Indane derivatives Number:6,762,199 from the United States Patent and Trademark Office (PTO) owispatent

Title: Indane derivatives

Abstract: The invention is directed to physiologically active compounds of general formula (I): ##STR1##wherein: R.sup.1 represents aryl, heteroaryl or a group R.sup.3 --L.sup.2 --Ar.sup.1 --L.sup.3 --; R.sup.2 represents hydrogen or lower alkyl; R.sup.3 represents aryl or heteroaryl; and Ar.sup.1 represents an optionally substituted saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system containing at least one heteroatom selected from O, S or N; Y is carboxy or an acid bioisostere; and their corresponding N-oxides or prodrugs, and pharmaceutically acceptable salts and solvates of such compounds and their corresponding N-oxides or prodrugs.Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (.alpha.4.beta.1).

Patent Number: 6,762,199 Issued on 07/13/2004 to Fenton,   et al.

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Inventors:	Fenton; Garry (West Malling, GB), McCarthy; Clive (West Malling, GB), MacKenzie; Robert Edward (West Malling, GB), Morley; Andrew David (West Malling, GB)
Assignee:	Aventis Pharma Limited (Kent, GB)
Appl. No.:	10/229,592
Filed:	August 28, 2002

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Foreign Application Priority Data

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Feb 28, 2000 [GB]			0004686

Current U.S. Class:	514/375 ; 514/377; 548/217; 548/237
Current International Class:	C07D 235/00 (20060101); C07D 235/30 (20060101); C07D 263/00 (20060101); C07D 263/58 (20060101)
Field of Search:	548/217,237,222 514/375,377

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Foreign Patent Documents

	WO00/05201		Feb., 2000		WO
	WO00/05223		Feb., 2000		WO
	WO00/05224		Feb., 2000		WO
	WO00/49005		Aug., 2000		WO
	WO00/68213		Nov., 2000		WO

Primary Examiner: Chang; Ceila
Assistant Examiner: Shameem; Golam M M
Attorney, Agent or Firm: Ort; Ronald G.

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Parent Case Text

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/GB01/00844, filed Feb. 28, 2001, which claims priority from GB Application No. 0004686.2, filed Feb. 28, 2000, both these applications incorporated herein by reference.

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Claims

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What is claimed is:

1. A compound of general formula (I): ##STR158##

wherein: R.sup.1 represents a group R.sup.3 --L.sup.2 --Ar.sup.1 --L.sup.3 --; R.sup.2 represents hydrogen or lower alkyl; R.sup.3 represents an optionally substituted aryl group; R.sup.8 is hydrogen or lower alkyl; Ar.sup.1 represents an optionally substituted saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system containing at least one heteroatom selected from O, S or N; L.sup.1 represents an alkylene, alkenylene or alkynylene linkage; L.sup.2 represents NR.sup.8 ; L.sup.3 represents an alkylene, alkenylene or alkynylene chain; and Y is carboxy or an acid bioisostere; wherein the group ##STR159##

is attached to the benzene ring of the indane system and the group --L.sup.1 --Y is attached to either ring of the indane system; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs.

2. A compound according to claim 1 wherein R.sup.3 is a monosubstituted or disubstituted phenyl, and wherein the optional substituents are selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy and halo.

3. A compound according to claim 1 wherein L.sup.2 is NH.

4. A compound according to claim 1 wherein Ar.sup.1 represents an 8 to 10 membered bicyclic system ##STR160##

in which ring ##STR161##

is a 5or6 membered heteroaryl ring and ring ##STR162##

is a 5 or 6 membered heteroaryl ring or a benzene ring, each ring optionally substituted by one or more groups selected from aryloxy, cyano, halo. lower alkoxy, lower alkyl, nitro and perfluoroloweralkyl, and the two rings are joined together by a carbon-carbon linkage or a carbon-nitrogen linkage.

5. A compound according to claim 4 in which Ar.sup.1 represents an optionally substituted 9 membered bicyclic system ##STR163##

in which ring ##STR164##

is a 5 membered fully unsaturated heterocycle, ##STR165##

is an optionally substituted benzene and the two rings are joined together by a carbon-carbon linkage.

