2-aminocarbonyl-9H-purine derivatives Number:7,094,769 from the United States Patent and Trademark Office (PTO) owispatent The present invention relates to compounds of the formula: ##STR00001## and pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such compounds.<H aminocarbonyl, derivatives, 2, aminocarbonyl, 7094769.html, Patent, pto, 7094769

Title: 2-aminocarbonyl-9H-purine derivatives

Abstract: The present invention relates to compounds of the formula: ##STR00001## and pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such compounds.

Patent Number: 7,094,769 Issued on 08/22/2006 to Mantell, et al.

Inventors: Mantell; Simon J. (County of Kent, GB), Stephenson; Peter T. (County of Kent, GB)
Assignee: Pfizer Inc (New York, NY)

Appl. No.: 10/676,782

Filed: October 1, 2003

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
09874007	Jun., 2001	6753322
60245243	Nov., 2000
60225236	Aug., 2000
60214307	Jun., 2000

Foreign Application Priority Data


Jun 06, 2000 [GB]			0014048.3
Jul 25, 2000 [GB]			0018246.9
Oct 11, 2000 [GB]			0024920.1

Current U.S. Class: 514/46 ; 514/19; 514/210.02; 514/217.06; 514/259.31; 514/45; 536/27.1; 536/27.2; 536/27.21; 536/27.23; 536/27.3; 544/208; 544/364

Current International Class: A61K 31/70 (20060101)

Field of Search: 514/46,45,19,210.12,217.06,259.31 536/27.1,27.3,27.2,27.21,27.23 544/364,208

References Cited [Referenced By]

U.S. Patent Documents


5424295	June 1995	Krenitsky et al.
5492897	February 1996	Krenitsky et al.
5747472	May 1998	Krenitsky et al.
5821236	October 1998	Krenitsky et al.
6525032	February 2003	Mantell et al.
6753322	June 2004	Mantell et al.

Foreign Patent Documents


0314011	Oct., 1988	EP
0601322	Jun., 1994	EP
WO 8910923	Nov., 1989	WO
WO 9111172	Aug., 1991	WO
WO 9402518	May., 1994	WO
WO 9855148	Dec., 1998	WO
WO 9965895	Dec., 1999	WO

Other References

Von Heinz A. Staab, et al., Justus Liebigs Ann. Che., 648, pp. 72-82 (1961). cited by other .
Jacobson, et al., J. of Medicinal Chemistry, 1992, 35(3), p. 407-422. cite- d by other .
Olsson, et al., J. of Medicinal Chemistry, 1986, 29(9), p. 1683-1689. cite- d by other .
Berge et al., J. Pharm. Sci, 66, p. 1-19, Jan. 1977. cited by other .
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J. Chem., Soc., Perkin Trans., 1, 11, p.1205-1211, 1996. cited by other .
J. Amer. Chem. Soc, 80, p. 5168-5173, 1958. cited by other.

Primary Examiner: Wilson; James O.
Assistant Examiner: Khare; Devesh
Attorney, Agent or Firm: Benson; Gregg C. Mulholland; William F.

Parent Case Text

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 09/874,007, filed Jun. 5, 2001, now U.S. Pat. No. 6,753,322 which claims benefit of U.S. Application No. 60/214,307, filed Jun. 27, 2000, which claims benefit of U.S. Application No. 60/225,236, filed Aug. 15, 2000 which claims benefit of 60/245,243, filed Nov. 2, 2000.

Claims

The invention claimed is:

1. A method of treating an inflammatory disease in a mammal, comprising administering to said mammal in need of such treatment an effective amount of a compound of formula (I) ##STR00134## or a pharmaceutically acceptable salt or solvate thereof, wherein R.sup.1 is H, C.sub.1 C.sub.6 alkyl or fluorenyl, said C.sub.1 C.sub.6 alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.1 C.sub.6 alkoxy, halo or cyano; (A) R.sup.2 is H or C.sub.1 C.sub.6 alkyl, R.sup.15 is H or C.sub.1 C.sub.6 alkyl, and X is either (i) unbranched C.sub.2 C.sub.3 alkylene optionally substituted by C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl, or (ii) a group of the formula: --(CH.sub.2).sub.n--W--(CH.sub.2).sub.p-- where W is C.sub.5 C.sub.7 cycloalkylene optionally substituted by C.sub.1 C.sub.6 alkyl, n is 0 or 1 and p is 0 or 1, or (B) R.sup.15 is H or C.sub.1 C.sub.6 alkyl, and R.sup.2 and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, or (C) R.sup.2 is H or C.sub.1 C.sub.6 alkyl, and R.sup.15 and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl; either, R.sup.3 and R.sup.4, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by --NR.sup.6R.sup.7, or, R.sup.3 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or benzyl and R.sup.4 is (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, benzyl or het, or (b) --(C.sub.2 C.sub.6 alkylene)--R.sup.8, (c) --(C.sub.1 C.sub.6 alkylene)--R.sup.13, or (d) C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl; R.sup.5 is CH.sub.2OH or CONHR.sup.14; R.sup.6 and R.sup.7 are either each independently H or C.sub.1 C.sub.6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C.sub.1 C.sub.6 alkyl; R.sup.8 is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, C.sub.1 C.sub.6 alkoxy-(C.sub.1 C.sub.6)-alkyl, R.sup.9R.sup.9N--(C.sub.1 C.sub.6 )-alkyl, fluoro-(C.sub.1 C.sub.6)-alkyl, --CONR.sup.9R.sup.9, --COOR.sup.9 or C.sub.2 C.sub.5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C.sub.1 C.sub.6)-alkoxy, halo, --OR.sup.9, cyano, --S(O).sub.mR.sup.10, --NR.sup.9R.sup.9, --SO.sub.2NR.sup.9R.sup.9, --NR.sup.9COR.sup.10 or --NR.sup.9SO.sub.2R.sup.10, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C.sub.2 C.sub.6 alkylene group by C.sub.1 C.sub.6 alkyl, phenyl, C.sub.1 C.sub.6 alkoxy-(C.sub.2 C.sub.6)-alkyl, R.sup.9R.sup.9N--(C.sub.2 C.sub.6)-alkyl, fluoro-(C.sub.1 C.sub.6)-alkyl, C.sub.2 C.sub.5 alkanoyl, --COOR.sup.10, C.sub.3 C.sub.8 cycloalkyl, --SO.sub.2R.sup.10, --SO.sub.2NR.sup.9R.sup.9 or --CONR.sup.9R.sup.9, or (ii) NR.sup.11R.sup.12; R.sup.9 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or phenyl; R.sup.10 is C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or phenyl; R.sup.11 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or benzyl; R.sup.12 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, benzyl, fluoro-(C.sub.1 C.sub.6)-alkyl, --CONR.sup.9R.sup.9, --COOR.sup.10, C.sub.2 C.sub.5 alkanoyl or --SO.sub.2NR.sup.9R.sup.9; R.sup.13 is (a) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.1 C.sub.6 alkoxy, --(C.sub.1 C.sub.3 alkylene)--(C.sub.1 C.sub.6 alkoxy), halo, cyano, --(C.sub.1 C.sub.3 alkylene)--CN, --CO.sub.2H, --(C.sub.1 C.sub.3 alkylene)--CO.sub.2H, --CO.sub.2(C.sub.1 C.sub.6 alkyl), --(C.sub.1 C.sub.3 alkylene)--CO.sub.2(C.sub.1 C.sub.6 alkyl), --(C.sub.1 C.sub.3 alkylene)--NR.sup.14R.sup.14, --CONR.sup.14R.sup.14 or --(C.sub.1 C.sub.3 alkylene)--CONR.sup.14R.sup.14, or (b) azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, benzyl or het; R.sup.14 is H or C.sub.1 C.sub.6 alkyl optionally substituted by cyclopropyl; m is 0, 1 or 2; Y is CO, CS, SO.sub.2 or C.dbd.N(CN); and "het", used in the definition of R.sup.4 and R.sup.13, is a C-linked, 4- to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, C.sub.1 C.sub.6 alkoxy, C.sub.3 C.sub.8 cycloalkoxy, hydroxy, oxo or halo.

