Sulphonamide derivatives

This invention concerns novel sulphonaimde deriatives and more particularly novel sulphonamide derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO. The invention also concerns processes for the manufacture of said sulphonamide derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said sulphonamide derivatives in the treatment of various inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use.

As stated above the sulphonamide derivatives described hereinafter are inhibitors of 5-LO, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B₄ (LTB₄) and the peptido-lipid leukotrienes such as leukotriene C₄ (LTC₄) and leukotriene D₄ (LTD₄) and various metabolites.

The biosynthetic relationship and physiological properties of the leukotrines are summarised by G. W. Taylor and S. R. Clarke in Trends in Pharmacological Sciences, 1986, 7, 100-103. The leukotrienes and their metabolities have been implicated in the production and development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, angina and peripheral vascular disease. In addition the leukotrienes are mediators of inflammatory diseases by virtue of their ability to modulate lymphocyte and leukocyte function. Other physiologically active metabolities of archidonic acid, such as the prostaglandins and thromboxanes, arise via the action of the enzyme cyclooxygenase on arachidonic acid.

It is disclosed in European Patent Application No. 0375404 A2 that certain heterocyclic derivatives possess inhibitory properties again 5-LO. Copending European Patent Application No. 90306765.0 published on Jan. 23, 1991 as European Patent Application No. 0409413) is concerned with diaryl ether heterocycles which also possess inhibitory properties against 5-LO. We have now discovered that certain sulphonamide derivatives which possess some structural features which are similar to those of the compounds disclosed in the above-mentioned applications but which possess other structural features, in particular a sulphonamido substituent, which were not envisaged in those earlier applications, are effective inhibitors of the enzyme 5-LO and thus of leukotriene biosyntheses. Thus such compounds are of value as therapeutic agents in the treatment of, for example allergic conditions, psoriasis, asthma, cardiovasular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, mediated alone or in part by one or more leukotrienes.

According to the invention there is provided a sulphonamide derivative of the formula I (set out hereinafter)

wherein R¹ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and wherein R² and R³ together form a group of the formula --A² --X² --A³ -- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 5 to 7 ring atoms, wherein A² and A³, which may be the same or different, each is (1-3C)alkylene and X² is oxy, thio, sulphinyl or sulphonyl, and which ring may bear one, two or three substituents, which may be the same or different, selected from hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

or wherein R¹ and R² together form a group of the formula --A² --X² --A³ -- which together with the oxygen atom to which A² is attached and with the carbon atom to which A³ is attached, defines a ring having 5 to 7 ring atoms, wherein A² and A³, which may be the same or different, each is (1-3C)alkylene and X² is oxy, thio, sulphinyl or sulphonyl and which ring may bear one, two or three (1-4C)alkyl substituents, and wherein R³ is (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl;

wherein A¹ is a direct link to X¹ or is (1-3C)alkylene;

wherein X¹ is oxy, thio, sulphinyl, sulphonyl or imino;

wherein Ar is phenylene which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, carbamoyl, ureido, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl and (2-4C)alkanoylamino; or Ar is pyridylene;

and wherein Q is nitrogen or of the formula CR⁷ wherein R⁷ is hydrogen, halogeno, (1-4C)alkyl, (1-4)alkoxy, hydroxy, amino, nitro, cyano, carbamoyl, ureido (1-4C)alkylamino, di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl, (2-4C)alkanoylamino or (2-4C)alkenyl;

wherein R⁴ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl or R⁴ is phenyl, benzyl or pyridyl each of which may optionally bear one or two substituents selected from halogeno, (1-4C)alkoxy, (1-4C)alkyl, hydroxy, cyano, nitro, amino, trifluoromethyl, carbamoyl, ureido, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoylamino;

wherein R⁵ is hydrogen, (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl, or R⁵ is phenyl, benzyl, or pyridyl each of which may optionally bear one or two substituents selected from halogeno, (1-4C)alkoxy, (1-4C(alkyl, hydroxy, cyano, nitro, amino, trifluoromethyl, carbamoyl, ureido, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4c)alkanoylamino;

wherein R⁶ is hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy, hydroxy, amino, nitro, cyano, carbamoyl, ureido, (1-4C)alkylamino, di-[(1-4C)-alkyl]amino, fluoro-(1-4C)alkyl or (2-4C)alkanoylamino;

or R⁵ and R⁶ may be joined to form (2-4C)alkylene or (2-4C)alkenylene either of which may optionally bear one or two substitutents selected from (1-4C)alkyl and halogeno;

or a pharmaceutically-acceptable salt thereof.

According to a further aspect of the invention there is provided a sulphonamide derivative of the formula I as defined hereinbefore wherein R⁴ may be phenyl, benzyl, naphthyl, pyridyl or quinolyl each of which may optionally bear one or two substituents selected from halogeno, (1-4C)alkoxy, (1-4C)alkyl, hydroxy, cyano, nitro, amino, trifluoromethyl, carbamoyl, ureido, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino and (1-4C)alkoxycarbonyl; or a pharmaceutically-acceptable salt thereof.

The chemical formulae referred to herein by Roman numerals are set out for convenience on a separate sheet hereinafter.

In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds of the formula I defined above may exhibit the phenomenon of tautomerism and any formula drawing presented herein may represent only one of the possible tautomeric forms, the invention includes in its definition any tautomeric form of a compound of the formula I which possesses the property of inhibiting 5-LO and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.

It is further to be understood that, insofar as certain of the compounds of formula I defined above may exist in optically active or racemic forms by virtue of one or more substituents containing an asymmetric carbon atom, the invention includes in its definition any such optically active or racemic form which posesses the property of inhibiting 5-LO. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against 5-LO may be evaluated using the standard laboratory techniques referred to hereinafter.

Suitable values for the generic terms referred to above include those set out below.

A suitable value for R¹ when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl or butyl; when it is (3-4C)alkenyl is, for example, allyl, 2-butenyl; and when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl.

When R² and R³ together form a group of the formula --A² --X² --A³ -- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 5 to 7 ring atoms then a suitable value for A² and A₃, which may be the same or different, when each is (1-3 C)alkylene is, for example, methylene, ethylene or trimethylene. Suitable values for the substituents which may be present on said 5- to 7-membered ring include for example:

______________________________________for (1-4C)alkyl:         methyl, ethyl, propyl, isopropyl,         butyl and isobutyl;for (1-4C)alkoxy:         methoxy, ethoxy, propoxy, isopropoxy         and butoxy.______________________________________

When R¹ and R² together form a group of the formula --A² --X² --A³ -- which together with the oxygen atom to which A² is attached and with the carbon atom to which A³ is attached, defines a ring having 5 to 7 ring atoms then a suitable value for A² and A³, which may be the same or different, when each is (1-3C)alkylene is, for example, methylene, ethylene or trimethylene. Suitable values for the (1-4C)alkyl substituents which may be present on said 5- to 7-membered ring include, for example, methyl, ethyl, propyl, isopropyl and butyl.

A suitable value for R³ when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl or butyl; when it is (2-4c)alkenyl is, for example, vinyl, allyl, 2-butenyl or 3-butenyl; and when it is (2-4C)alkynyl is, for example, ethynyl, 2-propynyl or 2-butynyl.

A suitable value for A¹ when it is (1-3C)alkylene is, for example, methylene, ethylene or trimethylene.

A suitable value for Ar when it is phenylene is, for example, 1,3-phenylene or 1,4-phenylene.

A suitable value for Ar when it is pyridylene is, for example 3,5- or 2,6-pyridylene.

A suitable value for a halogeno substituent which may be present on Ar is, for example, fluoro, chloro, bromo or iodo.

A suitable value for a (2-4C)alkanoylamino substituent which may be present on Ar is, for example, acetamido, propionamido or butyramido.

A suitable value for a (1-4C)alkyl substituent which may be present on Ar is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

A suitable value for a (1-4C)alkoxy substituent which may be present on Ar is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

A suitable value for a (1-14C)alkylamino substitutent which may be present on Ar is, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino or tert-butylamino.

A suitable value for a di-[(1-4C)alkyl]amino substituent whic ay be present on Ar is, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino or ethylmethylamino.

A suitable value for a fluoro-(1-4C)alkyl substitutent which may be present on Ar is, for example, fluoromethyl, fluoroethyl, fluoropropyl, fluorisoproyl, fluorobutyl, difluoromethyl or trifluoroethyl.