6. A compound according to claim 4 wherein ##STR166##

represents benzoxazolyl or benzimidazolyl, in which ring ##STR167##

is optionally substituted by one or more groups selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, amino, halogen, hydroxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, nitro and trifluoromethyl.

7. A compound according to claim 1 wherein L.sup.3 represents a straight or branched C.sub.1-6 alkylene chain.

8. A compound according to claim 1 wherein R.sup.2 represents hydrogen.

9. A compound according to claim 1 wherein L.sup.1 represents a methylene, ethylene or a straight or branched propylene linkage.

10. A compound according to claim 1 wherein Y represents carboxy.

11. A compound according to claim 1 selected from the following: 3-{7-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-indan-4-yl}-butyric acid; {5-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-indan-2-yl}-acetic acid; and {5-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-indan-1-yl)-acetic acid; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs.

12. A compound according to claim 1 selected from the following: ethyl 3-{7-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-indan-4-yl}-butanoat e; and ethyl {5-[2-(2o-tolylamino-benzoxazol-6-yl)-acetylamino]-indan-1-yl}-acetate; and their N-oxides and prodrugs.

13. A compound according to claim 1 of formula (Ia); ##STR168##

in which R.sup.2, R.sup.3, L.sup.1, L.sup.2, L.sup.3 and Y are as defined in claim 1; X is O; and R.sup.17 is hydrogen. alkoxy, halo or alkyl, and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs.

14. A compound according to claim 1 of formula (Ib): ##STR169##

in which R.sup.2, R.sup.3, L.sup.1, L.sup.2, L.sup.3 and Y are as defined in claim 1; X is O; and R.sup.17 is hydrogen, alkoxy, halo or alkyl, and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs.

15. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a corresponding N-oxide, or a prodrug thereof, or a pharmaceutically acceptable salt or solvate of such a compound or its N-oxide or a prodrug thereof, in association with a pharmaceutically acceptable carrier or excipient.

16. A method for the treatment of a patient suffering from, or subject to, asthma comprising administering to said patient an effective amount of a compound according to claim 1 or a corresponding N-oxide or prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or an N-oxide or prodrug thereof.

17. A method for the treatment of a patient suffering from, or subject to, an inflammatory disease comprising administering to said patient an effective amount of a compound according to claim 1 or a corresponding N-oxide or prodrug, or a pharmaceutically acceptable salt or solvate of such a compound or an N-oxide or prodrug thereof.

18. A method for the treatment of a patient suffering from, or subject to, asthma comprising administering to said patient an effective amount of a composition according to claim 15.

19. A method for the treatment of a patient suffering from, or subject to, an inflammatory disease comprising administering to said patient an effective amount of a composition according to claim 15.

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Description

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BACKGROUND OF THE INVENTION

This invention is directed to indane derivatives, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.

Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix. Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, VCAM-1 and vitronectin) and their integrin receptors [e.g. .alpha.5.beta.1 (VLA-5), .alpha.4.beta.1 (VLA-4) and .alpha.V.beta.3]. Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).

A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins. Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.

Integrins are heterodimeric cell surface receptors consisting of two subunits called .alpha. and .beta.. There are at least fifteen different .alpha.-subunits (.alpha.1-.alpha.9, .alpha.-L, .alpha.-M, .alpha.-X, .alpha.-IIb, .alpha.-V and .alpha.-E) and at least seven different .beta. (.beta.1-.beta.7) subunits. The integrin family can be subdivided into classes based on the .beta. subunits, which can be associated with one or more .alpha.-subunits. The most widely distributed integrins belong to the .beta.1 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte specific receptors and consist of one of three .alpha.-subunits .alpha.-L, .alpha.-M or .alpha.-X) complexed with the .beta.2 protein. The cytoadhesins .alpha.-IIb.beta.3 and .alpha.-V.beta.3, constitute the third class of integrins.

The present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor .alpha.4.beta.1 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.

The integrin .alpha.4.beta.1 mediates both cell-cell and cell-matrix interactions. Cells expressing .alpha.4.beta.1 bind to the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is upregulated by pro-inflammatory cytokines such as INF-.gamma., TNF-.alpha., IL-1.beta. and IL-4.

