WO1995009158A1

WO1995009158A1 - Tricyclic derivatives

Info

Publication number: WO1995009158A1
Application number: PCT/GB1994/002039
Authority: WO
Inventors: Francis Thomas Boyle
Original assignee: Zeneca Limited; British Technology Group Ltd.
Priority date: 1993-09-29
Filing date: 1994-09-20
Publication date: 1995-04-06
Also published as: AU7660694A; GB9320113D0; ZA947314B

Abstract

The invention relates to tricyclic derivatives of formula (I), wherein R1 includes hydrogen, amino, (1-4C)alkyl and (1-4C)alkoxy; R2 includes hydrogen, (1-4C)alkyl, (3-4C)alkenyl and (3-4C)alkynyl; Ar1 is optionally-substituted phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl; and Ar2 is optionally-substituted phenyl or heteroaryl; or a pharmaceutically-acceptable salt thereof; to processes for their manufacture; to pharmaceutical compositions containing them; and to their use as thymidylate synthase inhibitors.

Description

TRICYCLIC DERIVATIVES

This invention relates to tricyclic derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-cancer activity. The invention includes tricyclic derivatives, processes for their manufacture, pharmaceutical compositions containing them and their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal such as man.

One group of anti-tumour compounds comprises the antimetabolites, such as aminopterin and methotrexate, which are inhibitors of enzymes such as dihydrofolate reductase which utilise folic acid derivatives. One antimetabolite which inhibits the enzyme thymidylate synthase and which showed considerable promise in clinical trials is known as CB3717 and is described and claimed in United Kingdom Patent Specification No. 2065653B. Despite its promising activity against human breast, ovarian and liver cancer however, CB3717 shows symptoms of toxicity in humans, particularly in relation to the liver and kidney (Cancer Treatment Reports, 1986, ** 1335). A newer compound which possesses inhibitory activity against thymidylate synthase and which is showing promise in clinical trials is known as ZD1694 (N-(5- [N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino] -2-thenoyl)-L-glutamic acid) and is described and claimed in European Patent Application No. 0 239 362. The compound has been shown to possess promising activity against human breast, ovarian, colorectal and non-small cell lung cancer and against adenocarcinoma (8th NCI-EORTC Symposium, Amsterdam, March, 1994; Abstract Nos. 240 and 242 to 245).

Compounds of the ZD1694 and CB3717-type are believed to act as anti-tumour agents by inhibiting the enzyme thymidylate synthase, which enzyme catalyses the methylation of deoxyuridine monophosphate to produce thy idine monophosphate which is required for DNA synthesis. The anti-cancer activity of ZD1694 and CB3717 may be assessed in vitro by determining their inhibitory effects on that enzyme, and in cell cultures by their inhibitory effects on cancer cell lines such as the mouse leukaemia cell line L1210, the mouse lymphoma cell line L5178Y TK-/- and the human breast cancer cell line MCF-7. Other compounds of the ZD1694 and CB3717-type have been described and claimed in European Patent Application Nos. 0 239 362, 0 284 338, 0 339 976, 0 373 891, 0 459 730, 0 509 643 and 0 562 734 and in PCT Patent Application Nos. 93/1905, 94/07869 and 94/11354. These compounds and the new compounds of the present invention may have their anti-cancer activity assessed by their activity against, for example, thymidylate synthase and the L1210, L5178Y TK-/- and MCF-7 cell lines.

Antimetabolites, such as aminopterin and methotrexate, which are inhibitors of enzymes which utilise folic acid derivatives, have also shown promise in the treatment of various allergic diseases such as allergic rhinitis, atopic dermatitis and psoriasis. The tricyclic derivatives of the present invention, being antimetabolites, are thus of value as therapeutic agents in the treatment of, for example, allergic conditions such as psoriasis.

Antimetabolites such as methotrexate have also shown promise in the treatment of various inflammatory diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout) and inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis) [New England J. Med. , 1985, 3_12., 818]. The tricyclic derivatives of the present invention are thus of value as therapeutic agents in the treatment of, for example, inflammatory disease such as rheumatoid arthritis.

We have now found that the tricyclic derivatives of the present invention possess potent inhibitory activity against thymidylate synthase and also potent anti-cancer activity as demonstrated by inhibition of the growth of the L1210, L5178Y TK-/- and MCF-7 cell lines.

According to the invention there is provided a tricyclic derivative of the formula I:-

wherein R is hydrogen, amino, (l-4C)alkyl, ( l-4C)alkoxy, (l-4C)alkylamino, di-[ (1-4C)alkyl]amino, piperidino, morpholino, piperazin-1-yl, 4-[ (1-4C)alkyl]piperazin-l-yl, hydroxy-(1-4C)alkyl, (l-4C)alkoxy-(l-4C)alkyl, amino-(1-4C)alkyl,

(l-4C)alkylamino-(l-4C)alkyl, di- [ (1-4C)alkyl]amino-(1-4C)alkyl, piperidino-( 1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-l-yl-(l-4C)alkyl, 4-[ (1-4C)alkyl]piperazin-l-yl-(l-4C)alkyl or fluoro-(l-4C)alkyl;

R² is hydrogen, (l-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, hydroxy-(2-4C)alkyl, halogeno-(2-4C)alkyl or cyano-(l-4C)alkyl; Ar is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from the group consisting of halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, (l-4C)alkyl and (l-4C)alkoxy; and

2 Ar is phenyl or heteroaryl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, (l-4C)alkyl and (l-4C)alkoxy; and

Q is carbamoyl, sulphamoyl, di-[ (l-4C)alkoxy]phosphoryl,

(l-4C)alkylthio, (l-4C)alkylsulphinyl, (l-4C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenyl-(l-4C)alkylthio, phenyl-(l-4C)alkylsulphinyl, phenyl-(l-4C)alkylsulphonyl, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, heteroaryl-( 1-4C)alkylthio, heteroaryl-(1-4C)alkylsulphinyl, heteroaryl-(l-4C)alkylsulphonyl, N-(l-4C)alkylcarbamoyl,

N,N-di-[(l-4C)alkyl]carbamoyl, N-(l-4C)alkylsulphamoyl,

N,N-di-[ (1-4C)alkyl]sulphamoyl, morpholinosulphonyl, piperidinosulphonyl, piperazin-1-ylsulphonyl, 4-(l-4C)- alkylpiperazin-1-ylsulphonyl, 4-(l-4C)alkoxycarbonylpiperazin-l- ylsulphonyl, N-[amino-(2-4C)alkyl]sulphamoyl,

N-[(l-4C)alkylamino-(2-4C)alkyl]sulphamoyl, N-{di- [ (1-4C)alkyl]amino-

(2-4C)alkyl}sulphamoyl, N-(1-4C)alkyl-N- [amino-(2-4C)alkyl]sulphamoyl,

N-(l-4C)alkyl-N-[(l-4C)alkylamino-(2-4C)alkyl]sulphamoyl or

N-(l-4C)alkyl-N-{di-[ (l-4C)alkyl]amino-(2-4C)alkyl}sulphamoyl; and when

Q is a group comprising a phenyl or heteroaryl group, said phenyl or heteroaryl group may optionally bear one substituent selected from halogeno, cyano, hydroxy, amino, (1-4C)alkyl and ( l-4C)alkoxy; 2 and wherein the heteroaryl group when Ar is heteroaryl, or the heteroaryl group when Q is a heteroaryl-containing group, is a 5- or

6-membered heteroaryl ring which contains 1 or 2 nitrogen heteroatoms and optionally contains a further heteroatom selected from nitrogen, oxygen and sulphur; or a pharmaceutically-acceptable salt thereof.

In this specification terms such as alkyl and alkylene include both straight and branched chain groups but references to individual groups such as propyl or trimethylene are specific for the straight chain version only.

It will be observed that the tricyclic derivatives of the present invention possess at least one asymmetric carbon atom [at the

2 attachment point of the -N(R )- group to the tricyclic ring] and can therefore exist in racemic and optically active forms. It is to be understood that the present invention encompasses a racemic form of the tricyclic compound of the invention, any optically-active form thereof or a mixture thereof which possesses anti-cancer activity. It is a matter of common general knowledge how such optically-active forms may be obtained by stereospecific synthesis or by the separation of mixtures of isomeric compounds.

It is also to be understood that a tricyclic derivative of the formula I may exhibit the phenomenon of tautomerism and that the formulae drawings presented within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which possesses anti-cancer activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.

It is also to be understood that certain tricyclic derivatives of the formula I can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess anti-cancer activity.

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

1 2 A suitable value for R or R when it is (1-4C)alkyl, or for

1 2 a (1-4C)alkyl substituent which may be present on Ar or Ar or on a phenyl-containing or heteroaryl-containing group in Q, is, for example, methyl, ethyl, propyl, isopropyl or butyl.

A suitable value for R when it is (l-4C)alkoxy, or for a

1 2 (l-4C)alkoxy substituent which may be present on Ar or Ar or on a phenyl-containing or heteroaryl-containing group in Q, is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

A suitable value for a halogeno substituent which may be

1 2 present on Ar or Ar or on a phenyl-containing or heteroaryl-containing group in Q, is, for example, fluoro, chloro or bromo.