Suitable values for R⁷ include, for example:

______________________________________for halogeno:  fluoro, chloro, bromo and iodo;for (1-4C)alkyl:          methyl, ethyl, propyl, isopropyl,          butyl, isobutyl, sec-butyl and          tert-butyl;for (1-4C)alkoxy:          methoxy, ethoxy, propoxy, isopropoxy          and butoxy;for (1-4C)alkylamino:          methylamino, ethylamino, propyl-          amino, isopropylamino, butylamino,          sec-butylamino and tert-butylamino;for di-[(1-4C)alkyl]amino:          dimethylamino, diethylamino,          dipropylamino, ethylmethylamino and          dibutylamino;for fluoro-(1-4C)alkyl:          fluoromethyl, fluoroethyl,          difluoromethyl, trifluoromethyl,          fluoropropyl, fluorobutyl and          fluoroisopropyl;for (2-4C)alkanoylamino:          acetamido, propionamido and          butyramido;for (2-4C)alkenyl:          vinyl, allyl, 2-butenyl and 3-butenyl.______________________________________

A suitable value for R⁴ when is it (1-4C)alkyl is, for example, methyl, ethyl, propyl, ispropyl, butyl, sec-butyl or tert-butyl.

A suitable value for R⁴ when it is (3-4C)alkenyl is, for example, allyl, 2-butenyl or 3-butenyl.

A suitable value for R⁴ when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl.

A suitable value for R⁴ or R⁵ when it is pyridyl is, for example, 2-pyridyl, 3-pyridyl or 4-pyridyl.

A suitable value for R⁴ when it is naphthyl is, for example, 1-naphthyl or 2-naphthyl, especially 1-naphtyl.

A suitable value for R⁴ when it is quinolyl is, for example, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, especially 8-quinolyl.

A suitable value for R⁵ when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, ispropyl, butyl, sec-butyl or tert-butyl.

A suitable value for R⁵ when it is (3-4C)alkenyl is, for example, allyl, 2-butenyl or 3-butenyl.

A suitable value for R⁵ when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl.

Suitable values for substituents which may be present on R⁴ or R⁵ when each is phenyl, benzyl, naphthyl, pyridyl or quinolyl include, for example:

______________________________________for halogeno:  fluoro, chloro, bromo and iodo;for (1-4C)alkoxy:          methoxy, ethoxy, propoxy, isopropoxy          and butoxy;for (1-4C)alkyl:          methyl, ethyl, propyl, isopropyl,          sec-butyl and tert-butyl;for (1-4C)alkylamino:          methylamino, ethylamino, propyl-          amino, isopropylamino, butylamino,          sec-butylamino and tert-butylamino;for di-[(1-4C)alkyl]amino:          dimethylamino, diethylamino,          dipropylamino, dibutylamino and          ethylmethylamino;for (2-4C)alkanoylamino:          acetamido, propionamido and          butyramido;for (1-4C)alkoxycarbonyl:          methoxycarbonyl, ethoxycarbonyl,          propoxycarbonyl and tert-          butoxycarbonyl.______________________________________

Suitable values for R⁶ include, for example:

______________________________________for halogeno:  fluoro, chloro, bromo and iodo;for (1-4C)alkyl:          methyl, ethyl, propyl, isopropyl,          butyl, isobutyl, sec-butyl and          tert-butyl;for (1-4C)alkoxy:          methoxy, ethoxy, propoxy, isopropoxy          and butoxy;for (1-4C)alkylamino:          methylamino, ethylamino, propyl-          amino, isopropylamino, butylamino,          sec-butylamino and tert-butylamino;for di[(1-4C)alkyl]amino:          dimethylamino, diethylamino,          dipropylamino, ethylmethylamino and          dibutylamino;for fluoro-(1-4C)alkyl:          fluoromethyl, fluoroethyl,          difluoromethyl, trifluoromethyl,          fluoropropyl, fluorobutyl and          fluoroisopropyl;for (2-4C)alkanoylamino:          acetamido, propionamido and          butyramido;______________________________________

A suitable value for R⁵ and R⁶ when they are joined to form (2-4C)alkylene is, for example, ethylene or trimethylene. Conveniently R⁶ is located at the position ortho to the R⁴ SO₂ NR⁵ group.

A suitable value for R⁵ and R⁶ when they are joined to form (2-4C)alkylene is, for example, vinylene, prop-1-en-1,3diyl or prop-2-en-1,3-diyl. Conveniently R⁶ is located at the position ortho to the R⁴ SO₂ NR⁵ group.

Suitable values for the substituents which may be present on the (2-4C)alkylene or (2-4C)alkenylene group when R⁵ and R⁶ are joined include, for example:

______________________________________for halogeno:  fluoro, chloro, bromo and iodo;for (1-4C)alkyl:          methyl, ethyl and propyl.______________________________________

A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, triethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

Particular novel compounds of the invention include, for example, sulphonamide derivatives of the formula I wherein:

(a) R¹ is methyl, ethyl, allyl or 2-propynyl; and Q, R², R³, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(b) R² and R³ together form a group of the formula --A² --X² --A³ -- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 5 to 7 ring atoms, wherein A² and A³, which may be the same or different, each is methylene, ethylene or trimethylene and X² is oxy, and which ring may bear one or two substituents selected from hydroxy, methyl, ethyl, propyl, methoxy and ethoxy; and Q, R¹, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore:

(c) R¹ and R² together form a group of the formula --A² --X² --A³ -- which, together with the oxygen atom to which A² is attached and with the carbon atom to which A³ is attached, defines a ring having 5 to 7 ring atoms, wherein A² and A³, which may be the same or different, each is methylene or ethylene and X² is oxy, and which ring may bear one, two or three substituents selected from methyl, ethyl and propyl, and R³ is methyl or ethyl; and Q, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(d) A¹ is a direct link to X¹, and X¹ is oxy, thio, sulphinyl or sulphonyl; and Q, R¹, R², R³, Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(e) A¹ is methylene and X¹ is oxy, thio, sulphinyl or sulphonyl; and Q, R¹, R², R³, Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(f) Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, hydroxy, amino, nitro, ureido, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl and acetamido; and Q, A¹, X¹, R¹, R², R³, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(g) Ar is 3,5-pyridylene; and Q, A¹, X¹, R¹, R², R³, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(h) Q is nitrogen or a group of the formula CR⁷, wherein R⁷ is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoro, chloro or hydroxy; and R¹, R², R³, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(i) R⁴ is methyl, ethyl, propyl, phenyl, benzyl or 3-pyridyl each of which may bear one or two substituents selected from fluoro, chloro, methoxy, ethoxy, methyl, ethyl or hydroxy; and Q, R¹, R², R³, A¹, X¹, Ar, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(j) R⁴ is methyl, ethyl, propyl, phenyl, benzyl, 1-naphthyl, 3-pyridyl or 8-quinolyl each of which may bear one or two substituents selected from fluoro, chloro, methoxy, ethoxy, methyl, hydroxy, methoxycarbonyl or ethoxycarbonyl; and Q, R¹, R², R³, A¹, X¹, Ar, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(k) R⁵ is hydrogen, methyl, ethyl, propyl, allyl, phenyl or benzyl each of which may bear one or two substituents selected from fluoro, chloro, methoxy, ethoxy, methyl, ethyl or hydroxy; and Q, R¹, R², R³, A¹, X¹, Ar, R⁴ and R⁶ have any of the meanings defined hereinbefore;

(l) R⁶ is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, fluoro, chloro or hydroxy; and Q, R¹, R², R³, A¹, X¹, Ar, R⁴ and R⁵ have any of the meanings defined hereinbefore;

(m) R⁵ and R⁶ are joined together to form ethylene, trimethylene or vinylene which may bear one or two substituents selected from methyl, ethyl and propyl; and Q, R¹, R², R³, A¹, X¹, Ar and R⁴ have any of the meanings defined hereinbefore;

(n) Q is nitrogen; and R¹, R², R³, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(o) Q is a group of the formula CR⁷, wherein R⁷ is hydrogen, fluoro, chloro, methyl, ethyl or methoxy; and R¹, R², R³, A¹, X¹, Ar, R⁴, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(p) R⁴ is methyl, ethyl or propyl or R⁴ is phenyl which may bear one or two substituents selected from fluoro, chloro, methyl or methoxy; and Q, R¹, R², R³, A¹, X¹ Ar, R⁵ and R⁶ have any of the meanings defined hereinbefore;

(q) R⁵ is hydrogen, methyl, ethyl, propyl or allyl or R⁵ is phenyl or benzyl which may bear one or two substituents selected from fluoro, chloro, methyl or methoxy; and Q, R¹, R², R³, A¹, X¹, Ar, R⁴ and R⁶ have any of the meanings defined hereinbefore;

(r) R⁵ is hydrogen; and Q, R¹, R², R³, A¹, X¹, Ar, R⁴ and R⁶ have any of the meanings defined hereinbefore; or

(s) R⁶ is located at the position ortho to the R⁴ SO₂ NR⁵ group and R⁵ and R⁶ are joined together to form ethylene or trimethylene; and Q, R¹, R², R³, A¹, X¹, Ar and R⁴ have any of the meanings defined hereinbefore;

or a pharmaceutically-acceptable salt thereof.