Regulation of .alpha.4.beta.1 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, colitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which .alpha.4.beta.1 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation. For example, in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflammation (S. M. Wahl et al., J. Clin. Invest., 1994, 94, pages 655-662). In the oxazalone-sensitised model of inflammation (contact hypersensitivity response) in mice, intravenous administration of anti-.alpha.4 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P. L. Chisholm et al. J. Immunol., 1993, 23, pages 682-688). In a sheep model of allergic bronchoconstriction, HP1/2, an anti-.alpha.4 monoclonal antibody given intravenously or by aerosol, blocked the late response and the development of airway hyperresponsiveness (W. M. Abraham et al. J. Clin. Invest., 1994, 93 pages 776-787).

SUMMARY OF THE INVENTION

We have now found a novel group of indane derivatives which have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (.alpha.4.beta.1).

Thus, in one aspect, the present invention is directed to compounds of general formula (I): ##STR2##

wherein: R.sup.1 represents aryl, heteroaryl or a group R.sup.3 --L.sup.2 --Ar.sup.1 --L.sup.3 --; R.sup.2 represents hydrogen or lower alkyl; R.sup.3 represents aryl or heteroaryl; R.sup.4 is alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, an acidic functional group, cycloalkyl, heteroaryl, heterocycloalkyl, --S(O).sub.m R.sup.5, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ; R.sup.5 represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl; R.sup.6 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R.sup.7 is hydrogen, R.sup.5 or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or --NY.sup.3 Y.sup.4 ; R.sup.8 is hydrogen or lower alkyl; R.sup.9 and R.sup.11 are each independently selected from hydrogen or a group consisting of amino acid side chains, an acidic functional group, R.sup.5, --C(.dbd.O)--R.sup.5, or --C(.dbd.O)--NY.sup.3 Y.sup.4, or alkyl substituted by an acidic functional group or by R.sup.5, --NY.sup.3 Y.sup.4, --NH--C(.dbd.O)--R.sup.5, --C(.dbd.O)--R.sup.12 --NH.sub.2, --C(.dbd.O)--Ar.sup.2 --NH.sub.2, --C(.dbd.O)--R.sup.12 --CO.sub.2 H, or --C(.dbd.O)--NY.sup.3 Y.sup.4 ; or R.sup.7 and R.sup.9 together with the atoms to which they attached form a 3- to 6-membered heterocycloalkyl ring; R.sup.10 represents C.sub.16 alkylene, optionally substituted by R.sup.4 ; R.sup.12 is an alkylene chain, an alkenylene chain, or an alkynylene chain; R.sup.13 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; Ar.sup.1 represents an optionally substituted saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system containing at least one heteroatom selected from O, S or N; Ar.sup.2 is arylene or heteroaryldiyl; L.sup.1 represents (i) a direct bond; (ii) an alkenylene, alkylene or alkynylene linkage each optionally substituted by (a) an acidic functional group, cyano, oxo, --S(O).sub.m R.sup.4, R.sup.5, --C(.dbd.O)--R.sup.5, --C(.dbd.O)--OR.sup.5, --N(R.sup.6)--C(.dbd.Z)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 or --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4, or by (b) alkyl substituted by an acidic functional group, or by S(O).sub.m R.sup.4, --C(.dbd.Z)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ; (iii) a --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p -- linkage; (iv) a --Z.sup.1 --R.sup.10 -- linkage; (v) a --R.sup.10 --Z.sup.1 --R.sup.10 -- linkage; (vi) a --C(R.sup.8)(R.sup.11)--[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p -- linkage; or (vii) a --L.sup.4 --L.sup.5 --L.sup.6 -- linkage; L.sup.2 represents NR.sup.8 ; L.sup.3 represents an alkylene, alkenylene or alkynylene chain; L.sup.4 and L.sup.6 each independently represent a direct bond or an alkylene chain; L.sup.5 represents a cycloalkylene or an indanylene; Y is carboxy or an acid bioisostere; Y.sup.1 and Y.sup.2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group --NY.sup.1 Y.sup.2 may form a cyclic amine; Y.sup.3 and Y.sup.4 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, --NY.sup.1 Y.sup.2, or one or more --CO.sub.2 R.sup.6 or --C(.dbd.O)--NY.sup.1 Y.sup.2 groups; or the group --NY.sup.3 Y.sup.4 may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R.sup.7 ; (ii) may also contain a further heteroatom selected from O, S, SO.sub.2, or NY.sup.5 ; and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system; Y.sup.5 is hydrogen, alkyl, aryl, arylalkyl, --C(.dbd.O)--R.sup.13, --C(.dbd.O)--OR.sup.13 or --SO.sub.2 R.sup.13 ; Z is O or S; Z.sup.1 is O, S(O).sub.n, NR.sup.8, SO.sub.2 NR.sup.8, C(.dbd.O)NR.sup.8 or C(.dbd.O); m is an integer 1 or 2; n is zero or an integer 1 or 2; p is zero or an integer 1 to 4; the group ##STR3##