A suitable value for R when it is (l-4C)alkylamino is, for example, methylamino, ethylamino, propylamino or isopropylamino; when it is di-[ (l-4C)alkyl]amino is, for example, dimethylamino, N-ethyl-N-methylamino or diethylamino; and when it is 4-[ (l-4C)alkyl]piperazin-l-yl is, for example, 4-methylpiperazin-l-yl or 4-ethylpiperazin-l-yl.

A suitable value for R when it is hydroxy-(1-4C)alkyl is, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or 3-hydroxypropyl; when it is (l-4C)alkoxy-(l-4C)alkyl is, for example, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl; when it is amino-(1-4C)alkyl is, for example, a inomethyl, 1-aminoethyl, 2-aminoethyl or 3-aminopropyl; when it is ( l-4C)alkylamino-(l-4C)alkyl is, for example, methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl or 3-methylaminopropyl; and when it is di- [ (l-4C)alkyl]amino-(l-4C)alkyl is, for example, dimethylaminomethyl, N-ethyl-N-methylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl or 3-dimethylaminopropyl.

A suitable value for R when it is piperidino-( 1-4C)alkyl is, for example, piperidinomethyl, 1-piperidinoethyl, 2-piperidinoethyl or 3-piperidinopropyl; when it is morpholino-(1-4C)alkyl is, for example, morpholinomethyl, 1-morpholinoethyl, 2-morpholinoethyl or 3-morpholinopropyl; when it is piperazin-l-yl-(l-4C)alkyl is, for example, piperazin-1-ylmethyl, 1-(piperazin-1-yl)ethyl, 2-(piperazin-1-yl)ethyl or 3-(piperazin-l-yl)propyl; and when it is 4- [ ( l-4C)alkyl]piperazin-l- yl-(l-4C)alkyl is, for example, 4-methylpiperazin-l-ylmethyl, 4-ethylpiperazin-l-ylmethyl, l-(4-methylpiperazin-l-yl)ethyl, 2-(4-methylpiperazin-l-yl)ethyl or 2-(4-ethylpiperazin-l-yl)ethyl.

A suitable value of R when it is fluoro-(l-4C)alkyl is, for example, fluoromethyl, difluoromethyl, trifluoromethyl or

2-fluoroethyl.

2 A suitable value for R when it is (3-4C)alkenyl is, for example, prop-2-enyl, but-2-enyl, but-3-enyl or 2-methylprop-2-enyl; when it is (3-4C)alkynyl is, for example, prop-2-ynyl or but-3-ynyl; when it is hydroxy-(2-4C)alkyl is, for example, 2-hydroxyethyl or

3-hydroxypropyl; when it is halogeno-(2-4C)alkyl is, for example,

2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl,

3-chloropropyl or 3-bromopropyl; and when it cyano-(l-4C)alkyl is, for example, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl.

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

A suitable value for Ar when it is thiophenediyl is, for example, thiophene-2,4-diyl or thiophene-2,5-diyl; when it is thiazolediyl is, for example, thiazole-2,4-diyl or thiazole-2,5-diyl; when it is pyridinediyl is, for example, pyridine-2,4-diyl, pyridine-2,5-diyl, pyridine-2,6-diyl or pyridine-3,5-diyl; and when it is pyrimidinediyl is, for example, pyrimidine-2,4-diyl, pyrimidine-2,5-diyl or pyrimidine-4,6-diyl.

2 A suitable value for Ar when it is heteroaryl, or for the heteroaryl group when Q is a heteroaryl-containing group, is a 5- or

6-membered heteroaryl ring which contains 1 or 2 nitrogen heteroatoms and optionally contains a further heteroatom selected from nitrogen, oxygen and sulphur, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl or thiadiazolyl. The heteroaryl group may be attached through any available position including through any available nitrogen atom and the heteroaryl group may bear a substituent on any available nitrogen atom. A suitable value for Q when it is di- [ ( l-4C)alkoxy]phosphoryl is, for example, dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl or dibutoxyphosphoryl; when it is (l-4C)alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio or butylthio; when it is ( l-4C)alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl or butylsulphinyl; when it is (l-4C)alkylsulphonyl is, for example, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl or butylsulphonyl; when it is phenyl-(l-4C)alkylthio is, for example, benzylthio, phenethylthio or 3-phenylpropylthio; when it is phenyl-(l-4C)alkylsulphinyl is, for example, benzylsulphinyl, phenethylsulphinyl or 3-phenylpropylsulphinyl; when it is phenyl-(l-4C)alkylsulphonyl is, for example, benzylsulphonyl, phenethylsulphonyl or 3-phenylpropylsulphonyl; when it is N-(l-4C)alkylcarbamoyl is, for example, N-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl; when it is

N,N-di-[ (1-4C)alkyl]carbamoyl is, for example, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or N,N-dipropylcarbamoyl; when it is N-(1-4C)- alkylsulphamoyl is, for example, N-methylsulphamoyl, N-ethylsulphamoyl or N-propylsulphamoyl; when it is N,N-di[ (l-4C)alkyl]sulphamoyl is, for example, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N,N- dipropylsulphamoyl; and when it is 4-(l-4C)alkylpiperazin-l-yl- sulphonyl is, for example, 4-methyl-, 4-ethyl- or 4-propylpiperazin- 1-ylsulphonyl.

A suitable value for Q when it is a heteroaryl- (l-4C)alkylthio group is, for example, heteroarylmethylthio or 2-heteroarylethylthio; when it is a heteroaryl-(l-4C)alkylsulphinyl group is, for example, heteroarylmethylsulphinyl or 2-heteroaryl- ethylsulphinyl; and when it is a heteroaryl-(l-4C)alkylsulphonyl group is, for example, heteroarylmethylsulphonyl or 2-heteroarylethylsulphonyl.

A suitable value for Q when it is 4-(l-4C)alkoxycarbonyl- piperazin-1-ylsulphonyl is, for example, 4-methoxycarbonyl-, 4-ethoxycarbonyl-, 4-propoxycarbonyl-, 4-butoxycarbonyl- or 4-tert- butoxycarbonyl-piperazin-1-ylsulphonyl; when it is N-[amino-(2-4C)alkyl]sulphamoyl is, for example N-(2-aminoethyl)sulphamoyl or N-(3-aminopropyl)sulphamoyl) ; when it is

N-[ (l-4C)alkylamino-(2-4C)alkyl]sulphamoyl is, for example,

N-(2-methylaminoethyl)sulphamoyl, N-(2-ethylaminoethyl)sulphamoyl or

N-(3-methylaminopropyl)sulphamoyl; when it is

N-{di-[ (l-4C)alkyl]amino-(2-4C)alkyl]sulphamoyl is, for example,

N-(2-dimethylaminoethyl)sulphamoyl, N-(2-diethylaminoethyl)sulphamoyl or N-(3-dimethylaminopropyl)sulphamoyl; when it is N-(l-4C)alkyl-N-

[amino-(2-4C)alkyl]sulphamoyl is, for example,

N-methyl-N-(2-aminoethyl)sulphamoyl or

N-ethyl-N-(2-aminoethyl)sulphamoyl; when it is N-(l-4C)alkyl-N-

[(l-4C)alkylamino-(2-4C)alkyl]sulphamoyl is, for example,

N-methyl-N-(2-methylaminoethyl)sulphamoyl or

N-ethyl-N-(2-methylaminoethyl)sulphamoyl; and when it is

N-(l-4C)alkyl-N-{di-[(l-4C)alkyl]amino-(2-4C)alkyl}sulphamoyl is, for example, N-methyl-N-(2-dimethylaminoethyl)sulphamoyl or

N-ethyl-N-(2-dimethylaminoethyl)sulphamoyl.

A suitable pharmaceutically-acceptable salt of a tricyclic derivative of the invention which is sufficiently basic is 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 tricyclic derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a calcium or magnesium salt, an ammonium or tetra-(2-hydroxyethyl)ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, trimethylamine or tris-(2-hydroxyethyl)amine.

Particular novel compounds of the invention are, for example, tricyclic derivatives of the formula I as defined in paragraphs (a) to

1 2 (j) hereinafter and wherein, unless otherwise stated, each of R , R ,

3 Ar and R have any of the meanings defined hereinbefore or in this section concerning particular compounds of the invention:-

(a) R is hydrogen, amino, methyl or hydroxymethyl;

(b) R is methyl;

2

(c) R is hydrogen, methyl, ethyl, propyl, prop-2-enyl, prop-2-ynyl, 2-hydroxyethyl, 2-fluoroethyl, 2-bromoethyl or 2-cyanoethyl;

2

(d) R is prop-2-ynyl;

(e) Ar is 1,4-phenylene which may optionally bear one or two substituents selected from the group consisting of fluoro and chloro, particularly Ar is 1,4-phenylene which bears a 2-fluoro substituent (with the -CO- group in the 1-position);

(f) Ar is thiophene-2,5-diyl or thiazole-2,5-diyl;

(g) Ar is pyridine-2,5-diyl (with the -CO- group in the

2-position) ;

2 (h) Ar is phenyl which may optionally bear one or two substituents selected from fluoro, chloro, bromo, hydroxy, amino,

2 cyano, nitro, trifluoromethyl, methyl, ethyl and methoxy, or Ar is pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl which may optionally bear one or two substituents selected from hydroxy, amino, nitro, cyano and methyl;

2 (i) Ar is pyridyl or pyrimidinyl; or

(j) Q is carbamoyl, sulphamoyl, dimethoxyphosphoryl, diethoxyphosphoryl, methylthio, ethylthio, propylthio, isopropylthio, butylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, butylsulphinyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, benzylthio, benzylsulphinyl, benzylsulphonyl, pyridylthio, pyridylsulphinyl, pyridylsulphonyl,

N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,

N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl,

N,N-diethylsulphamoyl, morpholinosulphonyl, piperidinosulphonyl, piperazin-1-ylsulphonyl, 4-methylpiperazin-1-ylsulphonyl,

4-tert-butoxycarbonylpiperazin-l-ylsulphonyl, N-(2-methylaminoethyl)- sulphamoyl, N-(2-dimethylaminoethyl)sulphamoyl,

N-methyl-N-(2-methylaminoethyl)sulphamoyl or

N-methyl-N-(2-dimethylaminoethyl)sulphamoyl, and when Q is a group comprising a phenyl group (such as phenyl or benzyl), said phenyl group may optionally bear^* one substituent selected from fluoro, chloro, cyano, methyl and methoxy; or a pharmaceutically-acceptable salt thereof.