A preferred compound of the invention comprises a sulphonamide derivative of the formula I wherein

R¹ is methyl, ethyl, allyl or 2-propynyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methylene or ethylene, and X² is oxy, and which ring may bear one or two substituents selected from methyl, ethyl, propyl, methoxy and ethoxy;

or R¹ and R² together form a group of the formula --A² --X² --A³ -- which, together with the oxygen atom to which A² is attached and with the carbon atom to which A³ is attached, defines a ring having 5 or 6 ring atoms, wherein A² is methylene, A³ is methylene or ethylene, and X² is oxy, and which ring may bear one, two or three substituents selected from methyl, ethyl and propyl, and R³ is methyl or ethyl;

A¹ is a direct link to X¹ or is methylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, hydroxy, amino, nitro, ureido, methoxy, dimethylamino, trifluoromethyl and acetamido; or Ar is 3,5-pyridylene;

Q is nitrogen or of the formula CR⁷ wherein R⁷ is hydrogen, fluoro, chloro, methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, amino, methylamino, dimethylamino or trifluoromethyl;

R⁴ is methyl, ethyl, propyl, allyl, phenyl, benzyl, 3-pyridyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-chloroethyl or 3-chloropropyl;

R⁵ is hydrogen, methyl, ethyl, propyl, phenyl, benzyl, allyl, 3-pyridyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-chloroethyl, 3-chloropropyl or 2-methoxyethyl; and

R⁶ is hydrogen, fluoro, chloro, methyl, ethyl, propyl, methoxy, ethoxy, hydroxy, amino, methylamino, dimethylamino or trifluoromethyl; or

R⁵ and R⁶ may be joined to form ethylene, trimethylene or vinylene;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamide derivative of the formula I wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy, and which ring may bear a methyl or ethyl substituent alpha to X² ;

A¹ is a direct link to X¹, or is methylene;

X¹ is thio or oxy;

Ar is 1,3-phenylene which may optionally bear a fluoro substituent;

Q is nitrogen or of the formula CR⁷ wherein R⁷ is hydrogen, methyl or chloro;

R⁴ is methyl, ethyl or phenyl;

R⁵ is hydrogen, methyl, ethyl, allyl or benzyl; and

R⁶ is hydrogen, methyl or chloro; or

R⁵ and R⁶ may be joined to form ethylene or trimethylene;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamide derivative of the formula I wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy, and which ring may bear a methyl or ethyl substituent alpha to X² ;

A¹ is a direct link to X¹, or is methylene;

X¹ is thio or oxy;

Ar is 1,3-phenylene which may optionally bear a fluoro substituent;

Q is of the formula CR⁷ wherein R⁷ is hydrogen, methyl or chloro;

R⁴ is methyl, ethyl or phenyl;

R⁵ is hydrogen;

R⁶ is hydrogen, methyl, fluoro or chloro;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamide derivative of the formula I, wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy, and which ring may bear a methyl substituent alpha to X² ;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar is 1,3-phenylene;

Q is of the formula CR⁷ wherein R⁷ is hydrogen;

R⁴ is methyl;

R⁵ is methyl or ethyl; and

R⁶ is hydrogen or chloro;

of a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamide derivative of the formula I wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which, together with the carbon atom to which A² and A³ are attached, defines a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy, and which ring may bear a methyl or ethyl substituent alpha to X² ;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar is 1,3-phenylene which may optionally bear a fluoro substituent;

Q is of the formula CR⁷ wherein R⁷ is hydrogen or chloro;

R⁴ is methyl, ethyl, phenyl, 2-methoxycarbonylphenyl or 8-quinolyl;

R⁵ is hydrogen;

R⁶ is hydrogen, fluoro or chloro;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a sulphonamide derivative of the formula I, wherein

R¹ is methyl;

R² and R³ together form a group of the formula --A² --X² --A³ -- which , together with the carbon atom to which A² and A³ are attached, defines a ring having 6 ring atoms, wherein each of A² and A³ is ethylene and X² is oxy, and which ring may bear a methyl substituent alpha to X² ;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;

Q is of the formula CR⁷ wherein R⁷ is hydrogen or chloro;

R⁴ is methyl;

R⁵ is hydrogen; and

R⁶ is hydrogen, fluoro or chloro;

or a pharmaceutically-acceptable salt thereof.

A specific especially preferred compound of the invention is, for example, the following sulphonamide derivative of the formula I, or a pharmaceutically-acceptable salt thereof:

N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamide,

N-{3-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylethanesulphonamide,

N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-ethylmethanesulphonamide or

N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylethanesulphonamide.

A further specific especially preferred compound of the invention is, for example, the following sulphonamide derivative of the formula I, or a pharmaceutically-acceptable salt thereof:

N-{2-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}methanesulphonamide,

N-{2-chloro-4-[4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}methanesulphonamide,

N-{3-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}methansulphonamide or

N-{2-fluoro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}methanesulphonamide.

A compound of the invention comprising a sulphonamide derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated R¹, R², R³, A¹, X¹, Ar, Q, R⁴, R⁵, R⁶ and R⁷ have any of the meanings defined hereinbefore.

(a) The coupling, conveniently in the presence of a suitable base, of a compound of the formula II with a compound of the formula III, wherein Z is a displaceable group; provided that, when there is an amino, alkylamino or hydroxy group in Ar, R², R³, R⁴, R⁵, R⁶ or R⁷, any amino, alkylamino or hydroxy group may be protected by a conventional protecting group or alternatively any such group need not be protected, whereafter any desired protecting group in Ar, R², R³, R⁴, R⁵, R⁶ and R⁷ is removed by conventional means.

A suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, iodo, methanesulphonyloxy or toluene-4-sulphonyloxy group.

A suitable base for the coupling reaction is, for example, an alkali or alkaline earth metal carbonate, (1-4C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. The coupling reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example 10° to 190° C., conveniently at or near 140° C.

Conveniently the reaction may be performed in the presence of a suitable catalyst, for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)palladium, cuprous chloride or cuprous bromide.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group (especially acetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl). The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example by hydrogenation over a catalyst such as palladium-on-charcoal.

The starting materials of the formula II and of the formula III may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples which are provided for the purpose of illustration only. Alternatively necessary starting materials of the formula III are obtainable by analogous procedures to those illustrated in accompanying Scheme I (set out hereinafter) or by modifications thereto which are within the ordinary skill of an organic chemist.

A suitable protecting group R⁸, as employed in Scheme I, is any one of the many such groups known in the art and inlcudes any appropriate protecting group as defined hereinbefore. Examples of such groups are given in Scheme I. The conditions for the introduction and removal of such protecting groups are described in standard textbooks or organic chemistry such as, for example, "Protective Groups in Organic Synthesis" by T W Green (J Wiley and Sons, 1981).

(b) The coupling, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula IV with a compound of the formula V wherein Z is a displaceable group as defined hereinbefore; provided that, when there is an amino, alkylamino or hydroxy group in Ar, R², R³, R⁴, R⁵, R⁶ or R⁷ any amino, alkylamino or hydroxy group may be protected by a conventional protecting group as defined hereinbefore or alternatively any such group need not be protected, whereafter any undesired protecting group in Ar, R², R³, R⁴, R⁵, R⁶ or R⁷ is removed by conventional means.

The coupling reaction is conveniently performed in a suitable inert solvent as defined hereinbefore and at a temperature in the range, for example, 10° to 190° C., conveniently at or near 140° C. The reaction may conveniently be performed in the presence of a suitable catalyst as defined hereinbefore.

Conveniently intermediates of the formula V wherein Z, Ar, R¹, R² and R³ have the meanings defined hereinbefore, may be obtained by way of compounds of the formula Z--Ar--Y, wherein Z and Ar have the meanings defined hereinbefore and Y is, for example, a halogeno, formyl, alkanoyl, nitrile or alkoxycarbonyl group, as illustrated in accompanying Scheme II (set out hereinafter).