is attached to the benzene ring of the indane system and the group --L.sup.1 --Y is attached to either ring of the indane system; and any aryl or heteroaryl moieties present as a group or part of a group may be optionally substituted; but excluding compounds where an oxygen, nitrogen or sulfur atom is attached directly to a carbon carbon multiple bond of an alkenylene, alkynylene or cycloalkenylene residue; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

DETAILED DESCRIPTION

In the present specification, the term "compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, protected derivatives of compounds of formula (I) containing one or more acidic functional groups and/or amino-acid side chains, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.

As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

"Patient" includes both human and other mammals.

"Acid bioisostere" means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, page 283 "Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design"; Graham, Theochem, 1995, 343, pages 105-109 "Theoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteres"). Examples of suitable acid bioisosteres include: --C(.dbd.O)--NHOH, --C(.dbd.O)--CH.sub.2 OH, --C(.dbd.O)--CH.sub.2 SH, --C(.dbd.O)--NH--CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-l-methylpyrazolyl.

"Acidic functional group" means a group with an acidic hydrogen within it. The "protected derivatives" are those where the acidic hydrogen atom has been replaced with a suitable protecting group. For suitable protecting groups see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991. Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole. Exemplary protected derivatives include esters of carboxy groups (i.e. --CO.sub.2 R.sup.13), ethers of hydroxy groups (i.e. --OR.sup.13), thioethers of mercapto groups (i.e. --SR.sup.13), and N-benzyl derivatives of imidazoles.

"Acyl" means an H--CO-- or alkyl-CO-- group in which the alkyl group is as described herein.

"Acylamino" is an acyl-NH-- group wherein acyl is as defined herein.

"Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. "Branched", as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain.

"Lower alkenyl" means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

"Alkenylene" means an aliphatic bivalent radical derived from a straight or branched alkenyl group, in which the alkenyl group is as described herein. Exemplary alkenylene radicals include vinylene and propylene.

"Alkoxy" means an alkyl-O-- group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.

"Alkoxycarbonyl" means an alkyl-O--CO-- group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.

"Alkyl" means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain optionally substituted by alkoxy or by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. "Lower alkyl" as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.

"Alkylene" means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethylene and trimethylene.

"Alkylenedioxy" means an --O-alkyl-O-- group in which the alkyl group is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.

"Alkylsulfinyl" means an alkyl-SO-- group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those in which the alkyl group is C.sub.1-4 alkyl.

"Alkylsulfonyl" means an alkyl-SO.sub.2 -- group in which the alkyl group is as previously described. Preferred alkylsulfonyl groups are those in which the alkyl group is C.sub.1-4 alkyl.

"Alkylsulfonylcarbamoyl" means an alkyl-SO.sub.2 --NH--C(.dbd.O)-- group in which the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C.sub.1-4 alkyl.

"Alkylthio" means an alkyl-S-- group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.

"Alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.

"Alkynylene" means an aliphatic bivalent radical derived from a C.sub.2-6 alkynyl group. Exemplary alkynylene radicals include ethynylene and propynylene.