A particular compound of the invention comprises a tricyclic derivative of the formula I wherein R is methyl;

2 R is methyl, ethyl, propyl, prop-2-enyl or prop-2-ynyl;

Ar is 1,4-phenylene which may optionally bear one fluoro substituent, or Ar is thiophene-2,5-diyl, thiazole-2,5-diyl (with the group

2 -C0-CH(Ar )(Q) in the 2-position) or pyridine-2,5-diyl (with the group

-CO-CH(Ar )(Q) in the 2-position);

2 Ar is phenyl which may optionally bear a substituent selected from

2 fluoro, chloro, nitro, trifluoromethyl or methyl, or Ar is pyridyl; and Q is carbamoyl, sulphamoyl, dimethoxyphosphoryl, diethoxyphosphoryl, methylsulphinyl, isopropylsulphinyl, methylsulphonyl, isopropylsulphonyl, phenylsulphinyl, phenylsulphonyl, benzylsulphinyl, benzylsulphonyl, N-methylcarbamoyl,

N,N-dimethylcarbamoyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl, morpholinosulphonyl, piperazin-1-ylsulphonyl or

N-methyl-N-(2-dimethylaminoethyl)sulphamoyl; or a pharmaceutically-acceptable salt thereof.

A preferred compound of the invention comprises a tricyclic derivative of the formula I wherein R is methyl;

2 R is methyl or prop-2-ynyl;

Ar is 1,4-phenylene, 2-fluoro-1,4-phenylene (with the group

2 -C0-CH(Ar )(Q) in the 1-position) or pyridine-2,5-diyl (with the group

2 -C0-CH(Ar )(Q) in the 2-position);

2 Ar is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-nitrophenyl,

4-cyanophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; and

Q is methylsulphonyl, phenylsulphonyl, benzylsulphonyl,

N-methylsulphamoyl, N,N-dimethylsulphamoyl, morpholinosulphonyl, piperazin-1-ylsulphonyl or N-methyl-N-(2-dimethylaminoethyl)sulphamoyl; or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a tricyclic derivative of the formula I wherein R is methyl;

2 R is prop-2-ynyl;

Ar is 1,4-phenylene, 2-fluoro-l,4-phenylene (with the group -C0-CH(Ar )(Q) in the 1-position) or pyridine-2,5-diyl (with the group 2 -C0-CH(Ar )(Q) in the 2-position);

2 Ar is phenyl, 4-fluorophenyl, 4-cyanophenyl, 2-pyridyl, 3-pyridyl or

4-pyridyl; and

Q is methylsulphonyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl or morpholinosulphonyl; or a pharmaceutically-acceptable salt thereof.

A specific especially preferred tricyclic derivative of the invention includes, for example, the following tricyclic derivative of the formula I:- α-methylsulphonylbenzyl 5-[N-( (6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro- 6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyrid-2-yl ketone or l-methylsulphonyl-l-(2-pyridyl)methyl 5-[N-( (6RS)-2-methyl-4-oxo- 3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)- amino]pyrid-2-yl ketone; or a pharmaceutically-acceptable salt thereof.

A further specific especially preferred tricyclic derivative of the invention includes, for example, the following tricyclic derivative of the formula I:-

£-fluoro-c-methylsulphonylbenzyl 5-[N-( (6RS)-2-methyl-4-oxo-3,4,7,8- tetrahydro-6H-cyclopenta[£]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyrid- 2-yl ketone or l-methylsulphonyl-l-(3-pyridyl)methyl 5-[N-( (6RS)-2- methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta [g ]quinazolin-6-yl)-N- (prop-2-ynyl)amino]pyrid-2-yl ketone; or a pharmaceutically-acceptable salt thereof.

A compound of the invention comprising a tricyclic 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

1 2 1 2 stated, R , R , Ar , Ar and Q have any of the meanings defined hereinbefore, provided that, when there is an amino, alkylamino,

1 2 1 2 piperazin-1-yl or hydroxy group in R , R , Ar , Ar or Q, any such group may optionally be protected by a conventional protecting group which may be removed when so desired by conventional means. (a) The reaction of an acid of the formula II

or a reactive derivative thereof, wherein R is hydrogen or a

2 protecting group, with a compound of the formula Ar -CH--Q.

A suitable reactive derivative of an acid of the formula II is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide.

The reaction is preferably carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl-lithium, or a dialkylamino-lithium, for example lithium di-isopropylamide, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent, for example tetrahydrofuran, 1,2-dimethoxyethane,

N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a temperature in the range, for example, -78 to 150 C, conveniently at or near ambient temperature.

3 A suitable value for R when it is a protecting group is, for example, a pivaloyloxymethyl group which may be removed by hydrolysis with a base, for example sodium hydroxide or ammonia, in a suitable inert solvent or diluent, for example methanol or ethanol.

A suitable protecting group for an amino, alkylamino or piperazin-1-yl group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example 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 group 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-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate) . A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example 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-carbon.

The starting materials of the formula II and of the formula

2 Ar -CH₂-Q may be prepared by standard procedures of organic chemistry.

The preparation of examples of such starting materials is described within the accompanying non-limiting Examples which are provided for the purpose of illustration only. Other necessary starting materials are obtainable by analogous procedures to those described or by modifications thereto which are within the ordinary skill of an organic chemist. Thus, for example, the starting material of the formula II may be prepared by the reaction of a compound of the formula III

O

wherein Z is a displaceable group, with an amine of the formula:

HNR²-Ar¹-C0₂R⁴

wherein R is a protecting group which can be removed to provide a carboxylic acid.

A suitable value for the displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, mesyloxy or 4-toluenesulphonyloxy group.

4 A suitable value for R is, for example, an alkyl group such as a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or R is a tert-butyl group which may be removed by cleavage with an acid, for example an organic acid such as trifluoroacetic acid. The protecting group R may be, for example an esterifying group which can be removed while the protecting group for

1 2 1 any amino, alkylamino, hydroxy or carboxy group in R , R and Ar is retained. 3 (b) The reaction of a compound of the formula III wherein R and

Z have the meanings defined above, with an amine of the formula:

HNR²-Ar¹-CO-CH(Ar²)(Q)

The reaction is preferably carried out in the presence of a suitable base as defined above, in a suitable inert solvent or diluent as defined above, and at a temperature in the range, for example 25 to 150 C, conveniently at or near 90°C.

The starting materials of the formula III and of the formula:

HNR²-Ar¹-CO-CH(Ar²)(Q)

may be prepared by standard procedures of organic chemistry. The preparation of examples of compounds of the formula III is described within the following non-limiting Examples which are provided for the purpose of illustration only. Other necessary starting materials are obtainable by analogous procedures to those described or by modifications thereto which are within the ordinary skill of an organic chemist.

(c) For the production of a compound of the formula I wherein Q is a group which comprises a sulphinyl or sulphonyl group, the oxidation of the corresponding compound of the formula I wherein Q is a group which comprises 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 sulphony, 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 of the corresponding thio compound.

(d) For the production of a compound of the formula I wherein R is amino-(1-4C)alkyl or substituted-amino-(l-4C)alkyl, the reaction of a compound of the formula I wherein R is hydroxy-(1-4C)alkyl, or a reactive derivative thereof, with ammonia or a substituted-amine.

A suitable reactive derivative of a compound of the formula I wherein R is hydroxy-(1-4C)alkyl is, for example, a compound of the formula I wherein R is a halogeno-(l-4C)alkyl or sulphonyloxy-(1-4C)- alkyl group, for example a chloro-(1-4C)alkyl, mesyloxy-(l-4C)alkyl or a 4-toluenesulphonyloxy-(l-4C)alkyl group.

The reaction is preferably carried out in a suitable inert solvent or diluent, for example methanol, ethanol, tetrahydrofuran or N,N-dimethylformamide, and at a temperature in the range, for example,

0 to 100 C, conveniently at or near ambient temperature.

(e) For the production of a compound of the formula I wherein Q is a piperazin-1-ylsulphonyl group, the cleavage of a compound of the formula I wherein Q is a 4-(l-4C)alkoxycarbonylpiperazin-l-yl group.

The cleavage conditions for the removal of the (1-4C)alkoxycarbonyl group necessarily vary with the nature of the (l-4C)alkyl group therein. Thus, for example, a (l-4C)alkyl group such as methyl or ethyl may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a (l-4C)alkyl group such as a tert-butyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid.