It will also be appreciated that the intermediate of the formula V may conveniently be obtained from the compound of the formula Z--Ar--Y, as defined hereinbefore, by reversing the order of introduction of the groups R² and R³ which is used in Scheme II.

(c) The alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula VI with a compound of the formula R¹ --Z, wherein R¹ and Z have the meanings defined hereinbefore; provided that, when there is an amino, alkylamino or hydroxy group in Ar, R², R³, R⁴, R⁵, R⁶ or R⁷ any amino, alkylamino or hydroxy group may be protected by a conventional protecting group or alternatively any such group need not be protected, whereafter any undesired protecting group in Ar, R², R³, R⁴, R⁵, R⁶ and R⁷ is removed by conventional means.

The tertiary alcohol starting material of the formula VI may be obtained by standard procedures of organic chemistry. Conveniently, and as illustrated in accompanying Scheme III (set out hereinafter), intermediates of the formula VIII wherein A¹, X¹, Ar, Q, R⁴, R⁵ and R⁶ have the meanings defined hereinbefore and Y is, for example, a formyl, nitrile or alkoxycarbonyl group may be utilised in the preparation of the tertiary alcohol starting material of the formula VI.

(d) The sulphonamidification, conveniently in the presence of a Lewis base such as an organic amine, for example triethylamine, pyridine, 4-dimethylaminopyridine, morpholine and piperidine, of a compound of the formula VII with a compound of the formula R⁴ SO₂ Z, wherein Z is a displaceable group such as halogeno for example chloro, bromo or iodo; provided that when there is an amino, alkylamino or hydroxy group in Ar, R², R³, R⁵, R⁶ or R⁷, any amino, alkylamino or hydroxy group is protected by a conventional protecting group as defined hereinbefore, whereafter any undesired protecting group in Ar, R², R³, R⁵, R⁶ or R⁷ is removed by conventional means.

The reaction is conveniently performed in a suitable organic solvent, for example dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane, N-methylpyrrolidin-2-one or tetrahydrofuran and at a temperature in the range of -40° C. to 80° C. conveniently in the range 0°-25° C.

the starting material of the formula VII may be obtained by standard procedures of organic chemistry such as by analogous procedures to those described hereinbefore in process variants (a) to (c) above or by modifications thereto which are within the skill of an organic chemist.

(e) For the production of those compounds of the formula I wherein X¹ is a sulphinyl or sulphonyl group, or wherein R² and R³ together form a group of the formula --A² --X² --A³ -- and X² is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I wherein X¹ is a thio group, or wherein R² and R³ together form a group of the formula --A² --X² --A³ -- and X² is a thio group.

A suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate), chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups. In general the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15° to 35° C. When a compound carrying a sulphinyl group is required a milder oxidising agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol. It will be appreciated that when a compound of the formula I containing a sulphonyl group is required, it may be obtained by oxidation of the corresponding sulphinyl compound as well as the corresponding thio compound.

When a pharmaceutically-acceptable salt of a novel compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure. When an optically active form of a compound of the formula I is required, it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure.

Many of the intermediates defined herein are novel, for example those of the formulae IV and VI and these are provided as a further feature of the invention.

As stated previously, the novel compounds of the formula I are inhibitors of the enzyme 5-LO. The effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:

a) An in vitro assay system involving incubating a test compound with heparinised human blood, prior to challenge with the calcium ionophore A23187 and then indirectly measuring the inhibitory effects on 5-LO by assaying the amount of LTB₄ using specific radioimmunoassays described by Carey and Forder (Prostaglandins, Leukotrienes Med., 1986, 22, 57; Prostaglandins, 1984, 28, 666; Brit. J. Pharmacol., 1985, 84, 34P) which involve the use of a protein-LTB₄ conjugate produced using the procedure of Young et alia (Prostaglandins, 1983, 26(4), 605-613). The effects of a test compound on the enzyme cyclooxygenase (which is involved in the alternative metabolic pathway for arachidonic acid and gives rise to prostaglandins, thromboxanes and related metabolites) may be measured at the same time using the specific radioimmunoassay for thromboxane B₂ (TxB₂) described by Carey and Forder (see above). This test provides an indication of the effects of a test compound against 5-LO and also cyclooxygenase in the presence of blood cells and proteins. It permits the selectivity of the inhibitory effect on 5-LO or cyclooxygenase to be assessed.

b) An ex vivo assay system, which is a variation of test a) above, involving administration of a test compound (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to carboxymethylcellulose), blood collection, heparinisation, challenge with A23187 and radioimmunoassay of LTB₄ and TxB₂. This test provides an indication of the bioavailability of a test compound as an inhibitor of 5-LO or cyclooxygenase.

c) An in vivo system involving measuring the effects of a test compound administered orally against the liberation of LTB₄ induced by zymosan within an air pouch generated within the subcutaneous tissue of the back of male rats. The rats are anaesthetised and air pouches are formed by the injection of sterile air (20 ml). A further injection of air (10 ml) is similarly given after 3 days. At 6 days after the initial air injection the test compound is administered (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to hydroxypropylmethylcellulose), followed by the intrapouch injection of zymosan (1 ml of a 1% suspension in physiological saline). After 3 hours the rats are killed, the air pouches are lavaged with physiological saline, and the specific radioimmunoassay described above is used to assay LTB₄ in the washings. This test provides an indication of inhibitory effects against 5-LO in an inflammatory milieu.

Although the pharmacological properties of the compounds of the formula I vary with structural changes as expected, in general compounds of the formula I possess 5-LO inhibitory effects at the following concentrations or doses in one or more of the above tests a)-c):

______________________________________Test a):  IC50 (LTB4) in the range, for example, 0.01-40 μM  IC50 (TxB2) in the range, for example, 40-200 μM;Test b):  oral ED50 (LTB4) in the range, for example,  1-100 mg/kg;Test c):  oral ED50 (LTB4) in the range, for example,  0.5-50 mg/kg.______________________________________

No overt toxicity or other untoward effects are present in tests b) and/or c) when compound of the formula I are administered at several multiples of their minimum inhibitory dose or concentration.

Thus, by way of example, the compound N-{3-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamide has an IC₅₀ of 0.09 μM against LTB₄ in test a), and an oral ED₅₀ of 1 mg/kg versus LTB ₄ in test c); and the compound N-{2-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl)-methanesulphonamide has an IC₅₀ of 1 μM against LTB ₄ in test a), and an oral ED₅₀ of 1.5 mg/kg versus LTB₄ in test c). In general those compounds of the formula I which are particularly preferred have an IC₅₀ of <1 μM against LTB₄ in test a), and an oral ED₅₀ of <100 mg/kg against LTB₄ in tests b) and/or c).

These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-LO as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin.

According to a further featues of the invention there is provided a pharmaceutical composition which comprises a sulphonamide derivative of the formula I, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients.

The amount of active ingredient (that is a sulphonamide derivative of the formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one ore more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.

According to a further feature of the invention there is provided a sulphonamide derivative of the formula I, or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.

The invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above. The invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition.

The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the formula I are useful in treating those allergic and inflammatory conditions which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-LO catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-LO. As previously mentioned, such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders of an inflammatory nature, arthritic and inflammatory joint disease, and inflammatory bowel diseases.

In using a compound of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used.

Although the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the enzyme 5-LO. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

By virtue of their effects on leukotriene production, the compounds of the formula I have certain cytoprotective effects, for example they are useful in reducing or suppressing certain of the adverse gastrointestinal effects of the cyclooxygenase inhibitory non-steroidal anti-inflammatory agents (NSAIA), such as indomethacine, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore, co-administration of a 5-LO inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects. According to a further feature of the invention there is provided a pharmaceutical composition which comprises a sulphonamide derivative of the formula I, or a pharmaceutically-acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent (such as those mentioned above), and a pharmaceutically-acceptable diluent or carrier.

The cytoprotective effects of the compounds of the formula I may be demonstrated, for example in a standard laboratory model which assesses protection against indomethacin-induced or ethanol-induced ulceration in the gastrointestinal tract of rats.

The compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment. Thus, for example a known platelet aggregation inhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition. Similarly, by way of example, an anti-histamine, steroid (such as beclomethasone dipropionate), sodium cromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully also be present in a pharmaceutical composition of the invention for use in treating a pulmonary disease or condition.