"Amino acid side chains" means the substituent found on the carbon between the amino and carboxy groups in .alpha.-amino acids. For examples of "protected derivatives" of amino acid side chains, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

"Aroyl" means an aryl-CO-- group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.

"Aroylamino" is an aroyl-NH-- group wherein aroyl is as previously defined.

"Aryl" as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, --NY.sup.1 Y.sup.2, --CONY.sup.1 Y.sup.2, --SO.sub.2 NY.sup.1 Y.sup.2, --Z.sup.2 --C.sub.2-6 alkylene-NY.sup.1 Y.sup.2 {where Z.sup.2 is O, NR.sup.8 or S(O).sub.n }, --NY.sup.1 --(C.dbd.O)alkyl, --NY.sup.1 -SO.sub.2 alkyl or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or --NY.sup.1 Y.sup.2.

"Arylalkenyl" means an aryl-alkenyl-group in which the aryl and alkenyl are as previously described. Preferred arylalkenyls contain a lower alkenyl moiety. Exemplary arylalkenyl groups include styryl and phenylallyl.

"Arylalkyl" means an aryl-alkyl-group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C.sub.1-4 alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.

"Arylalkyloxy" means an arylalkyl-O-- group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.

"Arylalkyloxycarbonyl" means an arylalkyl-O--CO-- group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.

"Arylalkylthio" means an arylalkyl-S-- group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.

"Arylalkynyl" means an aryl-alkynyl-group in which the aryl and alkynyl are as previously described. Exemplary arylalkynyl groups include phenylethynyl and 3-phenylbut-2-ynyl.

"Arylene" means an optionally substituted bivalent radical derived from an aryl group. Exemplary arylene groups include optionally substituted phenylene, naphthylene and indanylene.

"Aryloxy" means an aryl-O-- group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.

"Aryloxycarbonyl" means an aryl-O--C(.dbd.O)-- group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

"Arylsulfinyl" means an aryl-SO-- group in which the aryl group is as previously described.

"Arylsulfonyl" means an aryl-SO.sub.2 -- group in which the aryl group is as previously described.

"Arylsulfonylcarbamoyl" means an aryl-SO.sub.2 --NH--C(.dbd.O)-- group in which the aryl group is as previously described.

"Arylthio" means an aryl-S-- group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.

"Azaheteroaryl" means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulfur, or nitrogen. Examples of azaheteroaryl groups include benzimidazolyl, imidazolyl, isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, quinazolinyl and thiazolyl.

"Azaheteroaryldiyl" means an optionally substituted bivalent radical derived from a heteroaryl group.

"Cyclic amine" means a 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen and which (i) may optionally contain an additional heteroatom selected from O, S or NY.sup.6 (where Y.sup.6 is hydrogen, alkyl, arylalkyl, and aryl) and (ii) may be fused to additional aryl or heteroaryl ring to form a bicyclic ring system. Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline and pyrindoline.

"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

"Cycloalkenylalkyl" means a cycloalkenyl-alkyl-group in which the cycloalkenyl and alkyl moieties are as previously described. Exemplary cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.

"Cycloalkenylene" means a bivalent radical derived from an unsaturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopentenylene and cyclohexenylene.

"Cycloalkyl" means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C.sub.3-8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

"Cycloalkylalkenyl" means a cycloalkyl-alkenyl-group in which the cycloalkyl and alkenyl moieties are as previously described. Exemplary monocyclic cycloalkylalkenyl groups include cyclopentylvinylene and cyclohexylvinylene.

"Cycloalkylalkyl" means a cycloalkyl-alkyl-group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

"Cycloalkylalkynyl" means a cycloalkyl-alkynyl-group in which the cycloalkyl and alkynyl moieties are as previously described. Exemplary monocyclic cycloalkylalkynyl groups include cyclopropylethynyl, cyclopentylethynyl and cyclohexylethynyl.

"Cycloalkylene" means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopropylene, cyclopentylene and cyclohexylene.

"Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.

"Heteroaroyl" means a heteroaryl-C(.dbd.O)-- group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.