When a pharmaceutically-acceptable salt of a 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

1 is required, it may be obtained by earring out one of the aforesaid processes using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure.

As stated above a tricyclic derivative of the present invention possesses anti-tumour activity. This activity may be assessed, for example, using one or more of the procedures set out below:-

(a) An iri vitro assay which determines the ability of a test compound to inhibit the enzyme thymidylate synthase. Thymidylate synthase was obtained in partially purified form from L1210 mouse leukaemia cells and utilised using the procedures described by Jackman et al. (Cancer Res. , 1986, 46, 2810 and Sikora et al. , Biochem. Pharmacol. 1988, 37, 4047);

(b) An assay which determines the ability of a test compound to inhibit the growth of the leukaemia cell line L1210 in cell culture. The test is similar to that described in UK Patent Specification No. 2065653B and has been described by Jones et al. , J. Med. Chem. , 1985, 28, 1468;

(c) An assay which determines the ability of a test compound to inhibit the growth of the human breast cancer cell line MCF-7 in cell culture. The test is similar to that described by Lippman et al. (Cancer Res. , 1976, 3_6, 4595); and

(d) An assay which determines the ability of a test compound to be cytotoxic to the lymphoma cell line L5178Y TK-/- in vitro. The lymphoma cell line L5178Y TK-/- is deficient in the enzyme thymidine kinase which phosphorylates thymidine and thus operates to generate a pool of thymidylate when de novo synthesis of thymidylate is prevented by the presence of an effective amount of an inhibitor of thymidylate synthase. The L5178Y TK-/- cell line is thereby more sensitive to the presence of an inhibitor of thymidylate synthase. [L5178Y TK-/- was obtained by mutation of the parent L5178Y cell line which is described by, for example, Fischer et al. , Methods in Medical Research, 1964, 10, 247].

Although the pharmacological properties of the tricyclic derivatives of the invention vary with structural changes, in general tricyclic derivatives of the invention possess activity in one or more of the above tests (a) to (d):- Test (a) ^IC5 ⁱⁿ the range, for example, 0.05-10 μM; Test (b) IC_5Q in the range, for example, 0.1-20 μM; Test (c) IC,-_n in the range, for example, 0.1-10 μM; Test (d) ICc₀ in the range, for example, 0.05-10 μM.

In general those tricyclic derivatives of the invention which are especially preferred possess activity in one or more of the above tests (a) to (d):-

Test (a) ICC_Q in the range, for example, 0.05-2 μM; Test (b) ICc₀ in the range, for example, 0.1-10 μM; Test (c) IC50 *i-ⁿ t e range, for example, 0.1-5 μM; Test (d) ICCQ in the range, for example, 0.05-2 μM.

Thus, by way of example, the compound α-methylsulphonylbenzyl 5-[N-( (6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]- quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyrid-2-yl ketone has an IC,--, of 0.05 μM in Test (a), an IC_5Q of 0.4 μM in Test (c) and an IC_5Q of 0.05 μM in Test (d).

A tricyclic derivative of the present invention may itself be active or it may be a pro-drug which is converted in vivo to an active compound.

A tricyclic derivative of the invention, or a pharmaceutically-acceptable salt thereof, may be administered to a warm-blooded animal, including a human, in the form of a pharmaceutical composition which comprises the tricyclic derivative, 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 such as a dry powder, a microcrystalline form 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, emulsion or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients.

The composition may contain, in addition to the tricyclic derivative of the invention, one or more other anti-tumour substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; other antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example asparaginase; topoisomerase inhibitors, for example etoposide; and biological response modifiers, for example interferon.

The tricyclic derivative will normally be administered to a warm-blooded animal at a unit dose within the range 50-5000 mg per square metre body area of the animal, i.e. approximately 1-100 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example, 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.

According to a further feature of the invention there is provided a tricyclic 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 tricyclic derivatives of the present invention are expected to possess pharmacological activities arising from their thymidylate synthase inhibitory properties. In particular tricyclic derivatives of the invention are expected to possess activity in medical conditions or disease states where abnormal cellular proliferation occurs as in allergic diseases such as dermatitis and psoriasis, in inflammatory disease such as rheumatoid arthritis and inflammatory bowel disease and in malignant disease such as cancer. Accordingly the compounds of the present invention are expected to be useful in the treatment of a disease or medical condition mediated alone or in part by inhibition of the enzyme thymidylate synthase, i.e. the compounds may be administered to produce a thymidylate synthase inhibitory effect in a warm-blooded animal in need of such treatment. Thus the compounds of the present invention can be administered to produce an anti-proliferative effect mediated alone or in part by inhibition of the enzyme thymidylate synthase. If the disease state involves the presence of malignant cells, the compounds of the invention can be administered to provide a method for treating the proliferation of malignant cells characterised by inhibition of the enzyme thymidylate synthase.

A tricyclic derivative of the present invention is expected to possess a wide range of anti-cancer activities. CB3717 showed promising activity against leukaemia and human breast, ovarian and liver cancer and ZD1694 showed promising activity against human breast, ovarian, colorectal and non-small cell lung cancer and against adenocarcinoma. Consequently it is expected that a tricyclic derivative of the present invention will possess such anti-cancer activity. It is in addition expected that a compound of the present invention will possess anti-tumour activity against a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas. The growth of such tumours is mediated by a requirement for the thymidine monophosphate which is produced by the action of thymidylate synthase on deoxyuridine monophosphate. Thymidine monophosphate is one of the essential nucleotides for the synthesis of cellular DNA. In the presence of an effective amount of a thymidylate synthase inhibitor such as an effective amount of a compound of the present invention it is expected that the growth of thymidylate synthase dependent tumours will be inhibited. Accordingly it is expected that a tricyclic derivative of the invention will possess activity against thymidylate synthase sensitive tumours selected from leukaemia and breast, lung, liver, colon, rectal, stomach, prostate, bladder, pancreatic and ovarian cancer.

According^' to a further feature of the present invention there is provided a method for the treatment of a disease or medical condition mediated alone or in part by inhibition of the enzyme thymidylate synthase which comprises administering to a warm-blooded animal, such as man, an effective amount of a tricyclic derivative of the formula I, or a pharmaceutically-acceptable salt thereof.

The invention also provides the use of a tricyclic derivative of the formula I, or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use against a disease or medical condition mediated alone or in part by inhibition of the enzyme thymidylate synthase.

According to a further feature of the present invention there is provided a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a tricyclic derivative of the present invention, or a pharmaceutically-acceptable salt thereof.

The invention also provides the use of a tricyclic derivative of the present invention, or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm blooded animal, such as man.

As previously mentioned a tricyclic derivative of the invention, or a pharmaceutically-acceptable salt thereof, is also of value in the treatment of, for example, allergic conditions such as psoriasis or, for example, inflammatory disease such as rheumatoid arthritis. In using a compound of the invention for such a purpose the compound will normally be administered at a dose within the range 5-500 mg per square metre body area of the animal. In general for the treatment of an allergic condition such as psoriasis topical administration of a tricyclic derivative of the invention is preferred. Thus, for example, for topical administration a daily dose in the range, for example, 0.1 to 5 mg/kg will be used.

The invention is illustrated but not limited by the following 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 ambient temperature, that is in the range 18-20 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 preformed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 reversed-phase silica (Art. 9303) obtained from E. Merck, Darmstadt, Germany;

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

(v) the end-products of the formula I have satisfactory microanalyses and their structures were confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were determined using a Jeol FX 90Q or a Bruker AM200 spectrometer operating at a field strength of 200 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; d, doublet; d of d's, doublet of doublet's; t, triplet, m, multiplet; fast-atom bombardment (FAB) mass spectral data were obtained using a VG Analytical MS9 spectrometer and xenon gas and, where appropriate, either positive ion data or negative ion data were collected] ;

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

(vii) melting points were determined using a Mettler SP62 automatic melting point apparatus, a Koffler hot plate apparatus or an oil-bath apparatus; and

(viii) the following abbreviations have been used:- THF tetrahydrofuran; DMF N,N-dimethylformamide; DMA N,N-dimethylacetamide; DMSO dimethylsulphoxide; NMP N-methylpyrrolidin-2-one. Example 1 n-Butyl lithium (1.6M in hexane, 0.93 ml) was added dropwise to a stirred solution of benzyl methyl sulphone (0.25 g) in THF (30 ml) which had been cooled to -70°C. The mixture was allowed to warm to -20°C and was stirred at that temperature for 5 minutes. The mixture was recooled to -70°C and a solution of methyl 5-[N-( (6RS)-2-methyl-4- oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta [g]quinazolin- 6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylate (0.25 g) in THF (5 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 18 hours. The mixture was poured into a saturated aqueous ammonium chloride solution (30 ml) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 x 30 ml). The organic phase and extracts were combined, washed with water, dried (MgSO.) and evaporated. The residue was purified by column chromatography using initially ethyl acetate and then a 19:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained α-methylsulphonylbenzyl 5-[N-( (6RS)-2-methyl-4-oxo- 3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)- amino]pyrid-2-yl ketone (0.175 g), m.p. 145-147°C;

NMR Spectrum: (CDC1₃) 2.25 (t, IH), 2.35 (m, IH), 2.5 (s, 3H), 2.6 (m, IH), 3.0 (s, 3H), 3.05 (m, IH), 3.25 (m, IH) , 3.85 (2 d's, IH) , 4.0 (2 d's, IH), 5.15 (t, IH), 7.15 (s, IH), 7.3 (2 t's, IH), 7.4 (m, 3H) , 7.6 (s, IH), 7.7 (m, 2H), 8.05 (s, IH), 8.15 (d, IH), 8.4 (d, IH) , 10.95 (broad ε, IH); Elemental Analysis: Found C, 64.7; H, 5.3; N, 9.8;

^C29^H26^N4°4^S °-^5H2° °-^3Et0Ac requires C, 64.4; H, 5.1; N, 9.9%.