The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;

(ii) operations were carried out at room temperature, that is in the range 18°-25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily the maximum attainable;

(v) the structures of the end-products of the formula I were confirmed by NMR and mass spectral techniques; unless otherwise stated, CDCl₃ solutions of the end-products of the formula I were used for the determination of the NMR spectral data, chemical shift values were measured on the delta scale;

(vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

(vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

THF: tetrahydrofuran;

DMF: N,N-dimethylformamide.

EXAMPLE 1

A solution of N-(4-bromomethylphenyl)-N-methylmethanesulphonamide (0.36 g), 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran (0.27 g) and potassium carbonate (0.36 g) in DMF was stirred at ambient temperature for 18 hours. The mixture was then partitioned between ethyl acetate (75 ml) and water (50 ml) and the organic phase washed with brine (50 ml) and dried (MgSO₄). The solvent was evaporated and the product purified by column chromatography. Thus was obtained N-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenoxymethyl]phenyl}-N-methylmethanesulphonamide (0.23 g, 47%), m.p. 128°-132° C. (recrystallised from ethyl acetate/hexane).

NMR Spectrum 1.82-2.05 (4H, m), 2.85 (3H, s), 2.98 (3H, s), 3.75-3.91 (4H, m), 5.04 (2H, 2), 6.60 (1H, m), 6.73 (1H, m), 6.80 (1H, m), 7.38-7.50 (4H, m).

The 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran used as starting material was prepared as described in European Patent Application No. 0385662 (example 2 therein).

The N-(4-bromomethylphenyl)-N-methylmethansulphonamide used as starting material was obtained as follows:

A solution of p-methyl-N-methylaniline (5.00 g) and triethylamine (5.05 g) in dichloromethane (140 ml) was cooled to 0° C. and methanesulphonyl chloride (4.73 g) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and quenched with water (100 ml). The organic phase was washed with 2N aqueous hydrochloric acid solution (75 ml) and 2N aqueous sodium hydroxide solution (75 ml), dried (MgSO₄) and the solvent removed by evaporation. Thus was obtained N-methyl-(4-tolyl)methanesulphonamide (5.3 g, 65%), m.p. 49°-52° C.

A solution of N-methyl-N-(4-tolyl)methanesulphonamide (0.31 g, 1.54 mmol), N-bromosuccinimide (0.28 g, 1.55 mmol) and 2,2'-azobisisobutyronitrile (20 mg) in carbon tetrachloride (20 ml) was refluxed for 2 hours. The mixture was then cooled to ambient temperature and filtered. The solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and water (50 ml), washed with brine (50 ml) and dried (MgSO₄). The solvent was evaporated yielding N-(4-bromomethylphenyl)-N-methylmethanesulphonamide (0.24 g, 54%) which was used without further purification.

EXAMPLE 2

Using a similar procedure to that described in Example 1, except that N-(4-bromomethyl-2-chlorophenyl)-N-methylmethanesulphonamide was used in place of N-(4-bromomethylphenyl)-N-methylmethanesulphonamide, there was obtained N-{2-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenoxymethyl]phenyl}-N-methylmethanesulphonamide (0.34 g, 60%), m.p. 126°-128° C. (triturated with ether).

The N-(4-bromomethyl-2-chlorophenyl)-N-methylmethanesulphonamide used as starting material was obtained as follows:

A solution of 2-chloro-4-methylaniline (5.00 g) and triethylamine (3.57 g) in dichloromethane (100 ml) was cooled to 0° C. Methanesulphonyl chloride (4.04 g) was added dropwise and the mixture stirred at ambient temperature overnight. The mixture was then washed with 2N aqueous hydrochloric acid solution (50 ml) and the solvent removed by evaporation. The residue was dissolved in ethyl acetate (75 ml) extracted with 2N aqueous sodium hydroxide solution (2×50 ml). The aqueous phase was acidified with 2N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×75 ml). This was subsequently dried (MgSO₄) and the solvent evaporated. Thus was obtained N-(2-chloro-4-methylphenyl)methanesulphonamide (2.5 g, 32%).

NMR Spectrum 2.33 (3H, s), 2.97 (3H, s), 6.6 (1H, s), 7.10 (1H, d), 7.25 (1H, s), 7.52 (1H, d).

A solution of the product so obtained (1.87 g) in DMF (20 ml) potassium carbonate (3.45 g) and methyl iodide (2.84 g) was stirred at ambient temperature for 18 hours. The mixture was then quenched with water (100 ml) and extracted with ethyl acetate (2×75 ml). The combined organic extracts were then washed with 2N aqueous sodium hydroxide solution (50 ml), brine (50 ml) and dried (MgSO₄). The solvent was evaporated to give N-(2-chloro-4-methylphenyl)-N-methylmethanesulphonamide as an oil (1.7 g, 85%).

NMR Spectrum 2.35 (3H, s), 3.00 (3H, s), 3.28 (3H, s), 7.10 (1H, m), 7.25 (1H, d), 7.36 (1H, d).

Bromination of N-(2-chloro-4-methylphenyl)-N-methylmethanesulphonamide was carried out using a similar procedure to that described in Example 1, except that N-(2-chloro-4-methylphenyl)-N-methylmethanesulphonamide was used in place of N-methyl-N-(4-tolyl)-methanesulphonamide. There was thus obtained N-(4-bromomethyl-2-chlorophenyl)-N-methylmethanesulphonamide which was used without further purification.

EXAMPLE 3

A solution of N-(4-iodophenyl)-N-methylmethanesulphonamide (0.31 g, 1 mmol), 4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.22 g), potassium carbonate (20 mg) and copper (I) chloride (30 mg) in DMF (20 ml) was heated to 140° C. and stirred for 3 hours. Ethyl acetate (40 ml) and water (40 ml) were added and the mixture was filtered through celite. The filtrate was washed with water (40 ml) and brine (40 ml), dried (MgSO₄) and the solvent evaporated. The product was purified by column chromatography, thus N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamide was obtained as an oil (1.12 g, 42%).

NMR Spectrum 1.85-2.10 (4H, m), 2.85 (3H, s) 3.00 (3H, s), 3.30 (3H, s), 3.75-3.90 (4H, m), 7.25-7.35 (8H, m).

The 4-(3-mercaptophenyl)-4-methoxytetrahydropyran used as starting material was obtained as follows:

A solution of 1,3-dibromobenzene (23.8 g) in THF (120 ml) was cooled to -78° C. under an atmosphere of argon and n-butyl lithium (1.6M in hexane, 62.5 ml) was added dropwise. The mixture was stirred at -78° C. for 30 minutes and a solution of tetrahydropyran-4-one (10 g) in THF (40 ml) was added. The resultant suspension was stirred at -78° C. for 1 hour, allowed to warm to ambient temperature and then stirred for 30 minutes. The mixture was poured into brine (250 ml) and extracted with diethyl ether. The organic phase was dried (MgSO₄) and evaporated. The residue was triturated under hexane and the resultant solid (16.8 g) was filtered off.

A solution of the product so obtained in DMF (100 ml) was added dropwise to a slurry of sodium hydride (60% w/w dispersion in mineral oil; 5.25 g) in DMF (10 ml) and the mixture was stirred at ambient temperature for 90 minutes. Methyl iodide (36.5 g) was added and the mixture was stirred at ambient temperature for 16 hours. Ethanol (2 ml) and water (500 ml) were added in turn and the mixture was extracted with diethyl ether (3×200 ml). The combined extracts were washed with water, dried (MgSO₄) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 4-(3-bromophenyl)-4-methoxytetrahydropyran (12 g, 44%) as a solid.

NMR Spectrum (CDCl₃, δ values) 1.88-2.1 (m, 4H), 3.0 (s, 3H), 3.78-3.95 (m, 4H), 7.2-7.35 (m, 2H), 7.42 (m, 1H), 7.55 (m, 1H).

A solution of a portion (1 g) of the product so obtained in THF (4 ml) was cooled to -80° C. under an atmosphere of argon and n-butyl lithium (1.6M in hexane, 2.4 ml) was added dropwise. The mixture was stirred at -80° C. for 30 minutes, sulphur (0.12 g) was added and the mixture was stirred at -80° C. for a further 30 minutes. Water (10 ml) was added and the mixture was allowed to warm to ambient temperature. The mixture was extracted with diethyl ether (10 ml). The aqueous phase was acidified to pH4 by the addition of dilute aqueous hydrochloric acid solution and extracted with diethyl ether (2×10 ml). The combined organic extracts were dried (MgSO₄) and evaporated. There was thus obtained the required starting material as an oil (0.5 g) which crystallised on standing and was used without further purification.