2. A method of claim 1 wherein said compound of formula (I) is 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,- 4-dihydroxytetrahydro-2-furanyl}-N-{2-[({[1-(2-pyridinyl)-4-piperidinyl]am- ino}carbonyl)amino]ethyl}-9H-purine-2-carboxamide or a pharmaceutically acceptable salt or solvate thereof.

Description

This invention relates to purine derivatives. More particularly, this invention relates to 2-aminocarbonyl-9H-purine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.

These derivatives are selective, functional agonists of the human adenosine A2a receptor and may be used as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.

Adenosine is a ubiquitous molecule having a central role in mammalian intermediary metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Adenosine receptor classification has revealed the presence of at least four subtypes: A1, A2a, A2b and A3. Stimulation of adenosine A2 receptors on the surface of human neutrophils has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils can damage lung tissue by release of reactive oxygen species, for example, superoxide anion radicals (O.sub.2.sup.-), and granule products, for example, human neutrophil elastase (HNE), amongst other inflammatory mediators. In addition, activated neutrophils perform both de novo synthesis and release of arachidonate products such as leukotriene B.sub.4 (LTB.sub.4). LTB.sub.4 is a potent chemo-attractant that recruits additional neutrophils to the inflammatory focus, whereas released O.sub.2.sup.- and HNE adversely affect the pulmonary extracellular matrix. The A2 receptor subtype mediating many of these responses (O.sub.2.sup.- and LTB.sub.4/HNE release and cell adhesion) is established as A2a. The A2 subtype (A2a or A2b) mediating the other effects remains to be established.

Selective agonist activity at the A2a receptor is considered to offer greater therapeutic benefit than the use of non-selective adenosine receptor agonists because interaction with other subtypes is associated with detrimental effects in the lung in animal models and human tissue studies. For example, asthmatics, but not non-asthmatics, bronchoconstrict when challenged with inhaled adenosine. This response is at least in part due to the activation of the A1 receptor subtype. Activation of A1 receptors also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung injury. Furthermore, many patients with respiratory disease will be co-prescribed .beta..sub.2-agonists, and negative interaction has been shown in animal studies between isoprenaline and adenosine receptors negatively coupled to adenylate cyclase. Degranulation of human mast cells is promoted by activation of adenosine A2b receptors, thus selectivity over the A2b receptor is also advantageous.

We have now surprisingly found the present purine derivatives inhibit neutrophil function and are selective agonists of the adenosine A2a receptor. They may also have antagonist activity at the adenosine A3 receptor. The present compounds may be used to treat any disease for which an adenosine A2a receptor agonist is indicated. They can be used to treat a disease where leukocyte (e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage)-induced tissue damage is implicated. They are useful as anti-inflammatory agents in the treatment of diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. The present compounds may also be used in the treatment of septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.

Accordingly, in a first embodiment, the present invention provides a compound of the formula:

##STR00002## or a pharmaceutically acceptable salt or solvate thereof, wherein

R.sup.1 is H, C.sub.1 C.sub.6 alkyl or fluorenyl, said C.sub.1 C.sub.6 alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.1 C.sub.6 alkoxy, halo or cyano;

(A) R.sup.2 is H or C.sub.1 C.sub.6 alkyl, R.sup.15 is H or C.sub.1 C.sub.6 alkyl, and X is either (i) unbranched C.sub.2 C.sub.3 alkylene optionally substituted by C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl, or (ii) a group of the formula: --(CH.sub.2).sub.n--W--(CH.sub.2).sub.p-- where W is C.sub.5 C.sub.7 cycloalkylene optionally substituted by C.sub.1 C.sub.6 alkyl, n is 0 or 1 and p is 0 or 1, or

(B) R.sup.15 is H or C.sub.1 C.sub.6 alkyl, and R.sup.2 and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, or

(C) R.sup.2 is H or C.sub.1 C.sub.6 alkyl, and R.sup.15 and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl;

either, R.sup.3 and R.sup.4, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by --NR.sup.6R.sup.7,

or, R.sup.3 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or benzyl and R.sup.4 is

(a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, benzyl or het, or

(b) --(C.sub.2 C.sub.6 alkylene)-R.sup.8,

(c) --(C.sub.1 C.sub.6 alkylene)-R.sup.13, or

(d) C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl;

R.sup.5 is CH.sub.2OH or CONR.sup.14R.sup.14;

R.sup.6 and R.sup.7 are either each independently H or C.sub.1 C.sub.6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C.sub.1 C.sub.6 alkyl;

