Ib)/(I) or otherwise. For instance, compounds of the formula (Ib)/(I) in which R.sup.2 is (2-amino-6-hydroxypyrimidin-4-yl)methyl may be prepared by the sequential reaction of a compound of the formula (Ib)/(I) in which R.sup.2 is H with methyl 4-chloroacetoacetate and then guanidine hydrochloride.

(j) Compounds of the formula (Ib)/(I) in which either R.sup.1 or R.sup.3 is an N-linked heterocycle of the formula R.sup.6 may be prepared from compounds of the formula (Ib)/(I) in which R.sup.1 or R.sup.3, respectively, is --NH.sub.2, by standard heterocycle-forming reactions well known to the skilled man (see, for example, Advanced Organic Chemistry, 3rd Edition, by Gerry March or Comprehensive Heterocyclic Chemistry, A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Volumes 1-11).

Compounds of the formula (Ib)/(I) containing an --OH, --NH-- or --NH.sub.2 group may be prepared by the deprotection of the corresponding compound bearing an --OP.sup.1, --NP.sup.1 -- or --NHP.sup.1 group, respectively, wherein the group P.sup.1 is a suitable protecting group. Examples of suitable protecting groups will be apparent to the skilled person [see, for instance, `Protecting groups in Organic Synthesis (Second Edition)` by Theodora W. Green and Peter G. M. Wuts, 1991, John Wiley and Sons]. Such compounds bearing an --OP.sup.1, --NP.sup.1 -- or --NHP.sup.1 group may be prepared using the routes described above, mutatis mutandis.

The compounds of the formula (I) and the compounds of the formula (Ib) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For example, the compounds of the formula (I) and the compounds of the formula (Ib) can be administered orally, buccally or sublingually in the form of tablets, capsules, multi-particulates, gels, films, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications. The compounds of the formula (I) and the compounds of the formula (Ib) may also be administered as fast-dispersing or fast-dissolving dosage forms or in the form of a high energy dispersion or as coated particles. Suitable formulations of the compounds of the formula (I) and the compounds of the formula (Ib) may be in coated or uncoated form, as desired.

Such solid pharmaceutical compositions, for example, tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

General Example

A formulation of the tablet could typically contain between about 0.01 mg and 500 mg of active compound whilst tablet fill weights may range from 50 mg to 1000 mg. An example of a formulation for a 10 mg tablet is illustrated below:

            Ingredient                             % w/w
            Compound of the formula (I)/(Ib) or salt        10.000*
            Lactose                                 64.125
            Starch                                  21.375
            Croscarmellose sodium                    3.000
            Magnesium Stearate                       1.500
    *Quantity adjusted in accordance with drug activity.