The N-(4-iodophenyl)-N-methylmethanesulphonamide used as starting material was obtained as follows:

A solution of 4-iodoaniline (3.50 g, 16 mmol) and pyridine (12.64 g) in dichloromethane (120 ml) was stirred at ambient temperature. Methanesulphonyl chloride (1.83 g, 16 mmol) was added dropwise and the whole mixture was stirred for 18 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (120 ml) and water (120 ml). The organic phase was washed with 2N aqueous sulphuric acid solution (2×75 ml), dried (MgSO₄) and the solvent evaporated. Thus was obtained N-(4-iodophenyl)methanesulphonamide (2.04 g, 43%), m.p. 131°-133° C. (recrystallised from ethyl acetate/hexane).

A solution of the product so obtained (0.89 g, 3 mmol) in acetone (50 ml) with potassium carbonate (1.38 g) and methyl iodide (0.71 g, 5 mmol) was stirred at ambient temperature for 20 hours. Ethyl acetate (100 ml) was added to the mixture which was then washed with brine (50 ml), dried (MgSO₄) and the solvent evaporated. Thus was obtained N-(4-iodophenyl)-N-methylmethanesulphonamide (0.56 g, 60%), m.p. 103°-104° C. (recrystallised from ethyl acetate/hexane).

EXAMPLE 4

Using a similar procedure to that described in Example 3, except that the appropriate N-(4-iodophenyl)sulphonamide was used in place of N-(4-iodophenyl)-N-methylmethanesulphonamide, there were obtained the compounds described in the following table:

              TABLE 1______________________________________ ##STR2##Ex 4Compd.                              YieldNo.     -- N-Phenyl substituent                 R1 R2                               (%)   m.p.______________________________________1a  3-chloro       methyl  methyl                               76    oil2b  no substituent methyl  H     68    oil3c  no substituent methyl  ethyl 82    gum4d  no substituent ethyl   methyl                               82    gum5e  3-methyl       methyl  methyl                               35    gum6f  2-chloro       methyl  methyl                               48    gum7g  no substituent methyl  allyl 31    gum8h  no substituent methyl  benzyl                               35    gum9i  no substituent phenyl  methyl                               30    gum______________________________________

Notes

a. The product gave the following characteristic NMR signals: 1.90-2.10 (4H, m), 2.85 (3H, s), 3.0 (3H, s), 3.30 (3H, s), 3.75-3.90 (4H, m), 6.90 (1H, d), 7.15 (1H, m), 7.35-7.45 (4H, m), 7.50 (1H, d).

The N-(3-chloro-4-iodophenyl)-N-methylmethanesulphonamide used as a starting material was obtained using the procedures described in Example 3 for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide except that 3-chloro-4-iodoaniline was used to place of 4-iodoaniline.

b. The product gave the following characteristic NMR signals: 1.85-2.05 (4H, m), 2.95 (3H, s), 3.05 (3H, s), 3.75-3,90 (4H, m), 6.65 (1H, s), 7.15-7.40 (8H, m).

The N-(4-iodophenyl)methanesulphonamide used as starting material was obtained as described in Example 3.

c. The product gave the following characteristic NMR signals: 1.15 (3H, t), 1.85-2.0 (4H, m), 2.85 (3H, s), 3.0 (3H, s), 3.70 (2H, q), 3.70-3.90 (4H, m), 7.30-7.45 (8H, m).

The N-(4-iodophenyl)-N-ethylmethanesulphonamide used as starting material was obtained as described in Example 3 for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide except that ethyl iodide was used in place of methyl iodide.

d. The product gave the following characteristic NMR signals: 1.20 (3H, t), 1.80-1.95 (4H, m), 2.85 (3H, s), 3.15 (2H, q), 3.25 (3H, s), 3.55-3.75 (4H, m), 7.25-7.45 (8H, m).

The N-(4-iodophenyl)-N-methylethanesulphonamide used as starting material was obtained as follows:

To a solution of N-methylaniline (14.9 g) and triethylamine (15.1 g) in dichloromethane (250 ml) at 0° C. was added acetyl chloride (11.0 g) dropwise. The mixture was stirred at ambient temperature for 1 hour, then washed with 2N aqueous hydrochloric acid solution (75 ml), dried (MgSO₄) and the solvent evaporated. Thus was obtained N-methylacetanilide (15.6 g, 75%), m.p. 95°-97° C. (recrystallised from ethyl acetate/hexane).

The product so obtained (5.96 g), iodine (5.08 g) and iodic acid (2.29 g) were heated in glacial acetic acid (30 ml) and concentrated sulphuric acid (4 ml) at 85° C. for 3.5 hours. The mixture was then cooled to ambient temperature and ethyl acetate (125 ml) and water (75 ml) were added. Solid sodium bicarbonate was added to neutralise the mixture which was then washed with water (75 ml) and brine (75 ml). After drying (MgSO₄) the solvent was evaporated to leave 4'-iodo-N-methylacetanilide (7.04, 64%), m.p. 140°-141° C. (recrystallised from ethyl acetate/hexane).

A solution of the product so obtained (6.05 g) in 2N aqueous sodium hydroxide solution (30 ml) and ethanol (30 ml) was refluxed for 8 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (110 ml) and water (100 ml). The organic phase was washed with brine (75 ml), dried (MgSO₄) and the solvent evaporated to give 4-iodo-N-methylaniline as an oil (4.97 g, 97%).

NMR Spectrum 2.80 (3H, s), 6.40 (2H, d), 7.45 (2H, d).

The product so obtained was used in place of 4-iodoaniline in the procedure described in Example 3 for the preparation of N-(4-iodophenyl)methanesulphonamide and ethanesulphonyl chloride was used in place of methanesulphonyl chloride. Thus was obtained N-(4-iodophenyl)-N-methylethanesulphonamide as an oil.

NMR Spectrum 1.45 (3H, t), 3.00 (2H, q), 3.35 (3H, s), 7.15 (2H, m), 7.70 (2H, m).

e. The product gave the following characteristic NMR signals: 1.85-2.05 (4H, m), 2.38 (3H, s), 2.85 (3H, s), 2.96 (3H, s), 3.30 (3H, s), 3.75-3.90 (4H, m), 7.05-7.35 (7H, m).

The N-(4-iodo-3-methylphenyl)-N-methylmethanesulphonamide used as starting material was obtained as follows:

N-Methyl-N-(3-tolyl)methanesulphonamide was prepared as for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide described in Example 3, except that 3-methylaniline was used in place of 4-iodoaniline.

A solution of N-methyl-N-(3-tolyl)methanesulphonamide (0.12 g), iodine (76 g) and iodic acid (35 mg) in glacial acetic acid (5 ml) and concentrated sulphuric acid (0.6 ml) was stirred at 80° C. for 2.5 hours. Ethyl acetate (40 ml) and water (40 ml) were then added and the mixture neutralised with solid sodium bicarbonate. The organic phase was washed with brine (30 ml), dried (MgSO₄) and the solvent evaporated to leave N-(4-iodo-3-methylphenyl)-N-methylmethanesulphonamide (0.22 g, 90%), m.p. 85°-87° C.

f. The product gave the following characteristic NMR signals: 1.90-2.10 (4H, m), 2.98 (3H, s), 3.02 (3H, s), 3.28 (3H, s), 3.75-3.90 (4H, m), 7.05-7.55 (7H, m).

The N-(2-chloro-4-iodophenyl)-N-methylmethanesulphonamide used as a starting material was obtained using the procedure described in Example 3 for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide except that 2-chloro-4-iodoaniline was used in place of 4-iodoaniline.

g. The product gave the following characteristic NMR signals: 1.90-2.10 (4H, m), 2.90 (3H, s), 3.0 (3H, s), 3.70-3.90 (4H, m), 4.24 (2H, d), 5.15 (1H, d), 5.25 (1H, d), 5.70-5.95 (1H, m), 7.1-7.6 (8H, m).

The N-allyl-N-(4-iodophenyl)methanesulphonamide used as a starting material was obtained using the procedures described in Example 3 for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide, except that allyl bromide was used in place of methyl iodide.

h. The product gave the following characteristic NMR signals: 1.85-2.05 (4H, m), 2.95 (6H, s), 3.75-3.90 (4H, m), 4.82 (2H, s), 7.10-7.45 (13H, m).