"Heteroaroylamino" means a heteroaroyl-NH-- group in which the heteroaryl moiety are as previously described.

"Heteroaryl" as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups). Optional substituents include one or more "aryl group substituents" as defined above. When R.sup.1 is an optionally substituted heteroaryl group this may particularly represent an optionally substituted "azaheteroaryl" group.

"Heteroarylalkenyl" means a heteroaryl-alkenyl-group in which the heteroaryl and alkenyl moieties are as previously described. Preferred heteroarylalkenyl groups contain a lower alkenyl moiety. Exemplary heteroarylalkenyl groups include pyridylethenyl and pyridylallyl.

"Heteroarylalkyl" means a heteroaryl-alkyl-group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C.sub.1-4 alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.

"Heteroarylalkyloxy" means an heteroarylalkyl-O-- group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.

"Heteroarylalkynyl" means a heteroaryl-alkynyl-group in which the heteroaryl and alkynyl moieties are as previously described. Exemplary heteroarylalkenyl groups include pyridylethynyl and 3-pyridylbut-2-ynyl.

"Heteroaryldiyl" means a bivalent radical derived from an aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur, and optionally substituted by one or more "aryl group substituents" as defined above.

"Heteroaryloxy" means an heteroaryl-O-- group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.

"Heteroarylsulfonylcarbamoyl" means a heteroaryl-SO.sub.2 --NH--C(.dbd.O)-- group in which the heteroaryl group is as previously described.

"Heterocycloalkyl" means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY.sup.3 and which may optionally be substituted by oxo; (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring) and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).

"Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl-group in which the heterocycloalkyl and alkyl moieties are as previously described.

"Heterocycloalkylene" means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 5 to about 7 atoms, which contains one or more heteroatoms selected from O, S or NY.sup.6 and is optionally substituted by oxo, by removing a hydrogen atom from each of two different carbon atoms of the ring, or when NY.sup.6 is NH by removing a hydrogen atom from one carbon atom of the ring and a hydrogen atom from the NH, or when the ring contains two NY.sup.6 heteroatoms and NY.sup.6 is NH by removing a hydrogen atom from both nitrogen atoms.

"Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.

Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-.beta.-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

Suitable esters of compounds of formula (I) containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379.

Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the moiety --L.sup.1 --Y, include lactones, formed by loss of water between said carboxy and hydroxy groups. Examples of lactones include caprolactones and butyrolactones.

An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.

Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.

Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.

Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.

With reference to formula (I) above, the following are particular and preferred groupings:

R.sup.1 may particularly represent optionally substituted aryl, such as optionally substituted phenyl [preferred optional substituents include one or more groups (e.g. 1 or 2) selected from aryloxy, cyano, halo (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), nitro and perfluoroloweralkyl (e.g. trifluoromethyl)]. R.sup.1 especially represents substituted phenyl selected from 2-chlorophenyl, 5-chloro-2-cyanophenyl, 2-chloro-6-methylphenyl, 2,6-dichlorophenyl, 2,6-difluoropheny,4-fluoro-2-trifluoromethyl, 2-methyl-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2-nitrophenyl, 3-nitrophenyl or 2-phenoxyphenyl.

R.sup.1 may also particularly represent optionally substituted heteroaryl, such as benzoxazole, benzimidazole, isoquinolinyl, isoxazolyl, pyrazolopyrimidinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl and triazolyl, each optionally substituted by one or more (e.g. 1 or 2) aryl group substituents as described hereinbefore [preferred optional substituents include alkyl-C(.dbd.O)--, aryl, cyano, halo, (e.g. chloro or fluoro), lower alkoxy (e.g. methoxy), lower alkyl (e.g. methyl), lower alkylsulfonyl, lower alkylthio, nitro and perfluoroloweralkyl (e.g. trifluoromethyl) and --NY.sup.1 Y.sup.2 ]. R.sup.1 especially represents an optionally substituted azaheteroaryl selected from quinolin-4-yl, isoquinolin-2-yl, 2,4-pyridin-3-yl, 2,6-dimethyl-4-trifluoromethylpyridin-3-yl, 4-trifluoromethylpyridin-3-yl, 2-phenyl-4-methyl-1,2,3-triazol-5-yl, 3,5-dimethylisoxazol-4-yl, 2,7-dimethylpyrazolo-[1,5-a]pyrimidin-6-yl, 2-isopropyl-4-methylthiazol-5-yl and 4-trifluoromethylpyrimidin-5-yl.