The methyl 5-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl- 3,4,7,8-tetrahydro-6H-cyclopenta[£]quinazolin-6-yl)-N-(prop-2-ynyl)- amino]pyridine-2-carboxylate used as a starting material was obtained as follows:-

A mixture of 5-aminoindan (100 g), acetic anhydride (84 g), pyridine (65 g) and ethyl acetate (500 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under diethyl ether (800 ml). The solid was filtered off, washed with diethyl ether (500 ml) and with hexane (500 ml) and dried. There was thus obtained 5-acetamidoindan (104.5 g), m.p. 107°C. Bromine (105 g) was added dropwise to a stirred mixture of 5-acetamidoindan (104.5 g) and acetic acid (400 ml), the rate of addition being such that the temperature of the reaction mixture was maintained in the range 20 to 25°C. The mixture was poured into a mixture (2 L) of ice and water. The precipitate was isolated, washed with water and dried. There was thus obtained 5-acetamido-6-bromoindan (143 g), m.p. 138°C.

A mixture of the material so obtained, cuprous cyanide (65.5 g) and NMP (600 ml) was stirred and heated to 125°C for 30 minutes. The mixture was cooled to ambient temperature and poured into a mixture of concentrated aqueous ammonia solution (specific gravity 0.88, 1 L) and ice (3 L) . The mixture was stirred for 15 minutes. The precipitate was isolated and washed with water (3 L). A mixture of the solid so obtained and methylene chloride (2 L) was stirred at ambient temperature for 30 minutes. The mixture was filtered and the filtrate was dried (MgSO,) and evaporated. The residue was triturated under diethyl ether (1.5 L) . There was thus obtained 5-acetamido-6- cyanoindan (104 g), m.p. 172°C.

A mixture of the material so obtained, hydrogen peroxide (30% solution in water, 400 ml), sodium hydroxide (35 g) , water (200 ml) and ethanol (1 L) was stirred and heated to 50°C for 1 hour. The mixture was cooled to ambient temperature and evaporated. The residue was dissolved in water (2 L) and the solution was acidified to pH5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 2-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (100 g), m.p. 284°C.

Potassium tert-butoxide (64 g) was added portionwise during 15 minutes to a stirred solution of 2-methyl-3,4,7,8-tetrahydro-6H- cyclopenta[j- quinazolin-4-one (89 g) in DMS0 (700 ml). The mixture was stirred at ambient temperature for 30 minutes. Chloromethyl pivaloate (131 g) was added dropwise during 30 minutes. The mixture was stirred at ambient temperature for 24 hours. The mixture was poured into a mixture of ammonium chloride (500 g) and a mixture (3 L) of ice and water. Ethyl acetate (2 L) was added and the mixture was filtered. The organic layer was dried (MgSO.) and evaporated. The residue was triturated under diethyl ether (500 ml). The mixture was cooled to 0°C for 2 hours. The solid was isolated, washed with diethyl ether and dried. There was thus obtained 2-methyl-3-pivaloyloxymethyl- 3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (72.4 g), m.p. 128°C

A mixture of a portion (50 g) of the material so obtained, N-bromosuccinimide (31.2 g), benzoyl peroxide (0.1 g) and carbon tetrachloride (500 ml) was stirred and heated to reflux for 90 minutes. The mixture was cooled to 0°C. The mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether (400 ml). The mixture was cooled to 0°C. The precipitate was isolated, washed with diethyl ether and dried. The solid so obtained was purified by column chromatography using a 1:1 mixture of hexane and ethyl acetate as eluent. There was thus obtained 6-bromo-2- methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g] - quinazolin-4-one (21 g) , m.p. 98°C (decomposes);

NMR Spectrum: 1.2 (s, 9H) , 2.55 (m, 2H) , 2.65 (s, 3H), 3.0 (m, IH), 3.3 (m, IH), 5.65 (d of d's, IH), 6.1 (q, 2H) , 7.5 (s, IH), 8.3 (s, IH).

A solution of potassium tert-butoxide (8.6 g) in a mixture of tert-butanol (100 ml) and DMA (100 ml) was added dropwise during 20 minutes to a stirred solution of a mixture of 6-bromo-2-methyl-3- pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta [g]quinazolin-4-one (30 g) and methyl 5-[N-(prop-2-ynyl)amino]pyridine-2-carboxylate [14.5 g; obtained in quantitative yield by treating methyl 5-[^-(tert- butoxycarbonyl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylate (J. Med. Chem. , 1991, 1594) with trifluoroacetic acid at 0°C for 1 hour] in DMA (300 ml) which had been cooled to -20°C. The mixture was allowed to warm to ambient temperature and was stirred for 24 hours. The mixture was evaporated. A mixture of ice and water (1 L) was added to the residue and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO.) and evaporated. The residue was purified by column chromatography using initially increasingly polar mixtures of hexane and ethyl acetate and then a 19:1 mixture of methylene chloride and methanol as eluent. There was thus obtained methyl 5-[N-( (6RS)-2- methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g] - quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylate (10.1 g) ; NMR Spectrum: (CDClg) 1.2 (s, 9H), 2.25 (t, IH) , 2.35 (m, IH), 2.6 ( , IH), 2.65 (s, 3H), 3.1 (m, IH), 3.3 (m, IH) , 3.88 (2 d's, IH) , 3.98 (s, 3H), 4.03 (2 d's, IH)*, 5.65 (t, IH), 6.1 (2 d's, 2H) , 7.3 (2 d's, IH), 7.55 (s, IH), 8.08 (d, IH), 8.1 (s, IH), 8.4 (s, IH).

Example 2 n-Butyl lithium (1.5M in hexane, 0.45 ml) was added dropwise to a stirred solution of di-isopropylamine (0.068 g) in THF (2 ml) which had been cooled to -70°C and the mixture was stirred at -70°C for 10 minutes. The solution of lithium di-isopropylamide so obtained was added dropwise to a stirred solution of pentafluorophenyl 5-[N-((6RS)- 2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N- (prop-2-ynyl)amino]pyridine-2-carboxylate (0.12 g) in THF (20 ml) which had been cooled to -70°C. The mixture was allowed to warm to -40°C and was stirred at that temperature for 5 minutes. The mixture was recooled to -70°C and a solution of methyl 2-pyridylmethyl sulphone (0.114 g) in THF (5 ml) was added during 3 minutes. The mixture was allowed to warm to -20°C and was stirred at that temperature for 15 minutes. The mixture was recooled to -60°C and a saturated aqueous ammonium chloride solution (20 ml) was added. The mixture was allowed to warm to ambient temperature. The organic phase was separated. The aqueous phase was extracted with THF (2 x 20 ml). The organic phase and extracts were combined, dried (MgSO,) and evaporated. The residue was purified by column chromatography using initially ethyl acetate and then a 9:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained 1-methylsulphonyl-1-(2-pyridyl)methyl 5-[N-( (6RS)-2- methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N- (prop-2-ynyl)amino]pyrid-2-yl ketone (0.048 g), m.p. 159-161°C; NMR Spectrum: (CD^OCD.-) 2.2 (m, IH), 2.35 (s, 3H) , 2.5 (m, IH) , 3.0 (m, IH), 3.15 (s, 3H), 3.2 (t, IH), 3.3 (m, IH) , 3.95 (2 d's, IH), 4.2 (2 d's, IH), 5.85 (t, IH), 7.05 (s, IH) , 7.4 ( , 2H), 7.5 (s, IH) , 7.8 (m, IH), 7.85 (s, IH), 7.9 (m, IH) , 8.0 (d, IH) , 8.4 (m, IH), 8.55 (d, IH), 12.1 (broad s, IH); Elemental Analysis: Found C, 61.9; H, 4.7; N, 12.4;

^C28^H25^N5°4^{S re(*}l^{uires C}' ⁶²'°5 ^H' ⁵-²' ^{N» 12}-^1%- The pentafluorophenyl 5- [N-( (6RS)-2-methyl-4-oxo-3,4,7,8- tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]- pyridine-2-carboxylate used as a starting material was obtained as follows:-

A mixture of methyl 5-[N-( (6RS)-2-methyl-4-oxo-3- pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta [g]quinazolin-6-yl)- N-(prop-2-ynyl)amino]pyridine-2-carboxylate (1 g), sodium hydroxide (0.32 g), water (10 ml) and methanol (30 ml) was stirred at ambient temperature for 24 hours. The mixture was evaporated. Water (60 ml) was added and the mixture was acidified to pH5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 5- [N-( (6RS)-2- methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta [g]quinazolin-6-yl)-N- (prop-2-ynyl)amino]pyridine-2-carboxylic acid (0.68 g); NMR Spectrum: (CD₃SOCD₃) 2.25 (m, IH) , 2.3 (s, 3H), 2.5 (m, IH) , 3.0 (s, IH), 3.05 (m, 2H) , 3.9 (2 d's, IH) , 4.15 (2 d's, IH) , 5.8 (t, IH), 7.4 (2 d's, IH), 7.5 (s, IH) , 7.8 (s, IH), 7.9 (d, IH), 8.35 (d, IH).