The N-benzyl-N-(4-iodophenyl)methanesulphonamide used as a starting material was obtained using the procedures described in Example 3 for the preparation of N-(4-iodophenyl)-N-methylmethanesulphonamide, except that benzyl bromide was used in place of methyl iodide.

i. The product gave the following characteristic NMR signals: 1.85-2.05 (4H, m), 2.97 (3H, s), 3.18 (3H, s), 375-3.90 (4H, m), 7.0-7.60 (13H, m).

The N-(4-iodophenyl)-N-methylbenzenesulphonamide used as a starting material was obtained using the procedures described in Example 3 for the preparation of N-(4-iodophenyl-N-methylmethanesulphonamide, except that benzenesulphonyl chloride was used in place of methanesulphonyl chloride.

EXAMPLE 5

A solution of 5-iodo-N-mesylindoline (0.32 g, 1 mmol), 4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.23 g, 1 mmol), copper (I) chloride (30 mg) and potassium carbonate (0.28 g) in DMF (10 ml) was heated at 140° C. for 5 hours. After cooling ethyl acetate (75 ml) and water (75 ml) were added and the mixture was filtered through celite. The filtrate was washed with brine (50 ml), dried (MgSO₄) and the solvent evaporated. The crude product was purified by column chromatography to give 5-[3-(4-methoxytetrahydropyran-4yl)phenylthio]-N-mesylindoline (0.23 g, 55%), m.p. 114°-118° C. (recrystallised from ethyl acetate/hexane).

NMR Spectrum 1.80-2.08 (4H, m), 2.90 (3H, s), 2.95 (3H, s), 3.12 (2H, t), 3.72-3.90 (4H, m), 4.00 (2H, t), 7.10-7.40 (7H, m).

The 5-iodo-N-mesylindoline used as starting material was prepared as follows:

N-mesylindoline was obtained using the procedure described in Example 3 for the preparation of N-(4-iodophenyl)methanesulphonamide, except that indoline was used in place of 4-iodoaniline. The N-mesylindoline so obtained (0.67 g, 5 mmol), iodine (0.65 g) and iodic acid (0.29 g) in glacial acetic acid (4 ml) and concentrated sulphuric acid (0.5 ml) were heated to 85° C. for 2 hours. The mixture was diluted with water (75 ml) and ethyl acetate (75 ml) and neutralised with solid sodium bicarbonate. The organic phase was washed with brine (50 ml), dried (MgSO₄) treated with charcoal (1 g), filtered and the solvent evaporated. Polar material was removed by filtration through silica and the 5-iodo-N-mesylindoline thus obtained was used without further purification.

EXAMPLE 6

Using a similar procedure to that described in Example 5, except that the appropriate iodosulphonamide was used in place of 5-iodo-N-mesylindoline, there were obtained the compounds described in the following table:

              TABLE II______________________________________ ##STR3##Ex 6Compd.No.        X"             R'      m.p.______________________________________1a    CH2 CH2 CH2                     methyl  gum2b    CH2 CH2                     ethyl   gum______________________________________

Notes

a. The product gave the following characteristic NMR signals: 1.85-2.10 (6H, m), 2.80 (2H, t), 2.92 (3H, s), 2.98 (3H, s), 3.75-3.90 (6H, m), 7.10-7.65 (7H, m).

The 6-iodo-N-mesyl-1,2,3,4-tetrahydroquinoline used as starting material was obtained using the procedures described in Example 5 for the preparation of 5-iodo-N-mesylindoline except that 1,2,3,4-tetrahydroquinoline was used in place of indoline.

b. The product gave the following characteristic NMR signals: 1.38 (3H, t), 1.82-2.05 (4H, m), 2.96 (3H, s), 3.05-3.20 (4H, m), 3.75-3.90 (4H, m), 4.10 (2H, m), 7.10-7.35 (7H, m).

The 5-iodo-N-ethylsulphonylindoline used as starting material was obtained using the procedures described in Example 5 for the preparation of 5-iodo-N-mesylindoline, except that ethanesulphonyl chloride was used in place of methanesulphonyl chloride.

EXAMPLE 7

Sodium hydride (79 mg, 50% dispersion in mineral oil, 1.65 mmol) was added to a solution of N-(6-chloropyrid-3-yl)-N-methylmethanesulphonamide (0.33 g) and 4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.34 g) in DMF (10 ml). The mixture was stirred at ambient temperature for 15 minutes and heated at 140° C. for 1.5 hours. After cooling, it was partitioned between water (75 ml) and ethyl acetate (75 ml). The organic phase was washed with brine (50 ml), dried (MgSO₄) and the solvent evaporated. The product was purified by column chromatography to give N-{6-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]pyrid-3-yl}-N-methylmethanesulphonamide as a gum (0.25) g, 41%).

NMR Spectrum 1.85-2.10 (4H, m), 2.85 (3H, s), 3.0 (3H, s), 3.30 (3H, s), 3.75-3.90 (3H, s), 6.90 (1H, d), 7.45-7.65 (5H, m), 8.40 (1H, d).

The N-(6-Chloropyrid-3-yl)-N-methylmethanesulphonamide used as starting material was prepared as follows:

N-(2-chloropyrid-5-yl)methanesulphonamide was obtained using the procedure described for the preparation of N-(4-iodophenyl)methanesulphonamide, except that 5-amino-2-chloropyridine was used in place of 4-iodoaniline.

Sodium hydride (0.12 g, 50% dispersion in mineral oil, 2.5 mmol) was added to a solution of the product so obtained (0.50 g) in DMF (10 ml). The mixture was stirred at ambient temperature for 15 minutes. Methyl iodide (0.36 g) was added and the mixture stirred at ambient temperature for a further 1 hours. The mixture was partitioned between water (75 ml) and ethyl acetate (75 ml), the organic phase washed with water (50 ml) and brine (50 ml), dried (MgSO₄) and the solvent evaporated to leave N-(6-chloropyrid-3-yl)-N-methylmethanesulphonamide (0.40 g, 75%), m.p. 87°-90° C.

EXAMPLE 8

Using a similar procedure to that described in Example 3, except that the appropriate N-(4-iodophenyl)sulphonamide was used in place of N-(4-iodophenyl)-N-methylmethanesulphonamide, there were obtained the compounds described in the following table:

              TABLE III______________________________________ ##STR4##Ex. 8Compd.   -- N-Phenyl       Yield m.p.No.     Substituent              R1 R2                           (%)   (°C.)______________________________________1a 2-chloro   methyl  H    50    101-1022b no substituent              phenyl  H    37    gum______________________________________

Notes

a. The product was recrystallised from a mixture of hexane and ethyl acetate. N-(4-Iodophenyl)methanesulphonamide is described in the portion of Example 3 which is concerned with the preparation of starting materials.

b. The product gave the following characteristic NMR signals: 1.85-2.05 (4H, m), 2.93 (3H, s), 3.75-3.90 (4H, m), 6.95-7.8 (13H, m).

The N-(4-iodophenyl)benzenesulphonamide used as a starting material was obtained by the reaction of benzenesulphonyl chloride and 4-iodoaniline using a similar procedure to that described in the portion of Example 3 which is concerned with the preparation of N-(4-iodophenyl)methanesulphonamide.

EXAMPLE 9

Using a similar procedure to that described in Example 3, except that the appropriate N-(4-iodophenyl)sulphonamide was used in place of N-(4-iodophenyl)-N-methylmethanesulphonamide and that 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran was used in place of 4-(3-mercaptophenyl)-4-methoxytetrahydropyran, there were obtained the compounds described in the following table:

              TABLE IV______________________________________ ##STR5##Ex. 9Compd.  -- N-Phenyl         Yield m.p.No.    Substituent R1 R2                            (%)   (°C.)______________________________________1a  no substituent              methyl  methyl                            67    108-1112a  3-chloro    methyl  methyl                            60    113-1153b  2-chloro    methyl  H     73    gum4c  3-chloro    methyl  H     44    gum5d  2-fluoro    methyl  H     58    101-102______________________________________

Notes

The 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran used as a starting material for each of the compounds described in Table IV was obtained as follows:

Benzyl mercaptan (0.94 ml) was added drop wise to a mixture of sodium hydride (60% w/w dispersion in mineral oil; 0.35 g) and DMF (5 ml) which was cooled in a water bath. The mixture was stirred at ambient temperature for 30 minutes. The mixture so obtained was added dropwise to a mixture of 1-bromo-3,5-difluorobenzene (2.78 ml) and DMF (5 ml) which was cooled in an ice bath to 5° C. The resultant mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between diethyl ether and water. The organic phase was washed with water, dried (MgSO₄) and evaporated. There was thus obtained benzyl 3-bromo-5-fluorophenyl sulphide (2.5 g).