R.sup.1 may also particularly represent a group R.sup.3 --L.sup.2 --Ar.sup.1 --L.sup.3 - in which: R.sup.3 and L.sup.2 are as define above; L.sup.3 represents a straight or branched C.sub.1-6 alkylene chain, more particularly a straight C.sub.1-4 alkylene chain such as methylene or ethylene, preferably methylene and Ar.sup.1 is an 8 to 10 membered bicyclic system ##STR4##

in which ring ##STR5##

is a 5 or 6 membered, preferably a 5 membered, heteroaryl ring and ring ##STR6##

is a 5 or 6 membered heteroaryl ring or a benzene ring, preferably a benzene ring, each ring optionally substituted by one or more (e.g. 1 or 2) "aryl group substituents" as defined above and the two rings are joined together by a carbon-carbon linkage or a carbon-nitrogen linkage. ##STR7##

is preferably benzoxazolyl or benzimidazolyl, in which ring ##STR8##

is optionally substituted by one or more (e.g. 1 or 2) "aryl group substituents" as defined above [examples of particular aryl group substituents include C.sub.1-4 alkyl (e.g. methyl or ethyl), C.sub.1-4 alkoxy (e.g. methoxy), amino, halogen, hydroxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, nitro or trifluoromethyl]. Within R.sup.3 --L.sup.2 --Ar.sup.1 --L.sup.3 --, L.sup.2 is preferably NH and R.sup.3 is particularly optionally substituted aryl, such as monosubstituted or disubstituted phenyl, [examples of particular aryl group substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y.sup.1 Y.sup.2 N-- (e.g. dimethylamino)].

R.sup.2 may particularly represent hydrogen.

R.sup.2 may also particularly represent lower alkyl, (e.g. methyl).

L.sup.1 may particularly represent an optionally substituted alkylene linkage (e.g. optionally substituted methylene, optionally substituted ethylene or optionally substituted propylene). Preferred optional substituents include lower alkyl, aryl, heteroaryl, --ZH, --ZR.sup.13, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 and --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4 or alkyl substituted by carboxy (or an acid bioisostere), --ZH, --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4. In one preferred embodiment L.sup.1 is methylene. In another preferred embodiment L.sup.1 is a group ##STR9##

[where R.sup.14 is hydrogen or lower alkyl (e.g. methyl) and R.sup.15 represents hydrogen or lower alkyl, or where R.sup.14 is hydrogen and R.sup.15 represents aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 or --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.)--NY.sup.3 Y.sup.4, or alkyl substituted by carboxy (or an acid bioisostere), --ZH, --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ], and is more preferably a group ##STR10##

particularly ##STR11##

[where R.sup.15 represents hydrogen, lower alkyl, aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4 or --NY.sup.3 Y.sup.4 or alkyl substituted by carboxy, --OH, --OR.sup.13 or --C(.dbd.O)--NY.sup.3 Y.sup.4 ]. In another preferred embodiment L.sup.1 is a group ##STR12##

[where R.sup.14 is hydrogen or lower alkyl (e.g. methyl) and R.sup.16 represents lower alkyl, or where R.sup.14 is hydrogen and R.sup.16 represents aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 or --[C(.dbd.O)--N(R.sup.7)-- C(R.sup.8 (R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4, or alkyl substituted by carboxy (or an acid bioisostere), --ZH, --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ], and is more preferably a group ##STR13##

particularly ##STR14##

[where R.sup.16 represents --N(R.sup.6)--C(.dbd.O)--R.sup.4, or --N(R.sup.6)--SO.sub.2 --R.sup.4 ].

L.sup.1 may also particularly represent a --L.sup.4 --L.sup.5 --L.sup.6 -- linkage, in which L.sup.4 and L.sup.6 are independently a direct bond or alkylene (e.g. methylene) and L.sup.5 is cycloalkylene, such as cyclopropylene or cyclopentylene, or indanylene.