R.sup.8 is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, C.sub.1 C.sub.6 alkoxy-(C.sub.1 C.sub.6)-alkyl, R.sup.9R.sup.9N-(C.sub.1 C.sub.6)-alkyl, fluoro-(C.sub.1 C.sub.6)-alkyl, --CONR.sup.9R.sup.9, --COOR.sup.9 or C.sub.2 C.sub.5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C.sub.1 C.sub.6)-alkoxy, halo, --OR.sup.9, cyano, --S(O).sub.mR.sup.10, --NR.sup.9R.sup.9, --SO.sub.2NR.sup.9R.sup.9, --NR.sup.9COR.sup.10 or --NR.sup.9SO.sub.2R.sup.10, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C.sub.2 C.sub.6 alkylene group by C.sub.1 C.sub.6 alkyl, phenyl, C.sub.1 C.sub.6 alkoxy-(C.sub.2 C.sub.6)-alkyl, R.sup.9R.sup.9N-(C.sub.2 C.sub.6)-alkyl, fluoro-(C.sub.1 C.sub.6)-alkyl, C.sub.2 C.sub.5 alkanoyl, --COOR.sup.10, C.sub.3 C.sub.8 cycloalkyl, --SO.sub.2R.sup.10, --SO.sub.2NR.sup.9R.sup.9 or --CONR.sup.9R.sup.9, or (ii) NR.sup.11R.sup.12;

R.sup.9 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or phenyl;

R.sup.10 is C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or phenyl;

R.sup.11 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or benzyl;

R.sup.12 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, benzyl, fluoro-(C.sub.1 C.sub.6)-alkyl, --CONR.sup.9R.sup.9, --COOR.sup.10, C.sub.2 C.sub.5 alkanoyl or --SO.sub.2NR.sup.9R.sup.9;

R.sup.13 is (a) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.1 C.sub.6 alkoxy, --(C.sub.1 C.sub.3 alkylene)-(C.sub.1 C.sub.6 alkoxy), halo, cyano, --(C.sub.1 C.sub.3 alkylene)-CN, --CO.sub.2H, --(C.sub.1 C.sub.3 alkylene)-CO.sub.2H, --CO.sub.2(C.sub.1 C.sub.6 alkyl), --(C.sub.1 C.sub.3 alkylene)-CO.sub.2(C.sub.1 C.sub.6 alkyl), --(C.sub.1 C.sub.3 alkylene)-NR.sup.4R.sup.4, --CONR.sup.14R.sup.14 or --(C.sub.1 C.sub.3 alkylene)-CONR.sup.14R.sup.14, or (b) azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, benzyl or het;

R.sup.14 is H or C.sub.1 C.sub.6 alkyl optionally substituted by cyclopropyl;

m is 0, 1 or 2;

Y is CO, CS, SO.sub.2 or C.dbd.N(CN); and

"het", used in the definition of R.sup.4 and R.sup.13, is a C-linked, 4-to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, C.sub.1 C.sub.6 alkoxy, C.sub.3 C.sub.8 cycloalkoxy, hydroxy, oxo or halo.

In a second embodiment, the present invention provides a compound of the formula:

##STR00003## or a pharmaceutically acceptable salt or solvate thereof, wherein

R.sup.1 is H, C.sub.1 C.sub.6 alkyl or fluorenyl, said C.sub.1 C.sub.6 alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.1 C.sub.6 alkoxy, halo or cyano;

R.sup.2 is H or C.sub.1 C.sub.6 alkyl;

either, R.sup.3 and R.sup.4, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by --NR.sup.6R.sup.7,

or, R.sup.3 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or benzyl and R.sup.4 is

(a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, benzyl or het, or

(b) --(C.sub.2 C.sub.6 alkylene)--R.sup.8, or

(c) --(C.sub.1 C.sub.6 alkylene)--R.sup.13;

R.sup.5 is CH.sub.2OH or CONR.sup.14R.sup.14;

R.sup.6 and R.sup.7 are either each independently H or C.sub.1 C.sub.6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C.sub.1 C.sub.6 alkyl;

R.sup.8 is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, C.sub.1 C.sub.6 alkoxy-(C.sub.1 C.sub.6)-alkyl, R.sup.9R.sup.9N-(C.sub.1 C.sub.6)-alkyl, fluoro-(C.sub.1 C.sub.6)-alkyl, --CONR.sup.9R.sup.9, --COOR.sup.9 or C.sub.2 C.sub.5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C.sub.1 C.sub.6)-alkoxy, halo, --OR.sup.9, cyano, --S(O).sub.mR.sup.10, --NR.sup.9R.sup.9, --SO.sub.2NR.sup.9R.sup.9, --NR.sup.9COR.sup.10 or --NR.sup.9SO.sub.2R.sup.10, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C.sub.2 C.sub.6 alkylene group by C.sub.1 C.sub.6 alkyl, phenyl, C.sub.1 C.sub.6 alkoxy-(C.sub.2 C.sub.6)-alkyl, R.sup.9R.sup.9N-(C.sub.2 C.sub.6)-alkyl, fluoro-(C.sub.1 C.sub.6)-alkyl, C.sub.2 C.sub.5 alkanoyl, --COOR.sup.10, C.sub.3 C.sub.8 cycloalkyl, --SO.sub.2R.sup.10, --SO.sub.2NR.sup.9R.sup.9 or --CONR.sup.9R.sup.9, or (ii) NR.sup.11R.sup.12;

R.sup.9 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or phenyl;

R.sup.10 is C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or phenyl;

R.sup.11 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or benzyl;

R.sup.12 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, phenyl, benzyl, fluoro-(C.sub.1 C.sub.6)-alkyl, --CONR.sup.9R.sup.9, --COOR.sup.10, C.sub.2 C.sub.5 alkanoyl or --SO.sub.2NR.sup.9R.sup.9;

R.sup.13 is phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.1 C.sub.6 alkoxy, halo or cyano;

R.sup.14 is H or C.sub.1 C.sub.6 alkyl optionally substituted by cyclopropyl;

R.sup.15 is H or C.sub.1 C.sub.6 alkyl;

m is 0, 1 or 2;

X is unbranched C.sub.2 C.sub.3 alkylene optionally substituted by C.sub.1 C.sub.6 alkyl or C.sub.3 C.sub.8 cycloalkyl;

Y is CO, CS, SO.sub.2 or C.dbd.N(CN); and

"het", used in the definition of R.sup.4, is a C-linked, 4- to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, C.sub.1 C.sub.6 alkoxy, C.sub.3 C.sub.8 cycloalkoxy, hydroxy, oxo or halo.