     Exam-
      ple
      No.      R.sup.3         R.sup.1      R.sup.Z  R.sup.Y     LRMS m/z =
     Analytical data, starting ester and variations in procedure.
       2    CH.sub.3 CH.sub.2 -- CH.sub.3 CH.sub.2 -- Cl  Cl  (thermospray):
     327 .sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta. =  1.06(t, 3H), 1.18(t,
     3H), 2.50(m,
                                                       [MH.sup.+ ]    4H),
     3.72(s, 2H), 4.05(m, 2H), 4.12(m, 2H), 4.19(br. t, 1H),
                                                                      6.99(s,
     2H), 7.19(s, 1H).
                                                                      Contains
     ca. 10% monodechlorinated impurity as judged by LCMS
                                                                      (50
     .times. 2 mm Magellen 3 micron C18 column, solvent gradient 0.1%, by
                                                                      volume
     aqueous formic acid:0.1%, by volume formic acid in
     acetonitrile (95:5, by volume) to 0.1%, by volume aqueous formic
     acid:0.1%, by volume formic acid in acetonitrile (5:95, by volume),
     electrospray MS).
                                                                      Ester of
     Example 9.
     Chromatography with a solvent gradient of toluene:ethyl acetate
                                                                      (1:1, by
     volume) then toluene:ethyl acetate (1:2, by volume).
       3    CH.sub.3 CH(CH.sub.3)--   CH.sub.3 --   Cl   H  (thermospray): 293
     .sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta.  = 1.15(d, 6H), 2.06(s, 3H),
     2.82(m,
                                                       [MH.sup.+ ]    1H),
     3.73(s, 2H), 3.99(m, 2H), 4.06(m, 2H), 4.29(br. s, 1H),
                                                                      6.96(m,
     1H), 7.05(s, 1H), 7.15(m, 2H).
     Microanalysis: Found: C, 65.58; H, 7.30; N, 9.33. C.sub.16 H.sub.21
     ClN.sub.2 O
                                                                      requires
     C, 65.63; H, 7.23; N, 9.57%.
                                                                      Ester of
     Example 15.
     Chromatography with a solvent gradient of pentane:ethyl acetate
                                                                      (2:1, by
     volume) then pentane:ethyl acetate (1:1, by volume).
       4    CH.sub.3 CH(CH.sub.3)--   CH.sub.3 --    F   F  (electrospray): 295
     .sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta. = 1.10(d, 6H), 2.10(s, 3H),
                                                       [MH.sup.+ ]
     2.80(heptet, 1H), 3.74(s, 2H), 4.00(m, 2H), 4.06(m, 2H), 4.20(t, 1H),
                                                                      6.60(m,
     3H).
                                                                      Ester of
     Example 16.
     Chromatography with a solvent gradient of pentane:ethyl acetate
                                                                      (2:1, by
     volume) then pentane:ethyl acetate (1:1, by volume).
       5    CH.sub.3 CH(CH.sub.3)--   CH.sub.3 --    F   H  (thermospray): 277
     .sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta. = 1.18(d, 6H), 2.08(s, 3H),
                                                       [MH.sup.+ ]
     2.84(heptet, 1H), 3.76(s, 2H), 3.98(m, 2H), 4.05(m, 2H), 4.23(t, 1H),
                                                                      6.75(d,
     1H), 6.86(m, 2H), 7.20(m, 1H).
     Microanalysis: Found: C, 69.45; H, 7.71; N, 9.96. C.sub.16 H.sub.21
     FN.sub.2 O
                                                                      requires
     C, 69.54; H, 7.66; N, 10.14%.
                                                                      Ester of
     Example 10.
     Chromatography with pentane:ethyl acetate (1:1, by volume).
       6      CH.sub.3 --   CH.sub.3 CH(CH.sub.3)-- Cl  Cl  (thermospray): 327
     .sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta. = 1.10(d, 6H), 2.06(s, 3H),
                                                       [MH.sup.+ ]
     3.06(heptet, 1H), 3.79(s, 2H), 4.00(m, 2H), 4.13(m, 2H), 6.95(s, 2H),
                                                                      7.18(s,
     1H).
                                                                      HRMS
     (electrospray): m/z [MH.sup.+ ] 327.1031 (calculated 327.1026).
                                                                      Ester of
     Example 8, using Method B
     Chromatography with a solvent gradient of pentane:ethyl acetate
                                                                      (1:1, by
     volume) then ethyl acetate.

     Example
       No.       R.sup.3        R.sup.1     R.sup.Z  R.sup.Y    LRMS m/z =
     Analytical data, starting pyrazole and variations in procedure.
        9     CH.sub.3 CH.sub.2 -- CH.sub.3 CH.sub.2 -- Cl   Cl
     (thermospray):  .sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta. =  1.14(t,
     3H), 1.16(t, 3H), 1.28(t,
                                                      369 [MH.sup.+ ] 3H),
     2.48(m, 4H), 3.75(s, 2H), 4.24(q, 2H), 4.84(s, 2H), 6.99(s,
                                                                      2H),
     7.19(s, 1H).
                                                                      Pyrazole
     of Example 11.
     Microanalysis: Found: C, 58.41; H, 5.95; N, 7.39. C.sub.18 H.sub.22
     Cl.sub.2 N.sub.2 O.sub.2
                                                                      requires
     C, 58.54; H, 6.00; N, 7.59%.
                                                                      Contains
     Ca. 10% monodechlorinated impurity as judged by LCMS.
     Chromatography with a solvent gradient of dichloromethane then
     dichloromethane:methanol (99:1, by volume).
       10     CH.sub.3 CH(CH.sub.3)--  CH.sub.3 --   F    H   (thermospray):
     .sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta. = 1.13(d, 6H), 1.23(t, 3H),
     2.03(s,
                                                      319 [MH.sup.+ ] 3H),
     2.80(heptet, 1H), 3.75(s, 2H), 4.20(q, 2H), 4.80(s, 2H),
                                                                      6.71(d,
     1H), 6.85(m, 2H), 7.16(m, 1H).
                                                                      HRMS
     (electrospray): m/z [MH.sup.+ ] 319.1814 (calculated 319.1817).
                                                                      Pyrazole
     of Example 19.
     Chromatography with pentane:ethyl acetate (5:1, by volume).