A mixture of a portion (0.66 g) of the material so obtained, pentafluorophenyl trifluoroacetate (0.99 g; prepared by the reaction of pentafluorophenol and trifluoroacetic acid), pyridine (0.28 g) and DMA (25 ml) was stirred at ambient temperature for 18 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and methanol as eluent. There was thus obtained pentafluorophenyl 5-[N-( (6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta [ ] - quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylate (0.54 g) , m.p. 165-167°C.

The methyl 2-pyridylmethyl sulphone used as a starting material was obtained as follows:-

Sodium methanethiolate (0.94 g) was added to a stirred solution of 2-(chloromethyl)pyridine (1 g) in DMF (5 ml) and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried (MgSO,) and evaporated. There was thus obtained methyl 2-pyridylmethyl sulphide as an oil (0.6 g, 70%).

NMR Spectrum: (CDC1₃) 2.07 (s, 3H), 3.8 (s, 2H), 7.16 (m, IH), 7.36 (d,

IH), 7.67 (m, IH), 8.54 (d, IH) .

A solution of 3-chloroperoxybenzoic acid (1.7 g) in methylene chloride (20 ml) was added to a solution of a portion (0.34 g) of the sulphide so obtained which had been cooled to 0°C. The mixture was stirred at 0°C to 5°C for 1.5 hours. The mixture was evaporated. The residue was basified by the addition of a saturated aqueous sodium bicarbonate solution and the mixture was re-evaporated. The residue was triturated under methylene chloride. There was thus obtained methyl 2-pyridylmethyl sulphone (0.17 g).

NMR Spectrum: (CD₃SOCD₃) 3.02 (s, 3H), 4.62 (s, 2H), 7.46 (m, 2H) , 7.87 (m, IH), 8.60 (m, IH) .

Example 3

Using an analogous procedure to that described in Example 1, except that the appropriate sulphone was used in place of benzyl methyl sulphone, there were obtained the tricyclic derivatives described in the following Table, the structures of which were confirmed by proton magnetic resonance and mass spectroscopy and by elemental analysis.

Table I

| Example 3 Ar² Q' m.p. 1

| Compound No. CC) |

1 ι^a p_-fluorophenyl methyl 157-159 |

1 2^b'^C 3-pyridyl methyl 166-168 |

| 3^b'^d p_-cyanophenyl methyl 158-160 |

| 4^b'^e JJ-fluorophenyl dimethylamino 167-169 |

Notes

a. The product contained 1 equivalent of water.

The p_-fluorophenyl methyl sulphone used as a starting material was obtained from £-fluorobenzyl chloride using an analogous procedure to that described in the portion of Example 2 which is concerned with the preparation of methyl 2-pyridylmethyl sulphone. b. Lithium di-isopropylamide (prepared as described in Example 2 above except that the di-isopropylamine was dissolved in a 2:1 mixture of THF and l,3-dimethylimidazolidin-2-one) was used in place of n-butyl lithium to generate the lithium salt of the appropriate sulphone. c. The product contained 0.5 equivalents of water and 0.75 equivalents of ethyl acetate.

The methyl 3-pyridylmethyl sulphone used as a starting material was obtained from 3-(chloromethyl)pyridine using an analogous procedure to that described in the portion of Example 2 which is concerned with the preparation of methyl 2-pyridylmethyl sulphone. d. The product contained 1 equivalent of ethyl acetate.

The p_-cyanobenzyl methyl sulphone used as a starting material was obtained from £-cyanobenzyl bromide using an analogous procedure to that described in the portion of Example 2 which is concerned with the preparation of methyl 2-pyridylmethyl sulphone. e. The product contained 0.5 equivalents of ethyl acetate. The £-fluoro-N,N-dimethyl-α-toluenesulphonamide used as a starting material was obtained as follows:-

A solution of (4-fluorophenyl)methanesulphonyl chloride (J. Phar . Science., 64, 1961; 0.5 g) in methylene chloride (10 ml) was added to a stirred ethanolic solution of dimethylamine (33% in ethanol, 5 ml) which had been cooled to 0°C. The mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The mixture was evaporated and the residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained £-fluoro-N,N-dimethyl-α- toluenesulphonamide (0.25 g, 48%).

NMR Spectrum: (CDC1₃) 2.78 (s, 6H), 4.18 (s, 2H) , 7.09 (t, 2H), 7.38 (m, 2H).

Example 4

Using an analogous procedure to that described in Example 2, except that the appropriate sulphone was used in place of methyl 2-pyridylmethyl sulphone, there were obtained the tricyclic derivatives described in the following Table, the structures of which were confirmed by proton magnetic resonance and mass spectrometry and by elemental analysis. Table II

| Example 4 Ar² Q' m.p.

| Compound No. (°C)

1 ι^a phenyl methylamino 171-175

1 2^b phenyl dimethylamino 160-163

1 3^C 4-pyridyl methyl 167-169

1 4^d £-fluorophenyl morpholino 179-182

1 5^e £-fluorophenyl N-(2-dimethylamino¬ 195-197 ethyl)-N-methylamino

1 6^f £-fluorophenyl 4-tert-butoxycarbonyl- 169-172 piperidin-1-yl

Notes

a. The product contained 0.5 equivalents of water.

The N-methyl-α-toluenesulphonamide used as a starting material was obtained as follows:-

A solution of α-toluenesulphonyl chloride (3.59 g) in methylene chloride (50 ml) was added dropwise to a stirred mixture of a 33% weight/volume solution of methylamine in ethanol (20 ml) and methylene chloride (200 ml) which had been cooled to 5°C. The mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water (200 ml). The organic phase was washed with water and with brine, dried (MgSO.) and evaporated. The resultant solid was recrystallised from a 4:1 mixture of hexane and ethyl acetate. There was thus obtained the required starting material (1.49 g).

NMR Spectrum: 2.69 (d, 3H), 4.10 (broad s, IH), 4.25 (s, 2H), 7.39 (s,

5H). b. The product was triturated under diethyl ether and was shown by elemental analysis to contain 0.5 equivalents of water and 0.5 equivalents of diethyl ether.

The N,N-dimethyl-α-toluenesulphonamide used as a starting material was obtained as follows:-

A solution of α-toluenesulphonyl chloride (8.64 g) in methylene chloride (20 ml) was added dropwise to a vigorously stirred mixture of a 40% weight/volume solution of dimethylamine in water (80 ml) and methylene chloride (100 ml) which had been cooled to 0°C. The mixture was stirred at ambient temperature for 2 hours. The organic layer was separated, dried (MgSO,) and evaporated. The resultant solid was recrystallised from a 10:2:1 mixture of toluene, hexane and ethanol. There was thus obtained the required starting material (5.8 g, 65%), m.p. 98-100°C. c. The product contained 1 equivalent of water.

The methyl 4-pyridylmethyl sulphone used as a starting material was obtained from 4-(chloromethyl)pyridine using an analogous procedure to that described in the portion of Example 2 which is concerned with the preparation of methyl 2-pyridylmethyl sulphone. d. The product contained 1.5 equivalents of water and 0.5 equivalents of ethyl acetate.

The £-fluorobenzyl morpholino sulphone used as a starting material was obtained as follows:-

A solution of (4-fluorophenyl)methanesulphonyl chloride (10.4 g) in methylene chloride (50 ml) was added dropwise to a stirred solution of morpholine (9.6 g) in methylene chloride (30 ml) which had been cooled to 5°C. The mixture was stirred at ambient temperature for 1 hour. The mixture was washed with 2N aqueous hydrochloric acid and with water, dried (MgSO,) and evaporated. There was thus obtained the required starting material (12 g, 92%), m.p. 158-159°C (recrystallised from a 1:1 mixture of hexane and ethyl acetate). e. The product contained 1 equivalent of water and 0.5 equivalents of ethyl acetate.

The £-fluoro-N-methyl-N-(2-dimethylaminoethyl)-α-toluene- sulphonamide used as a starting material was obtained by the reaction of (4-fluorophenyl)methanesulphonyl chloride and N-methyl-N-(2- dimethylaminoethyl)amine using an analogous procedure to that described in Note b. above. f. The product contained 0.5 equivalents of ethyl acetate. The £-fluorobenzyl 4-tert-butoxycarbonylpiperazin-l-yl sulphone used as a starting material was obtained by the reaction of (4-fluorophenyl)methanesulphonyl chloride and N-tert-butoxycarbonyl- piperazine using an analogous procedure to that described in Note b. above.