In the above definitions, halo means fluoro, chloro, bromo or iodo and alkyl, alkylene, alkanoyl and alkoxy groups containing the requisite number of carbon atoms, except where indicated, can be unbranched or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkanoyl include acetyl and propanoyl. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl (the corresponding examples for cycloalkoxy also apply). Examples of cycloalkylene include cyclopentylene, cyclohexylene and cycloheptylene. "Het" can be aromatic or partially or fully saturated and "C-linked" means that it is attached to the neighbouring group by a ring carbon atom. Examples of "het" include pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

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

Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, pamoate, adipate and xinafoate (1-hydroxy-2-naphthoate) salts.

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

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

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

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

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

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

Preferably, R.sup.1 is C.sub.1 C.sub.6 alkyl optionally substituted by 1 or 2 phenyl substituents, said phenyl being optionally substituted by C.sub.1 C.sub.6 alkyl or halo.

Preferably, R.sup.1 is C.sub.1 C.sub.6 alkyl optionally substituted by 1 or 2 phenyl substituents, said phenyl being optionally substituted by methyl or chloro.

Preferably, R.sup.1 is C.sub.1 C.sub.6 alkyl optionally substituted by 1 or 2 phenyl substituents.

Preferably, R.sup.1 is C.sub.1 C.sub.6 alkyl substituted by 1 or 2 phenyl substituents, said phenyl being optionally substituted by methyl or chloro.

Preferably, R.sup.1 is C.sub.1 C.sub.6 alkyl substituted by 1 or 2 phenyl substituents.

Preferably, R.sup.1 is C.sub.1 C.sub.6 alkyl substituted by 2 phenyl substituents, said phenyl being optionally substituted by methyl or chloro.

Preferably, R.sup.1 is C.sub.1 C.sub.6 alkyl substituted by 2 substituents each independently selected from phenyl, 3-methylphenyl and 3-chlorophenyl.

Preferably, R.sup.1 is C.sub.1 C.sub.6 alkyl substituted by 2 phenyl substituents.

Preferably, R.sup.1 is diphenylethyl, bis(3-methylphenyl)ethyl or bis(3-chlorophenyl)ethyl.

Preferably, R.sup.1 is diphenylethyl.

Preferably, R.sup.1 is 2,2-diphenylethyl, 2,2-bis(3-methylphenyl)ethyl or 2,2-bis(3-chlorophenyl)ethyl.

Preferably, R.sup.1 is 2,2-diphenylethyl.

Preferably, R.sup.2 is H.

Preferably, R.sup.15 is H.

Preferably, X is 1,2-ethylene or 1,3-propylene.

Preferably, X is 1,2-ethylene.

Preferably, R.sup.2 is H, R.sup.15 is H and X is 1,2-ethylene, 1,3-propylene or a group of the formula: --(CH.sub.2).sub.n--W--(CH.sub.2).sub.p-- where W is C.sub.5 C.sub.7 cycloalkylene, n is 0 or 1 and p is 0 or 1.

Preferably, R.sup.2 is H, R.sup.15 is H and X is 1,2-ethylene, 1,3-propylene or a group of the formula: --(CH.sub.2).sub.n--W--(CH.sub.2).sub.p-- where W is C.sub.5 C.sub.7 cycloalkylene, n is 0 and p is 0.

Preferably, R.sup.2 is H, R.sup.15 is H and X is 1,2-ethylene, 1,3-propylene or cyclohexylene.

Preferably, R.sup.2 is H, R.sup.15 is H and X is 1,2-ethylene, 1,3-propylene or 1,4-cyclohexylene.

Preferably, R.sup.2 is H, R.sup.15 is H and X is 1,2-ethylene, 1,3-propylene or trans-1,4-cyclohexylene.

Preferably, R.sup.2 is H, R.sup.15 is H and X is 1,2-ethylene.

Preferably, R.sup.15 is H and R.sup.2 and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 3- or 4-piperidinyl, each being optionally substituted by C.sub.1 C.sub.6 alkyl.

Preferably, R.sup.15 is H and R.sup.2 and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 4-piperidinyl each being optionally substituted by C.sub.1 C.sub.6 alkyl.

Preferably, R.sup.15 is H and R.sup.2 and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 3- or 4-piperidinyl.

Preferably, R.sup.15 is H and R.sup.2 and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 4-piperidinyl.

Preferably, R.sup.15 is H and R.sup.2 and X, taken together with the nitrogen atom to which they are attached, represent (3R)-pyrrolidinyl or 4-piperidinyl.

Preferably, R.sup.2 is H and R.sup.15 and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 3- or 4-piperidinyl, each being optionally substituted by C.sub.1 C.sub.6 alkyl.

Preferably, R.sup.2 is H and R.sup.15 and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 4-piperidinyl each being optionally substituted by C.sub.1 C.sub.6 alkyl.

Preferably, R.sup.2 is H and R.sup.15 and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 3- or 4-piperidinyl.

Preferably, R.sup.2 is H and R.sup.15 and X, taken together with the nitrogen atom to which they are attached, represent 3-pyrrolidinyl or 4-piperidinyl.

Preferably, R.sup.2 is H and R.sup.15 and X, taken together with the nitrogen atom to which they are attached, represent (3R)-pyrrolidinyl, (3S)-pyrrolidinyl or 4-piperidinyl.

Preferably, R.sup.3 is H.

Preferably, R.sup.4 is piperidin-3-yl or piperidin-4-yl, each optionally substituted by benzyl or het as previously defined.

Preferably, R.sup.4 is piperidin-3-yl or piperidin-4-yl, each optionally substituted by benzyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, said pyridin-2-yl, pyridin-3-yl and pyridin-4-yl each optionally substituted by C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl, C.sub.1 C.sub.6 alkoxy, C.sub.3 C.sub.8 cycloalkoxy, hydroxy, oxo or halo.

Preferably, R.sup.4 is piperidin-3-yl or piperidin-4-yl, each substituted by benzyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

Preferably, R.sup.4 is piperidin-3-yl or piperidin-4-yl, each substituted by benzyl.

Preferably, R.sup.4 is piperidin-3-yl or piperidin-4-yl, each substituted by pyridin-2-yl.

Preferably, R.sup.4 is piperidin-4-yl substituted by pyridin-2-yl.

Preferably, R.sup.4 is 1-benzylpiperidin-4-yl.

Preferably, R.sup.4 is 1-(pyridin-2-yl)piperidin-4-yl.

Preferably, R.sup.4 is --(C.sub.2 C.sub.6 alkylene)-R.sup.8.

Preferably, R.sup.4 is --CH.sub.2CH.sub.2R.sup.8.

Preferably, R.sup.4 is --(C.sub.1 C.sub.6 alkylene)-R.sup.13.