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A solution of the amine of Example 87 (18 mg, 0.06 mmol) in dichloromethane (0.3 ml) was treated with triethylamine (8.0 .mu.L, 0.06 mmol) followed by paraformaldehyde (4.0 mg, 0.13 mmol) and stirred at room temperature for 1 hour. Acetic acid was added (3.5 .mu.L, 0.06 mmol) and after a further hour sodium triacteoxyborohydride (19 mg, 0.09 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. Further paraformaldehyde (2.2 eq) and sodium triacteoxyborohydride (1.5 eq) were added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane (10 ml) and washed with 10% aqueous potassium carbonate solution (10 ml). The organic extract was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.5) to afford the title compound as a colourless oil (4.5 mg).

.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.=2.08 (s, 3H), 2.70 (s, 6H), 3.78 (s, 2H), 4.00 (s, 4H), 4.19 (m, 1H), 7.02 (s, 2H), 7.20 (s, 1H).

LRMS (thermospray): m/z [MNH.sub.4.sup.+ ] 346.

EXAMPLE 30

2-[4-(3,5-Dimethylbenzyl)-3,5-diethyl-1H-pyrazol-1-yl]ethanol

##STR33##

The title compound was prepared by a method similar to that of Example 25, using the .beta.-diketone of Preparation 24. The crude material was purified by flash chromatography on silica gel eluting with methanol:dichloromethane (2:98, by volume) to afford the title compound as a yellow oil, which solidified on standing, m.p. 49.5-51.5.degree. C.

.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.=1.03 (t, 3H), 1.16 (t, 3H), 2.29 (s, 6H), 2.55 (m, 4H), 3.71 (s, 2H), 4.03 (m, 2H), 4.13 (m, 2H), 4.35 (brs, 1H), 6.77 (s, 2H), 6.84 (s, 1H).

LRMS (thermospray): m/z [MH.sup.+ ] 287.

EXAMPLE 31

2-[4-(3,5-Dichlorobenzyl)-5-methoxy-3-methyl-1H-pyrazol-1-yl]ethanol

##STR34##

A solution of the ester of Example 88 (42 mg, 0.12 mmol) in tetrahydrofuran (2 ml) at 0.degree. C. was treated dropwise with a solution of lithiumaluminiumhydride (1M in THF) and the resulting mixture was allowed to warm to room temperature and was stirred at this temperature for a further 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound (34 mg) as a white solid.

.sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta.=2.07 (s, 3H), 3.45 (brs, 1H), 3.72 (s, 2H), 3.79 (s, 3H), 3.95 (m, 2H), 4.03 (m, 2H), 7.02 (s, 2H), 7.20 (s, 1H).

LRMS (thermospray): m/z [MH.sup.+ ] 315.

EXAMPLE 32

2-[4-(3,5-Dichlorobenzyl)-5-(2-furyl)-3-methyl-1H-pyrazol-1-yl]ethanol

##STR35##

A solution of the .beta.-diketone of Preparation 27 (1.0 g, 3.20 mmol) in ethanol (38 ml) was treated with 2-hydroxyethyl hydrazine (239 .mu.L, 3.53 mmol) and heated under reflux for 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (2:1, by volume) to afford the title compound as a yellow oil, which solidified on standing (703 mg).

.sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta.=2.16 (s, 3H), 3.58 (t, 1H), 3.80 (s, 2H), 4.01 (m, 2H), 4.28 (m, 2H), 6.37 (d, 1H), 6.49 (m, 1H), 6.99 (s, 2H), 7.18 (s, 1H), 7.36 (s, 1H).

LRMS (thermospray): m/z [MH.sup.+ ] 351.

Microanalysis: Found: C, 58.12; H, 4.63; N, 7.84. C.sub.17 H.sub.16 Cl.sub.2 N.sub.2 O.sub.2 requires C, 58.13; H, 4.59; N, 7.98%.

EXAMPLE 33

(3,5-Dichlorophenyl)[3,5-diethyl-1-(2-hydroxyethyl )-1H-pyrazol-4-yl]methanone

##STR36##

A solution of the protected alcohol of Preparation 32 (70 mg, 0.15 mmol) in tetrahydrofuran (1 ml) was treated with tetrabutylammonium fluoride (1 M in THF) (300 .mu.L, 0.30 mmol), at room temperature, under a nitrogen atmosphere. After the reaction mixture had been stirred for 18 hours the solution was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with cyclohexane:ethyl acetate (5:1, by volume) to afford the title compound (30 mg) as a white solid, m.p. 133.5-134.4.degree. C.

.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.=1.13 (m, 6H), 2.52 (q, 2H), 2.74 (q, 2H), 3.65 (t, 1H), 4.10 (m, 2H), 4.19 (m, 2H), 7.61 (m, 3H).