Example 5

A mixture of α-(4-tert-butoxycarbonylpiperazin-l- ylsulphonyl)-£-fluorobenzyl 5-[N-( (6RS)-2-methyl-4-oxo-3,4,7,8-tetra- hydro-6H-cyclopenta[£]quinazoline-6-yl)-N-(prop-2-ynyl)amino]pyrid-2-yl ketone (Example 4(6) above, 0.153 g) and trifluoroacetic acid (10 ml) was stirred at ambient temperature for 30 minutes. The mixture was evaporated. Diethyl ether (20 ml) was added and the mixture was stirred at ambient temperature for 1 hour. The solid so obtained was isolated and dried. There was thus obtained £-fluoro-α-(piperazin-l- ylsulphonyl)benzyl 5- [N-( (6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H- cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyrid-2-yl ketone trifluoroacetate salt (0.156 g), m.p. 180-182°C;

NMR Spectrum: (CD₃SOCD₃ + CD₃C0₂D) 2.25 (m, IH), 2.45 (s, 3H) , 2.6 (m, IH), 3.05 (t, IH), 3.1 (m, 5H) , 3.25 (m, IH) , 3.35 (m, 4H), 4.0 (d, IH), 4.25 (d, IH), 5.4 (t, IH), 7.23 (d, IH), 7.27 (d, IH), 7.3 (s, IH), 7.5 (2 t's, IH), 7.6 (s, IH) , 7.75 (d, IH) , 7.8 (d, IH), 7.9 (s, IH), 8.05 (d, IH), 8.45 (t, IH) ;

Elemental Analysis: Found C, 50.2; H, 3.8; N, 9.7; ^C32^H31^FN6°4^{S 1H}2° ^2CF3^C02^{H re(}I^uires C, 50.2; H, 4.0; N, 9.7%.

Example 6

Using an analogous procedure to that described in Example 1, except that lithium di-isopropylamide was used in place of n-butyl lithium, pentafluorophenyl £-fluoro-£-[N-methyl-N-( (6RS)-2-methyl-4- oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin- 6-yl)amino]benzoate was reacted with £-fluorobenzyl methyl sulphone to give 2,4'-difluoro-4-[N-methyl-N-( (6RS)-2-methyl-4-oxo-3,4,7,8-tetra- hydro-6H-cyclopenta [g]quinazolin-6-yl)amino]-α-methylsulphonyldesoxy- benzoin in 57% yield, m.p. 153-154°C;

NMR Spectrum: (CD₃SOCD₃) 2.05 (m, IH) , 2.33 (s, 3H), 2.45 (m, IH) , 2.7 (s, 3H), 2.95 (m, IH), 3.0 (s, 3H) , 3.1 (m, IH) , 5.82 (t, IH), 6.3 (s, IH), 6.75 (2 t's, IH), 6.9 (2 d's, IH), 7.29 (t, 2H), 7.5 (s, IH) , 7.6 (2 d's, 2H), 7.65 (s, IH), 7.85 (t, IH), 12.1 (broad s, IH); Elemental Analysis: Found C, 61.7; H, 5.1; N, 7.1;

^C28^H25^F2^N3°4^S °-^75EtAc requires C, 61.6; H, 5.1; N, 7.0%.

The pentafluorophenyl o-fluoro-£-[N-methyl-N-((6RS)-2-methyl- 4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta [ ] - quinazolin-6-yl)amino]benzoate used as a starting material was obtained as follows:-

A mixture of 6-bromo-2-methyl-3-pivaloyloxymethyl-3,4,7,8- tetrahydro-6H-cyclopenta[g]quinazolin-4-one (26 g) , £-amino-o- fluorobenzoic acid 1,l-dimethyl-2-hydroxyethylammonium salt (42 g), calcium carbonate (21.4 g) and DMSO (200 ml) was stirred at ambient temperature for 72 hours. The mixture was poured onto a mixture of ice and water (1 L) . The precipitate was isolated, washed with water and dried under vacuum. The product was purified by column chromatography using initially a 9:1 mixture of methylene chloride and methanol and then a 9:1:0.1 mixture of methylene chloride, methanol and acetic acid as eluent. There was thus obtained o-fluoro-£-[N-( (6RS)-2- methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[£]- quinazolin-6-yl)aminoJbenzoic acid as a gum (20 g).

A mixture of a portion (15 g) of the material so obtained, pentafluorophenol (35 g), N,N-dicyclohexylcarbodiimide (13 g), N-hydroxybenzotriazole (0.2 g) and methylene chloride (500 ml) was stirred at ambient temperature for 18 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained pentafluorophenyl o-fluoro-£- [N- ( (6RS) -2-methyl-4-oxo-3-pivaloyloxymethyl-3 , 4, 7 , 8- tetrahydro-6H-cyclopenta[g] quinazolin-6-yl) amino ] benzoate as a gum ( 14 g) ^;

NMR Spectrum: (CDC1₃) 1.23 (s, 9H) , 2.05 (m, IH) , 2.65 (s, 3H), 2.75 (m, IH), 3.13 (m, 2H), 4.8 (d, IH), 5.15 (2 d's, IH), 6.1 (2 d's, 2H), 6.3 (m, 2H), 7.5 (s, IH), 7.95 (t, IH), 8.2 (s, IH).

An aqueous solution of formaldehyde (37% weight/volume, 17.55 ml) was added dropwise during 15 minutes to a stirred solution of pentafluorophenyl o-fluoro-£-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxy- methyl-3,4,7,8-tetrahydro-6H-cyclopenta [g]quinazolin-6-yl)amino]- benzoate (13 g) in glacial acetic acid (100 ml). The mixture was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (1.36 g) was added portionwise during 30 minutes and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was poured onto a mixture of ice and water (500 ml) and extracted with ethyl acetate. The organic phase was dried (MgSO,) and evaporated. The product was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate. There was thus obtained the required starting material (11 g) ;

NMR Spectrum: (CDCL_j) 1.23 (s, 9H), 2.15 (m, IH), 2.55 (m, IH) , 2.65 (s, 3H), 2.8 (s, 3H), 3.15 (m, 2H), 5.65 (t, IH), 6.1 (2 d's, 2H) , 6.6 (2 d's, IH), 6.72 (2 d's, IH), 7.53 (s, IH) , 7.97 (d, IH) , 8.03 (s, IH).

Example 7

Using an analogous procedure to that described in Example 1, except that lithium di-isopropylamide was used in place of n-butyl lithium, pentafluorophenyl £-fluoro-£-[N-methyl-N-( (6RS)-2-methyl-4- oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin- 6-yl)amino]benzoate was reacted with £-fluorobenzyl 4-pyridyl sulphone to give 2,4'-difluoro-4-[N-methyl-N-( (6RS)-2-methyl-4-oxo-3,4,7,8- tetrahydro-6H-cyclopenta[£]quinazolin-6-yl)amino]-α-( -pyridyl- sulphonyl)desoxybenzoin in 28% yield, m.p. 185-187°C;

NMR Spectrum: (CD₃SOCD₃) 2.05 (m, IH), 2.33 (s, 3H) , 2.45 (m, IH), 2.69 (s, 3H), 3.0 (m, IH), 3.1 (m, IH), 5.8 (t, IH) , 6.65 (s, IH), 6.7 (2 t's, IH), 6.8 (2 d's, IH), 7.22 (t, 2H), 7.41 (d, IH), 7.45 (d, IH), 7.48 (s, IH), 7.62 (d, 2H), 7.68 (s, IH), 7.8 (t, IH) , 8.85 (d, 2H),

12.1 (broad s, IH);

Elemental Analysis: Found C, 63.3; H, 4.9; N, 8.2;

^C32^H26^F2^N4°4^S °'^75EtAc requires C, 63.0; H, 4.8; N, 8.4%.

The £-fluorobenzyl 4-pyridyl sulphone used as a starting material was obtained as follows:-

4-Mercaptopyridine (1.7 g) was added portionwise to a stirred mixture of sodium hydride (60% dispersion in mineral oil, 0.63 g) and DMF (10 ml) which had been cooled in an ice-bath. The mixture was stirred at 0°C for 10 minutes. £-Fluorobenzyl chloride (1 g) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained £-fluorobenzyl 4-pyridyl sulphide (1.1 g, 72%).

NMR Spectrum: (CDC1₃) 4.19 (s, 2H) , 7.03 (m, 2H), 7.13 (d, 2H) , 7.35 (m, 2H), 8.41 (broad s, 2H) .

The material so obtained was oxidised with 3-chloroperoxybenzoic acid using an analogous procedure to that described in the last paragraph of the portion of Example 2 which is concerned with the preparation of starting materials. There was thus obtained £-fluorobenzyl 4-pyridyl sulphone.

NMR Spectrum: (CD₃SOCD₃) 4.85 (s, 2H), 7.21 (m, 4H), 7.7 (m, 2H) , 8.87 (m, 2H).

Example 8

Lithium di-isopropylamide (2M in THF, 0.56 ml) was added dropwise to a stirred solution of benzyl methyl sulphone (0.189 g) in THF (50 ml) which had been cooled to -70°C. The mixture was allowed to warm to -20°C and was stirred at that temperature for 5 minutes. The mixture was recooled to -70°C and a solution of pentafluorophenyl £-[N-((6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta [g] - quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoate (PCT Patent Application No. WO 94/11354, Example 3 thereof; 0.2 g) in THF (5 ml) was added. The mixture was allowed to warm to -20^CC and was stirred at that temperature for 5 minutes. A saturated aqueous ammonium chloride solution (50 ml) was added and the mixture was allowed to warm to ambient temperature. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 x 50 ml). The organic phase and extracts were combined, dried (MgSO,) and evaporated. The residue was purified by column chromatography using initially ethyl acetate and then a 19:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained 4-[N-( (6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H- cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-α-methylsulphonyl- desoxybenzoin (0.09 g, 46%), m.p. 162-164°C;

NMR Spectrum: (CD₃SOCD₃) 2.25 (m, 2H), 2.32 (s, 3H), 2.5 (m, IH), 3.0 (s, 3H), 3.1 (m, IH), 3.15 (s, IH) , 3.3 (m, IH), 3.92 (m, IH) , 4.2 (m, IH), 5.88 (t, IH), 6.68 (s, IH), 7.0 (d, 2H) , 7.42 (s, IH), 7.48 (m, 3H), 7.65 (m, 2H), 7.78 (s, IH), 8.0 (d, 2H), 12.1 (s, IH); Elemental Analysis: Found C, 62.5; H, 4.6; N, 7.4; ^C30^H27^N3°4^S °-^75EtAc 0-5H₂0 requires C, 62.2; H, 4.8; N, 7.3%.