Preferably, R.sup.4 is --CH.sub.2R.sup.13 or --CH.sub.2CH.sub.2R.sup.13.

Preferably, R.sup.4 is C.sub.3 C.sub.8 cycloalkyl.

Preferably, R.sup.4 is cyclohexyl.

Preferably, R.sup.5 is --CH.sub.2OH or --CONH(C.sub.1 C.sub.6 alkyl).

Preferably, R.sup.5 is --CH.sub.2OH or --CONHCH.sub.2CH.sub.3.

Preferably, R.sup.5 is --CONHCH.sub.2CH.sub.3.

Preferably, R.sup.8 is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C.sub.1 C.sub.6 alkyl and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C.sub.2 C.sub.6 alkylene group by C.sub.1 C.sub.6 alkyl, or (ii) is NR.sup.11R.sup.2.

Preferably, R.sup.8 is piperidin-1-yl or tetrahydroisoquinolin-1-yl each optionally substituted on a ring carbon atom by C.sub.1 C.sub.6 alkyl.

Preferably, R.sup.8 is piperidin-1-yl optionally substituted on a ring carbon atom by isopropyl.

Preferably, R.sup.8 is piperidin-1-yl, 4-isopropylpiperidin-1-yl or tetrahydroisoquinolin-1-yl.

Preferably R.sup.8 is NR.sup.11R.sup.12where NR.sup.11R.sup.12 is N(C.sub.1 C.sub.6 alkyl).sub.2, N(C.sub.1 C.sub.6 alkyl)(C.sub.3 C.sub.8 cycloalkyl) or N(C.sub.1 C.sub.6 alkyl)(benzyl).

Preferably R.sup.8 is NR.sup.11R.sup.12 where NR.sup.11R.sup.12 is N,N-diisopropylamino, N,N-di-n-butylamino, N-cyclopentyl-N-isopropylamino, N-cyclohexyl-N-isopropylamino or N-benzyl-N-isopropylamino.

Preferably, R.sup.11 is H or C.sub.1 C.sub.6 alkyl.

Preferably, R.sup.11 is C.sub.1 C.sub.6 alkyl.

Preferably, R.sup.11 is isopropyl or n-butyl.

Preferably, R.sup.12 is H, C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or benzyl.

Preferably, R.sup.12 is C.sub.1 C.sub.6 alkyl, C.sub.3 C.sub.8 cycloalkyl or benzyl.

Preferably, R.sup.12 is isopropyl, cyclopentyl, cyclohexyl or benzyl.

Preferably, R.sup.13 is either phenyl optionally substituted by --(C.sub.1 C.sub.3 alkylene)-NR.sup.14R.sup.14 or --CO.sub.2H, or piperidin-2-yl, piperidin-3-yl or piperidin-4-yl each optionally substituted by benzyl.

Preferably, R.sup.13 is phenyl optionally substituted by --CH.sub.2N(CH.sub.2CH.sub.3).sub.2 or --CO.sub.2H, or piperidin-4-yl substituted by benzyl.

Preferably, R.sup.13 is phenyl, 4-(N,N-diethylamino)methylphenyl, 4-carboxyphenyl or 1-benzylpiperidin-4-yl.

Preferably, R.sup.14 is H or C.sub.1 C.sub.6 alkyl.

Preferably, R.sup.14 is H or ethyl.

Preferably, Y is CO.

Preferably,

##STR00004## ##STR00005## ##STR00006## ##STR00007##

In the above preferred groups, "Et" means ethyl, "iPr" means isopropyl, "nBu" means n-butyl and "Ph" means phenyl.

Particularly preferred embodiments of a compound of the formula (I) are those of the Examples section hereafter, particularly those of Examples 8 and 34, together with pharmaceutically acceptable salts and solvates thereof.

The compounds of the formula (I) can be prepared using conventional procedures such as by the following illustrative methods in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.5, X and Y are as previously defined for a compound of the formula (I) unless otherwise stated.

1. A compound of the formula (I) wherein Y is CO may be prepared by reaction of a compound of the formula:

##STR00008## with a compound of the formula: R.sup.3R.sup.4NCOZ.sup.1 (III) wherein Z.sup.1 is a suitable leaving group such as chloro or 1H-imidazol-1-yl.

In a typical procedure the compounds are reacted together in a suitable solvent such as toluene, isopropanol or dichloromethane, or any combination thereof, optionally with heating such as at the reflux temperature of the solvent.

The compounds of the formula (III) may be prepared by conventional procedures.

A compound of the formula (II) may be prepared as shown in Scheme 1.

##STR00009## ##STR00010## wherein R.sup.16 is C.sub.1 C.sub.4 alkyl, R.sup.17 is a suitable protecting group such as tetrahydro-2H-pyran-2-yl, R.sup.18 is a suitable ester-forming group such as C.sub.1 C.sub.6 alkyl or benzyl, preferably C.sub.1 C.sub.4 alkyl, and R.sup.19 and R.sup.20 are either each a suitable protecting group such as acetyl or benzoyl, or, taken together, are a suitable protecting group such as C.sub.1 C.sub.6 alkylene optionally substituted by phenyl, e.g. 1,1-dimethylmethylene or phenylmethylene.

In a typical procedure, where R.sup.17 is tetrahydro-2H-pyran-2-yl, a chloropurine of the formula (IV) is N-protected by reaction with 3,4-dihydro-2H-pyran in the presence of a suitable acid catalyst such as p-toluenesulphonic acid (PTSA), benzenesulphonic acid, camphorsulphonic acid, hydrochloric acid, sulphuric acid, methanesulphonic acid or pyridinium p-toluenesulphonate, and in a suitable solvent such as ethyl acetate, toluene, dichloromethane, dimethylformamide (DMF), tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran (THF) or acetonitrile, at from 0.degree. C. to the reflux temperature of the solvent. Preferably the reaction is carried out in ethyl acetate in the presence of PTSA with heating. Other suitable protecting groups R.sup.17 are mentioned in the Greene et al reference mentioned herein.

A compound of the formula (V) prepared may be converted to an amine of the formula (VI) by reaction with a compound of the formula: R.sup.1NH.sub.2 (XVI). The compounds are reacted in the presence of a suitable acid acceptor, e.g. triethylamine, 4-methylmorpholine or N-ethyldiisopropylamine, and in a suitable solvent such as methanol, ethanol or isopropanol at from room temperature to the reflux temperature of the solvent. Preferably, N-ethyldiisopropylamine and isopropanol are used under reflux conditions.