LRMS (thermospray): m/z [MH.sup.+ ] 341.

Microanalysis: Found: C, 56.03; H, 5.28; N, 8.13. C.sub.16 H.sub.15 Cl.sub.2 N.sub.2 O.sub.2 requires C, 56.32; H, 5.32; N, 8.21%.

EXAMPLE 34

(.+-.)-2-{4-[(3,5-Dichlorophenyl)(methoxy)methyl]-3,5-diethyl-1H-pyrazol-1- yl}ethanol

##STR37##

The title compound was prepared by a similar method to that of Example 33 using the protected alcohol of Preparation 33. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (5:1, by volume) gradually changing to cyclohexane:ethyl actetate (1:2, by volume) to afford the title compound as a colourless oil.

.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta.=1.00 (t, 3H), 1.20 (t, 3H), 2.55 (m, 4H), 3.39 (s, 3H), 4.06 (m, 4H), 5.23 (s, 1H), 7.26 (m, 3H).

LRMS (thermospray): m/z [MH.sup.+ ] 357.

EXAMPLE 35

2-[4-(2,6-Difluorobenzyl)-3,5-diethyl-1H-pyrazol-1-yl]ethanol

##STR38##

A mixture of the .beta.-diketone of Preparation 35 (89 mg, 0.35 mmol), 2-hydroxyethyl hydrazine (24 .mu.L, 0.35 mmol) and ethanol (350 .mu.L) was heated at 80.degree. C. in a sealed Reacti-vial (Trade Mark) for 18 hours. After cooling, the solution was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with pentane:ethyl actetate (2:1, by volume) to afford the title compound (67 mg) as a white solid, m.p. 70-71.degree. C.

.sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta.=1.00 (t, 3H), 1.15 (t, 3H), 2.55 (q, 2H), 2.62 (q, 2H), 3.73 (s, 2H), 3.97 (m, 2H), 4.00 (m, 2H), 4.26 (t, 1H), 6.84 (t, 2H), 7.15 (m, 1H).

LRMS (electrospray): m/z [MH.sup.+ ] 295.

Microanalysis: Found: C, 65.20; H, 6.87; N, 9.48. C.sub.16 H.sub.20 F.sub.2 N.sub.2 O requires C, 65.29; H, 6.85; N, 9.52%.

EXAMPLE 36

2-[4-(3,5-Dichlorobenzyl)-3,5-diethyl-1H-pyrazol-1-yl]ethyl carbamate

##STR39##

A solution of the alcohol of Example 2 (50 mg, 0.15 mmol) in dichloromethane (1.5 ml) was cooled to 0.degree. C. and treated dropwise with trichloroacetyl isocyanate (22 .mu.L, 0.18 mmol) under a nitrogen atmosphere. After stirring at 0.degree. C. for 1.5 hours the solution was concentrated under reduced pressure. The residue was dissolved in methanol (1 ml) and water (0.5 ml) and cooled to 0.degree. C. Potassium carbonate (64 mg, 0.46 mmol) was added and the resulting mixture was stirred at this temperature for 1 hour. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to afford the title compound (42 mg) as a white solid, m.p. 145-147.degree. C.

.sup.1 H-NMR (400 MHz, CDCl.sub.3): .delta.=1.02 (t, 3H), 1.10 (t, 3H), 2.42 (m, 2H), 2.50 (m, 2H), 3.68 (s, 2H), 4.21 (t, 2H), 4.42 (t, 2H), 4.55 (brs, 2H), 6.94 (s, 2H), 7.15 (s, 1H).

LRMS (thermospray): m/z [MH.sup.+ ] 370.

Microanalysis: Found: C, 54.95; H, 5.65; N, 11.20. C.sub.17 H.sub.21 Cl.sub.2 N.sub.3 O.sub.2 requires C, 55.14; H, 5.72; N, 11.35%.

EXAMPLES 37 and 38

Methyl 3-[4-(3,5-dichlorobenzyl)-3,5-diethyl-1H-pyrazol-1-yl]propanoate (Example 37)

##STR40##

A solution of the pyrazole of Example 11 (198 mg, 0.70 mmol) in ethanol (1 ml) was treated with sodium ethoxide (21% w/v, in EtOH) (261 .mu.L, 0.81 mmol) and then methyl-3-bromopropionate (153 .mu.L, 1.40 mmol) and heated at 70.degree. C. in a sealed Reacti-vial (Trade Mark) for 18 hours. Over a period of 3 days more so