Example 9

The following illustrate representative pharmaceutical dosage forms containing the compound of formula I, or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:-

(a) Tablet I mg/tablet

Compound X 100

Lactose Ph.Eur 182.75

Croscarmellose sodium 12.0

Maize starch paste (5% w/v paste) 2.25

Magnesium stearate 3.0 (b) Tablet II mg/tablet

Compound X 50

Lactose Ph.Eur 223.75

Croscarmellose sodium 6.0

Maize starch 15.0

Polyvinylpyrrolidone (5% w/v paste) 2.25

Magnesium stearate 3.0

(c) Tablet III mg/tablet

Compound X 1.0

Lactose Ph.Eur 93.25

Croscarmellose sodium 4.0

Maize starch paste (5% w/v paste) 0.75

Magnesium stearate 1.0

(d) Capsule mg/capsule

Compound X 10 mg

Lactose Ph.Eur 488.5

Magnesium stearate 1.5

(e) Injection I (50 mg/ml)

Compound X 5.0% w/v

1M Sodium hydroxide solution 15.0% v/v

0.1M Hydrochloric acid

(to adjust pH to 7.6)

Polyethylene glycol 400 4.5% w/v

Water for injection to 100%

(f) Injection II (10 mg/ml)

Compound X 1.0% w/v

Sodium phosphate BP 3.6% w/v

0.1M Sodium hydroxide solution 15.0% v/v

Water for^* injection to 100% (g) Injection III (lmg/ml,buffered to pH6)

Compound X 0.1% w/v

Sodium phosphate BP 2.26% w/v

Citric acid 0.38% w/v

Polyethylene glycol 400 3.5% w/v

Water for injection to 100%

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a) to (c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

Claims

A tricyclic derivative of the formula I:*

wherein R is hydrogen, amino, (l-4C)alkyl, (l-4C)alkoxy,

(l-4C)alkylamino, di-[(1-4C)alkyl]amino, piperidino, morpholino, piperazin-1-yl, 4-[ (l-4C)alkyl]piperazin-l-yl, hydroxy-(l-4C)alkyl,

(l-4C)alkoxy-(l-4C)alkyl, amino-(l-4C)alkyl,

(l-4C)alkylamino-(l-4C)alkyl, di-[ (l-4C)alkyl]amino-(l-4C)alkyl, piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl, 4-[(1-4C)alkyl]piperazin-1-yl-(1-4C)alkyl or fluoro-(l-4C)alkyl;

R² is hydrogen, (l-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, hydroxy-(2-4C)alkyl, halogeno-(2-4C)alkyl or cyano-(1-4C)alkyl;

Ar is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from the group consisting of halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, (l-4C)alkyl and (l-4C)alkoxy; and

Q is carbamoyl, sulphamoyl, di-[ (l-4C)alkoxy]phosphoryl,

(l-4C)alkylthio, (l-4C)alkylsulphinyl, (l-4C)alkylsulphonyl, phenylthio, phenylsulphinyl, phenylsulphonyl, phenyl-(l-4C)alkylthio, phenyl-(l-4C)alkylsulphinyl, phenyl-(l-4C)alkylsulphonyl, heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, heteroaryl-(l-4C)alkylthio, heteroaryl-(l-4C)alkylsulphinyl, heteroaryl-(1-4C)alkylsulphonyl, N-(1-4C)alkylcarbamoyl,

N,N-di-[ (l-4C)alkyl]carbamoyl, N-(l-4C)alkylsulphamoyl,

N,N-di-[(1-4C)alkyl]sulphamoyl, morpholinosulphonyl, piperidinosulphonyl, piperazin-1-ylsulphonyl, 4-(l-4C)- alkylpiperazin-1-ylsulphonyl, 4-( l-4C)alkoxycarbonylpiperazin-l- ylsulphonyl, N-[amino-(2-4C)alkyl]sulphamoyl,

N-[(l-4C)alkylamino-(2-4C)alkyl]sulphamoyl, N-{di-[ (1-4C)alkyl]amino-

(2-4C)alkyl}sulphamoyl, N-(1-4C)alkyl-N- [amino-(2-4C)alkyl]sulphamoyl,

N-(1-4C)alkyl-N- [ (l-4C)alkylamino-(2-4C)alkyl]sulphamoyl or

N-(l-4C)alkyl-N-{di-[(l-4C)alkyl]amino-(2-4C)alkyl}sulphamoyl; and when

Q is a group comprising a phenyl or heteroaryl group, said phenyl or heteroaryl group may optionally bear one substituent selected from halogeno, cyano, hydroxy, amino, (l-4C)alkyl and (l-4C)alkoxy;

2 and wherein the heteroaryl group when Ar is heteroaryl, or the heteroaryl group when Q is a heteroaryl-containing group, is a 5- or

2. A tricyclic derivative of the formula I as claimed in claim 1 wherein R is methyl;

2 R is methyl, ethyl, propyl, prop-2-enyl or prop-2-ynyl;

2 -C0-CH(Ar )(Q) in the 2-position) or pyridine-2,5-diyl (with the group

2 -C0-CH(Ar )(Q) in the 2-position);

2 Ar is phenyl which may optionally bear a substituent selected from

3. A tricyclic derivative of the formula I as claimed in claim 1 wherein R is methyl;

2 R is methyl or prop-2-ynyl; Ar is 1,4-phenylene, 2-fluoro-1,4-phenylene (with the group

2 -C0-CH(Ar )(Q) in the 1-position) or pyridine-2,5-diyl (with the group

2 -C0-CH(Ar )(Q) in the 2-position);

2 Ar is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-nitrophenyl,

4-cyanophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; and

Q is methylsulphonyl, phenylsulphonyl, benzylsulphonyl,

4. A tricyclic derivative of the formula I as claimed in claim 1 wherein R is methyl;

2 R is prop-2-ynyl;

Ar is 1,4-phenylene, 2-fluoro-1,4-phenylene (with the group

2 -C0-CH(Ar )(Q) in the 1-position) or pyridine-2,5-diyl (with the group

9 -C0-CH(Ar )(Q) in the 2-position);

2 Ar is phenyl, 4-fluorophenyl, 4-cyanophenyl, 2-pyridyl, 3-pyridyl or

4-pyridyl; and

5. A tricyclic derivative of the formula I as claimed in claim 1 selected from α-methylsulphonylbenzyl 5-[N-((6RS)-2-methyl-4-oxo- 3,4,7,8-tetrahydro-6H-cyclopenta[£]quinazolin-6-yl)-N-(prop-2-ynyl)- amino]pyrid-2-yl ketone and l-methylsulphonyl-l-(2-pyridyl)methyl 5-[N-((6RS)-2-methyl-4-oxo- 3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)- amino]pyrid-2-yl ketone; or a pharmaceutically-acceptable salt thereof.

6. A tricyclic derivative of the formula I as claimed in claim 1 selected from £-fluoro-α-methylsulphonylbenzyl 5-[N-((6RS)-2-methyl-4- oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2- ynyl)amino]pyrid-2-yl ketone and l-methylsulphonyl-l-(3-pyridyl)methyl 5-[N-( (6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta [g] - quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyrid-2-yl ketone; or a pharmaceutically-acceptable salt thereof.

7. A process for the preparation of a tricyclic derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 which comprises:-

(a) the reaction of an acid of the formula II

or a reactive derivative thereof, wherein R is hydrogen or a

2 protecting group, with a compound of the formula Ar -CH-.-Q;

(b) the reaction of a compound of the formula III

wherein R is hydrogen or a protecting group and Z is a displaceable group, with an amine of the formula:

HNR -Ar -C0-CH(Ar ) (Q)

(c) for the production of a compound of the formula I wherein Q is a group which comprises a sulphinyl or sulphonyl group, the oxidation of the corresponding compound of the formula I wherein Q is a group which comprises a thio group;

(d) for the production of a compound of the formula I wherein R is amino-(1-4C)alkyl or substituted-amino-(l-4C)alkyl, the reaction of a compound of the formula I wherein R is hydroxy-(1-4C)alkyl, or a reactive derivative thereof, with ammonia or a substituted-amine; or (e) for the production of a compound of the formula I wherein Q is a piperazin-1-ylsulphonyl group, the cleavage of a compound of the formula I wherein Q is a 4-(l-4C)alkoxycarbonylpiperazin-l-yl group; and when a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained by reaction of said compound with a suitable acid or base using a conventional procedure and when an optically active form of a compound of the formula I is required, it may be obtained by earring out one of the aforesaid processes using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure.

8. A pharmaceutical composition which comprises a tricyclic derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in association with a pharmaceutically-acceptable diluent or carrier.

9. The use of a tricyclic derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use against a disease or medical condition mediated alone or in part by inhibition of the enzyme thymidylate synthase.

10. The use of a tricyclic derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm blooded animal.