An amine of the formula (VI) is then reacted with a sodium or potassium thioalkoxide in a suitable solvent such as dimethylsulphoxide (DMSO), DMF or 1-methyl-2-pyrrolidinone, at from room temperature to the reflux temperature of the solvent. Preferably, sodium or potassium thiomethoxide in DMF at 100.degree. C. are used as the reaction conditions.

A thioether of the formula (VII) prepared is then oxidised to a sulphone of the formula (VIII) using a suitable oxidant such as Oxone (trade mark) (potassium peroxymonosulphate), dimethyl dioxirane, m-chloroperbenzoic acid or peracetic acid, optionally in the presence of a suitable base, e.g. sodium bicarbonate, and in a suitable solvent such as aqueous acetone or dichloromethane, at a temperature of from room temperature to 50.degree. C. Preferably, Oxone (trade mark) and sodium bicarbonate are used in a aqueous acetone at room temperature.

A sulphone of the formula (VIII) may be converted to a nitrile of the formula (IX) by reaction with a suitable cyanide source such as potassium cyanide, zinc cyanide, sodium cyanide or copper cyanide, and in a suitable solvent such as DMSO, DMF, 1-methyl-2-pyrrolidinone, THF or acetonitrile, at a temperature of from room temperature to the reflux temperature of the solvent. Preferred conditions are potassium cyanide in DMF at 120.degree. C.

Alternatively, a chloropurine of the formula (VI) may be converted to a nitrile of the formula (IX) using a suitable cyanide source, e.g. potassium cyanide, zinc cyanide, sodium cyanide or copper cyanide, and in a suitable solvent, e.g. DMF, DMSO, 1-methyl-2-pyrrolidinone, THF or acetonitrile, optionally in the presence of a suitable palladium catalyst, e.g. tetrakis(triphenylphosphine)palladium(0), or palladium(II) acetate in combination with triphenylphosphine, tri-o-tolylphosphine, (R)- or (S)- or racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or 1,1'-bis(diphenylphosphino)ferrocene, and optionally in the presence of a suitable base, e.g. triethylamine, 4-methylmorpholine or N-ethyldiisopropylamine, at temperature of from room temperature to the reflux temperature of the solvent (optionally under pressure). Alternatively the reaction may be carried out by reacting a chloropurine of the formula (VI) with sodium or potassium cyanide in a suitable solvent such as DMSO, 1-methyl-2-pyrrolidinone or DMF, at from room temperature to the reflux temperature of the solvent. Preferably the reaction is carried out using zinc cyanide, triethylamine and tetrakis(triphenylphosphine)palladium(0) in DMF at 80 85.degree. C. under an elevated argon pressure.

A nitrile of the formula (IX) may be deprotected to provide a nitrile of the formula (X) under conventional conditions. For example, where R.sup.17 is tetrahydro-2H-pyran-2-yl, the deprotection may be carried out in the presence of a suitable acid as hydrochloric acid, trifluoroacetic acid, sulphuric acid, trichloroacetic acid, phosphoric acid, p-toluenesulfonic acid, benzenesulphonic acid, methanesulphonic acid or camphorsulphonic acid, and in a suitable solvent such as a C.sub.1 C.sub.4 alkanol that may optionally contain water, preferably at an elevated temperature such as the reflux temperature of the solvent. The pH may be adjusted to between pH 8 and pH11 in the work-up procedure with an aqueous base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate to generate the free base of the compound of the formula (X). Preferred conditions are using 2M aqueous hydrochloric acid in ethanol at room temperature or using trifluoroacetic acid in aqueous isopropanol under reflux conditions, followed by adjustment of the pH in the work-up to from pH 9 10.5 with aqueous sodium hydroxide solution.

A nitrile of the formula (X) may be converted to an ester of the formula (XII) by reaction with a sodium or potassium C.sub.1 C.sub.4 alkoxide in a corresponding C.sub.1 C.sub.4 alkanol solvent, optionally at an elevated temperature, and including an acid treatment during the work-up. Preferably, the reaction is carried out using sodium methoxide in methanol at the reflux temperature, with treatment with aqueous hydrochloric acid during the work-up.

Alternatively, an ester of the formula (XII) may be prepared by carbonylation of a compound of the formula (VI) with a compound of the formula: R.sup.18OH using carbon monoxide, optionally under pressure, together with a suitable palladium catalyst in the presence of a suitable base, e.g. a tertiary amine base, and optionally at an elevated temperature, to provide a compound of the formula:

##STR00011## Typically, a catalytic quantity of palladium (II) acetate together with a suitable ligand such as 1,1'-bis(diphenylphosphino)ferrocene, triphenyl phosphine, tri-o-tolyl phosphine or BINAP ((R)- or (S)- or racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), a suitable alcohol of the formula R.sup.18OH, e.g. methanol, ethanol, 1-propanol, isopropanol, or 1-butanol (employed as the solvent also) and a base such as a triethylamine, Hunigs base (ethyldiisopropylamine), 4-methylmorpholine, sodium carbonate, sodium hydrogencarbonate, potassium carbonate or caesium carbonate, are used under carbon monoxide, optionally under 1 3000 kPa pressure in a sealed vessel at from 20 to 200.degree. C. A compound of the formula (VIA) may be deprotected to provide a compound of the formula (XII) using suitable deprotection conditions such as those described for the conversion of a compound of the formula (IX) to a compound of the formula (X).

The ester of the formula (XII) may be coupled with a compound of the formula:

##STR00012## wherein Z.sup.2 is a suitable leaving group such as acetoxy, benzoyloxy, methoxy or halo, e.g. chloro, and R.sup.19 and R.sup.20 are suitable protecting groups as previously defined, in the presence of a suitable acid or Lewis acid, e.g. trimethylsilyl trifluoromethanesulphonate, preferably using an excess thereof. The reaction can be performed using a compound of the formula (XI) in the form of a 2R- or 2S-diastereoisomer, or as an epimeric mixture thereof. The reaction is typically carried out in a suitable solvent, e.g. 1,2-dimethoxyethane, dichloromethane, acetonitrile, 1,1,1-trichloroethane or toluene, or a mixture thereof, preferably by pre-treating the compound of the formula (XII) in situ with a suitable silylating agent, e.g. trimethylsilyl trifluoromethanesulphonate, N,O-bis(trimethylsilyl)acetamide, trimethylsilyl chloride or hexamethyldisilazane, optionally in the presence of a tertiary amine base, e.g. N-methylmorpholine, before adding a compound of the formula (XI). Elevated temperatures may be used in the reaction. Preferred conditions involve treating a compound of the formula (XII) first with N,O-bis(trimethylsilyl)acetamide in 1,1,1-trichloroethane, heating the reaction under reflux, before treatment with a solution of a compound of the formula (XI) and trimethylsilyl trifluoromethanesulphonate in toluene and then heating at above 100.degree. C. It will be appreciated that where a compound of the formula (XI) wherein R.sup.5 is CH.sub.2OH is to be used, the hydroxyl group may be suitably protected for the purpose of this reaction (see later R.sup.5A definition), which can then be deprotected in the subsequent transformation to provide a compound of the formula (XIV).