NMR Spectrum (CDCl₃, δ values) 4.13 (s, 2H), 6.90 (m, 1H), 7.04 (m, 1H), 7.2-7.35 (m, 6H).

A Grignard reagent was prepared by heating a mixture of 1,2-dibromoethane (10 drops), magnesium (0.24 g) and THF (25 ml) to 60° C. for 5 minutes, by adding benzyl 3-bromo-5-fluorophenyl sulphide (2.5 g) and by heating the resultant mixture to 60° C. for 30 minutes. The reagent was cooled in an ice bath, tetrahydropyran-4-one (0.8 ml) was added and the mixture was stirred for 30 minutes and then allowed to warm to ambient temperature. A saturated aqueous ammonium chloride solution (30 ml) was added and the mixture was partitioned between diethyl ether and water. The organic phase was washed with water and with brine, dried (MgSO₄) and evaporated. The residue was purified by column chromatography using initially hexane and then increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 4-(3-benzylthio-5-fluorophenyl)-4-hydroxytetrahydropyran (1.02 g).

Sodium hydride (60% w/w dispersion in mineral oil; 0.2 g) was added portionwise to a mixture of the product so obtained and DMF (5 ml) and the mixture was stirred at ambient temperature for 1 hour. Methyl iodide (0.6 ml) was added and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between diethyl ether and water. The organic phase was dried (MgSO₄) and evaporated. There was thus obtained 4-(3-benzylthio-5-fluorophenyl)-4-methoxytetrahydropyran (0.8 g) as an oil.

NMR Spectrum (CDCl₃, δ values(1.85 (m, 4H), 2.91 (s, 3H), 3.78 (m, 4H), 4.12 (s, 2H), 6.85-7.05 (m, 3H), 7.25 (m, 5H).

3 -Chloroperbenzoic acid (55% w/w technical grade; 0.38 g) was added portionwise to a mixture of a portion (0.4 g) of the product so obtained and chloroform (4 ml) which was cooled in an ice bath to 0° C. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to ambient temperature. Calcium hydroxide (0.13 g) was added and the mixture was stirred at ambient temperature for 15 minutes. The mixture was filtered and the filtrate was evaporated. Trifluoroacetic anhydride (3 ml) was added to the residue so obtained and the mixture was heated to reflux for 30 minutes. The mixture was evaporated. Methanol (10 ml) and triethylamine (10 ml) were added to the residue and the resultant mixture was evaporated. There was thus obtained 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran (0.37 g) as a gum which was used as the required starting material without further purification.

a. The product was recrystallised from a mixture of hexane and ethyl acetate.

b. The product gave the following characteristic NMR signals: 1.85-2.05 (4H, m), 3.0 (3H, s), 3.05 (3H, s), 3.75 (4H, m), 6.85-7.22 (4H, m), 7.43 (1H, d), 7.63 (1H, d).

The N-(2-chloro-4-iodophenyl)methanesulphonamide used as a starting material was obtained by the reaction of 2-chloro-4-iodoaniline and methanesulphonyl chloride using a similar procedure to that described in the portion of Example 3 which is concerned with the preparation of N-(4-iodophenyl)methanesulphonamide.

c. The product gave the following characteristic NMR signals: 1.85-2.05 (4H, m), 2.98 (3H, s), 3.08 (3H, s), 3.75-3.9 (4H, m), 6.85-7.38 (6H, m).

The N-(3-chloro-4-iodophenyl)methanesulphonamide used as a starting material was obtained by the reaction of 3-chloro-4-iodoaniline and methanesulphonyl chloride using a similar procedure to that described in the portion of Example 3 which is concerned with the preparation of N-(4-iodophenyl)methansulphonamide.

d. The product was recrystallised from a mixture of hexane and ethyl acetate.

the N-(2-fluoro-4-iodophenyl)methanesulphonamide, m.p. 117°-119° C., used as a starting material was obtained in 70% yield by the reactions of 2-fluoro-4-iodoaniline and methanesulphonyl chloride using a similar procedure to that described in the portion of Example 3 which is concerned with the preparation of N-(4-iodophenyl)-methanesulphonamide.

EXAMPLE 10

Using a similar procedure to that described in Example 3, except that the appropriate N-(4-iodophenyl)sulphonamide was used in place of N-(4-iodophenyl)-N-methylmethanesulphonamide and that 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran was used in place of 4-(3-mercaptophenyl)-4-methoxytetrahydropyran, there were obtained the compounds described in the following table:

              TABLE V______________________________________ ##STR6##Ex. 10Compd.                           Yield                                 m.p.No.     R1          R2 (%)  (°C.)______________________________________1a ethyl            H       45   78-812b phenyl           H       45   gum3c 2-methoxycarbonylphenyl                    H       44   92-944d 1-naphthyl       H       68   138-1395e 8-quinolyl       H       15   gum6f 8-quinolyl       methyl  35   gum______________________________________

Notes

a. The produce was recrystallised from a mixture of hexane and ethyl acetate.

The N-(2-fluoro-4-iodophenyl)ethanesulphonamide used as a starting material was obtained by the reaction of 2-fluoro-4-iodoaniline and ethanesulphonyl chloride using a similar procedure to that described in the portion of Example 3 which is concerned with the preparation of N-(4-iodophenyl)methanesulphonamide. There was thus obtained the required starting material in 77% yield, m.p. 66°-68° C.

b. The product gave the following characteristic NMR signals: 1.82-2.05 (m, 4H), 2.96 (s, 3H), 3.76-3.88 (m, 4H), 6.8 (m, 2H), 6.97 (m, 2H), 7.12 (m, 2H), 7.41-7.62 (m, 4H), 7.8 (m, 2H).

The N-(2-fluoro-4-iodophenyl)benzenesulphonamide used as a starting material was obtained by the reaction of 2-fluoro-4-iodoaniline and benzenesulphonyl chloride using a conventional procedure as described in Example 3. There was thus obtained the required starting material in 50% yield, m.p. 150°-152° C.

c. The produce was recrystallised from a mixture of hexane and ethyl acetate.

The N-(2-fluoro-4-iodophenyl)-2-methoxycarbonylbenzene-sulphonamide used as a starting material was obtained by the reaction of 2-fluoro-4-iodoaniline and 2-methoxycarbonylbenzenesulphonyl chloride using a conventional procedure as described in Example 3. There was thus obtained the required starting material in 58% yield, m.p. 103°-104° C.

d. The produce was recrystallised from a mixture of hexane and ethyl acetate.

The N-(2-fluoro-4-iodophenyl)-1-naphthalene sulphonamide used as a starting material was obtained by the reaction of 2-fluoro-4-iodoaniline and 1-naphthalenesulphonyl chloride using a conventional procedure as described in Example 3. There was thus obtained the required starting material in 44% yield, m.p. 130°-132° C.

e. The product gave the following characteristic NMR signals: 1.74-2.02 (m, 4H), 2.92 (s, 3H), 3.70-3.90 (m, 4H), 6.70 (m, 1H), 6.82 (m, 1H), 6.92 (m, 1H), 7.04 (m, 2H), 7.52-7.73 (m, 3H), 8.06 (m, 1H), 8.30 (m, 1H, 8.38 (m, 1H), 9.11 (m, 1H).

The N-(2-fluoro-4-iodophenyl)-8-quinolinesulphonamide used as a starting material was obtained by the reaction of 2-fluoro-4-iodoaniline and 8-quinolinesulphonyl chloride using a conventional procedure as described in Example 3. There was thus obtained the required starting material in 39% yield, m.p. 154°-156° C.

f. The product gave the following characteristics NMR signals: 1.83-2.02 (m, 4H), 2.97 (s, 3H), 3.54 (s, 3H), 3.73-3.90 (m, 4H), 6.83 (m, 1H), 6.91-7.08 (m, 3H), 7.18 (m, 1H), 7.30 (m, 1H), 7.51 (m, 2H), 8.03 (m, 1H), 8.23 (m, 1H), 8.37 (m, 1H), 8.98 (m, 1H).

The N-(2-fluoro-4-iodophenyl)-N-methyl-8-quinolinesulphonamide used as a starting material was obtained by the reaction of N-(2-fluoro-4-iodophenyl)-8-quinolinesulphonamide and methyl iodide using a conventional procedure as described in the last paragraph of Example 3. There was thus obtained the required starting material in 55% yield, m.p. 90°-93° C. ##STR7##