Deprotection of a compound of the formula (XIII) may be achieved using conventional conditions, e.g., where R.sup.19 and R.sup.20 are each acetyl or benzoyl, under basic conditions such as using sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or caesium carbonate in a solvent such as methanol, ethanol, isopropanol, 1,2-dimethoxyethane, THF, DMF, acetone, 2-butanone or 4-methyl-2-pentanone, optionally also in the presence of water, at a temperature of from 0 to 80.degree. C. Alternatively, either a tertiary amine base such as triethylamine, diisopropylethylamine or 4-methylmorpholine, in an alcohol solvent such as methanol, ethanol, isopropanol or 1-propanol may be used at a temperature of from 0 to 80.degree. C., or a sodium or potassium C.sub.1 C.sub.4 alkoxide, e.g. sodium methoxide or ethoxide, in a corresponding C.sub.1 C.sub.4 alkanol, e.g. methanol or ethanol, may be used. Further, an amine such as ammonia, methylamine, ethylamine, dimethylamine and a suitable solvent such as methanol, ethanol, isopropanol, THF or dichloromethane can be used at a temperature of from 0 to 80.degree. C. Preferably, sodium carbonate in methanol at room temperature is used.

An ester of the formula (XIV) may be converted to an amide of the formula (II) by reaction with a compound of the formula: R.sup.15NH--X--NHR.sup.2 (XV), optionally at an elevated temperature, optionally in an inert solvent such as 1,2-dimethoxyethane or 2-methoxyethyl ether and optionally under pressure. Preferably, the reaction is carried out in the absence of solvent at a temperature of from 100 120.degree. C. The skilled person will appreciate that to achieve the desired regioselectivity, a suitable protecting group (e.g. trifluoroacetyl) may optionally be used for this reaction located on a chosen N atom of a compound of the formula (XV), and the protected intermediate prepared subsequently deprotected.

A compound of the formula (II) may also be prepared by aminocarbonylation reaction of a compound of the formula (XVII) with a compound of the formula: R.sup.15NH--X--NHR.sup.2 (XV) by a similar procedure to that described for the conversion of a compound of the formula (XVII) to a compound of the formula (I) below. The skilled person will appreciate that to achieve the desired regioselectivity, a suitable protecting group (e.g. trifluoroacetyl) may optionally be used for this reaction located on a chosen N atom of a compound of the formula (XV)), and the protected intermediate prepared subsequently deprotected.

A compound of the formula (XI) or (XV) may be prepared by conventional procedures.

2. The compounds of the formula (I) wherein Y is CO may be prepared by aminocarbonylation reaction of a compound of the formula:

##STR00013## wherein Z.sup.3 is a suitable leaving group such as bromo, iodo, --Sn(C.sub.1 C.sub.12 alkyl).sub.3 or CF.sub.3SO.sub.2O--, preferably iodo, with a compound of the formula: R.sup.15NH--X--NR.sup.2--Y--NR.sup.3R.sup.4 (XVIII) in the presence of carbon monoxide and a suitable coupling catalyst (it will be appreciated that this route may also be used for compounds of the formula (I) where Y is other than CO). Preferably, the catalyst is a palladium (II) catalyst, more preferably 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (optionally as a 1:1 complex with dichloromethane). Alternatively, palladium (II) acetate may be used in the presence of a suitable ligand such as 1,1'-bis(diphenylphosphino)ferrocene, triphenylphosphine, tri(o-tolyl)phosphine or (R)-, (S)- or racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

In a typical procedure the reaction is carried out in a sealed vessel in the presence of carbon monoxide at an elevated pressure, e.g. about 345 kPa (50 psi), at an elevated temperature, e.g. about 60.degree. C., and in a suitable solvent, e.g. tetrahydrofuran, methanol or ethanol. Optionally, a suitable organic base may be present such as tertiary amine, e.g. triethylamine, N-ethyldiisopropylamine or 4-methylmorpholine.

The intermediates of the formula (XVII) can be prepared as shown in Scheme 2.

##STR00014## wherein, R.sup.5A is as defined hereafter, Z.sup.3 is as previously defined for a compound of the formula (XVII) and "Ac" is acetyl (although it will be appreciated that alternative suitable protecting groups as exemplified herein may be used in this transformation).

In a typical procedure a compound of the formula (XIX) is reacted with an amine of the formula: R.sup.1NH.sub.2 (XVI) in the presence of a suitable acid acceptor, e.g. triethylamine, and in a suitable solvent, e.g. acetonitrile, at an elevated temperature, if necessary. The product of the formula (XX) obtained can be deprotected by hydrolysis to provide a compound of the formula (XVII) by a conventional procedure such as by using a suitable inorganic base, e.g. sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or caesium carbonate, and in a suitable solvent, e.g. methanol, ethanol, isopropanol, 1,2-dimethoxyethane, tetrahydrofuran, dimethylformamide, acetone, 2-butanone or 4-methyl-2-pentanone, optionally under aqueous conditions, at from 0.degree. C. to the reflux temperature of the solvent, e.g. room temperature. Alternatively, the deprotection can be carried out using a suitable amine base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, ammonia, methylamine, ethylamine or dimethylamine in a suitable solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or dichloromethane at from 0.degree. C. to the reflux temperature of the solvent.

An intermediate of the formula (XIX) can be prepared by a conventional procedure.

An intermediate of the formula (XVIII) may be prepared by reacting a compound of the formula: R.sup.15NH--X--NHR.sup.2 (XV) with a compound of the formula: R.sup.3R.sup.4NCOZ.sup.1 (III) under similar conditions to those previously described for the conversion of compounds of the formulae (II) and (III) to a compound of the formula (I). The skilled person will appreciate that to achieve the desired regioselectivity, a suitable protecting group (e.g. trifluoroacetyl) may optionally be used for this reaction located on a chosen N atom of a compound of the formula (XV) and the protected intermediate prepared subsequently deprotected.

3. A compound of the formula (I) wherein Y is CO may be prepared by deprotection of a compound of the formula:

##STR00015## wherein R.sup.21 and R.sup.22 are either each a suitable protecting group such as acetyl or benzoyl, or, taken together, are a suitable protecting group such as C.sub.1 C.sub.6 alkylene optionally substituted by phenyl, e.g. 1,1-dimethylmethylene or phenylmethylene, R.sup.5A is CH.sub.2OH, CH.sub.2OR.sup.23 or CONR.sup.14R.sup.14 and R.sup.23 is a suitable protecting group such as acetyl or benzoyl (it will be appreciated that this route may also be used for compounds of the formula (I) where Y is other than CO).

Conventional deprotection conditions may be used and will depend on the nature of the protecting groups R.sup.21, R.sup.22 and R.sup.23 to be removed. Further, the skilled person will realise that the protecting groups R.sup.21, R.sup.22 and R.sup.23 may be removed all together, separately or in any combination to provide a compound of the formula (I). For example, where R.sup.5A is CH.sub.2OR.sup.23, either R.sup.21 and R.sup.22 may first be deprotected followed then by R.sup.23, or vice-versa. In a typical procedure where R.sup.2, R.sup.22 and R.sup.23 are each acetyl, the deprotection is achieved using a suitable inorganic base, e.g. sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or caesium carbonate, and in a suitable solvent, e.g. methanol, ethanol, isopropanol, 1,2-dimethoxyethane, tetrahydrofuran, dimethylformamide, acetone, 2-butanone or 4-methyl-2-pentanone, optionally under aqueous conditions, at from 0.degree. C. to the reflux temperature of the solvent, e.g. room temperature. Alternatively, the deprotection can be carried out using a suitable amine base such as triethylamine, diisopropylethylamine, 4-methylmorpholine, ammonia, methylamine, ethylamine or dimethylamine in a suitable solvent such as methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran or dichloromethane at from 0.degree. C. to the reflux temperature of the solvent, or using a sodium or potassium C.sub.1 C.sub.4 alkoxide, e.g. sodium methoxide or ethoxide, in a corresponding C.sub.1 C.sub.4 alkanol, e.g. methanol or ethanol.

In a typical procedure, where R.sup.21 and R.sup.22 taken together are 1,1-dimethylmethylene, a compound of the formula (XXI) may be deprotected by treatment with a suitable acid such as hydrochloric acid, trifluoroacetic acid, sulphuric acid, phosphoric acid, pyridinium p-toluenesulphonate, p-toluenesulphonic acid, benzenesulphonic acid, methanesulphonic acid, acetic acid or formic acid, or a mixture thereof, or an acidic ion-exchange resin, optionally in the presence of a suitable solvent, e.g. ethanol, and optionally under aqueous conditions. The reaction may be carried out at an elevated temperature such as at the reflux temperature of the solvent.

Deprotection of a compound of the formula (XXI) to provide a compound of the formula (I) may also be accomplished in situ following the conversion of a compound of the formula (XXII) to a compound of the formula (XXI) as described below. Here, where R.sup.21, R.sup.22 and R.sup.23 are each acetyl, the deprotection method using inorganic base is preferred, e.g. the reaction mixture containing a compound of the formula (XXI) is treated with aqueous sodium hydroxide solution in 1,2-dimethoxyethane at from 5 20.degree. C.

A compound of the formula (XXI) may be prepared by coupling a compound of the formula:

##STR00016## with a compound of the formula:

##STR00017## wherein Z.sup.4 is a suitable leaving group such as acetoxy, benzoyloxy, methoxy or halo, e.g. chloro, under similar conditions to those previously described for the conversion of a compound of the formula (XII) to (XIII).

A compound of the formula (XXII) may be prepared using conventional procedures as illustrated in Scheme 3. Such methods may be adapted from those previously described herein.

##STR00018## wherein R.sup.24 is a suitable protecting group such as tetrahydro-2H-pyran-2-yl.

An acid of the formula (XXVI) may be prepared using conventional procedures, e.g. by basic hydrolysis of a compound of the formula (IX) such as by using aqueous sodium hydroxide solution followed by acidification in the work-up.

A compound of the formula (XXIII) may be prepared by conventional procedures.

A compound of the formula (XXI) where R.sup.5A is CONR.sup.14R.sup.14 may also be prepared as shown in Scheme 4.

##STR00019## ##STR00020##

In a typical procedure a compound of the formula (XII) is reacted with a compound of the formula (XXIII) where R.sup.5A is CH.sub.2OR.sup.23 using similar conditions to those previously described for the conversion of a compound of the formula (XII) to (XIII).

The compound of the formula (XXX) prepared may be deprotected under conventional conditions, e.g. where R.sup.21-23 are each acetyl, using a suitable base such as sodium carbonate, potassium carbonate, sodium ethoxide, sodium methoxide or potassium tertiary-butoxide in the presence of a suitable alcohol solvent, e.g. ethanol, optionally in the presence of another solvent such as 1,2-dimethoxyethane, optionally in the presence of water and optionally at an elevated temperature for up to 24 hours, and also optionally directly using the crude reaction mixture from the previous step.

The compound of the formula (XXXI) prepared may be protected with a suitable protecting group or suitable protecting groups. Where R.sup.21 and R.sup.22, taken together, represent 1,1-dimethylmethylene, this may be carried out by reaction with acetone, or a ketal of acetone, or a combination of both, in the presence of an acid such as hydrochloric acid, p-toluenesulphonic acid, methanesulphonic acid, sulphuric acid, phosphoric acid or trifluoroacetic acid, in a solvent such as acetone, toluene, dichoromethane or tetrahydrofuran, optionally at an elevated temperature. Preferably, the reaction is carried out using acetone and 2,2-dimethoxypropane in the presence of sulphuric acid.

Alternatively, a compound of the formula (XXX) may be converted directly to a compound of the formula (XXXII) by selective enzymatic hydrolysis, e.g. using a suitable lipase enzyme.

The compound of the formula (XXXII) prepared may be oxidised to a carboxylic acid of the formula (XXXIII) in either one step by treatment with a suitable oxidising agent in a suitable solvent or in two steps by treatment first with a suitable oxidising agent in a suitable solvent to generate the corresponding aldehyde and then subsequent treatment with a suitable oxidising agent in a suitable solvent. Typical single step conditions include treatment of the primary alcohol with an oxidising agent such as chromic acid, sodium periodate, chromium trioxid