Y may particularly represent carboxy.

It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.

A particular group of compounds of the invention are compounds of formula (Ia): ##STR15##

in which R.sup.2, R.sup.3, L.sup.1, L.sup.2, L.sup.3 and Y are as hereinbefore defined; X is O or NR.sup.18 (where R.sup.18 is hydrogen or lower alkyl); and R.sup.17 is hydrogen, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, --NY.sup.1 Y.sup.2, --CONY.sup.1 Y.sup.2, --SO.sub.2 NY.sup.1 Y.sup.2, --Z.sup.2 --C.sub.2-6 alklene-NY.sup.1 Y.sup.2, --NY.sup.1 --(C.dbd.O)alkyl, --NY.sup.1 --SO.sub.2 alkyl or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or --NY.sup.1 Y.sup.2 (where Y.sup.1, Y.sup.2 and Z.sup.2 are as defined hereinbefore), and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

Compounds of formula (Ia) in which R.sup.3 represents optionally substituted aryl, especially monosubstituted or disubstituted phenyl, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y.sup.1 Y.sup.2 N-- (e.g. dimethylamino). R.sup.3 especially represents phenyl substituted in at least the 2-position, for example by a C.sub.1-4 alkyl group such as methyl.

Compounds of formula (Ia) in which L.sup.2 represents NH are preferred.

Compounds of formula (Ia) in which R.sup.17 represents hydrogen, halo (e.g. chloro), lower alkyl (e.g. methyl or ethyl) or lower alkoxy (e.g. methoxy) are preferred.

Compounds of formula (Ia) in which L.sup.3 represents a straight or branched C.sub.1-6 alkylene chain, especially a straight C.sub.1-4 alkylene chain, more especially methylene, are preferred.

Compounds of formula (Ia) in which R.sup.2 represents hydrogen are preferred.

Compounds of formula (Ia) in which R.sup.2 represents lower alkyl, (e.g. methyl) are also preferred.

Compounds of formula (Ia) in which L.sup.1 represents an optionally substituted alkylene linkage (e.g. optionally substituted methylene, optionally substituted ethylene or optionally substituted propylene) are preferred. Preferred optional substituents include lower alkyl, aryl, heteroaryl, --ZH, --ZR.sup.13, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 and --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4 or alkyl substituted by carboxy (or anacid bioisostere), --ZH --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4. In one preferred embodiment L.sup.1 is methylene. In another preferred embodiment L.sup.1 is a group ##STR16##

[where R.sup.14 is hydrogen or lower alkyl (e.g. methyl) and R.sup.15 represents hydrogen or lower alkyl, or where R.sup.14 is hydrogen and R.sup.15 represents aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 T.sup.4 or --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4, or alkyl substituted by carboxy (or an acid bioisostere), --ZH, --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ], and is more preferably a group ##STR17##

particularly ##STR18##

[where R.sup.15 represents hydrogen, lower alkyl, aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4 or --NY.sup.3 Y.sup.4 or alkyl substituted by carboxy, --OH, --OR.sup.13 or --C(.dbd.O)--NY.sup.3 Y.sup.4 ]. In another preferred embodiment L.sup.1 is a group ##STR19##

[where R.sup.14 is hydrogen or lower alkyl (e.g. methyl) and R.sup.16 represents lower alkyl, or where R.sup.14 is hydrogen and R.sup.16 represents aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 or --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4, or alkyl substituted by carboxy (or an acid bioisostere), --ZH, --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ], and is more preferably a group ##STR20##

particularly ##STR21##

[where R.sup.16 represents --N(R.sup.6)--C(.dbd.O)--R.sup.4, or --N(R.sup.6)--SO.sub.2 --R.sup.4 ].

Compounds of formula (Ia) in which L.sup.1 represents a --L.sup.4 --L.sup.5 --L.sup.6 -- linkage, in which L.sup.4 and L.sup.6 are independently a direct bond or alkylene (e.g. methylene) and L.sup.5 is cycloalkylene, such as cyclopropylene or cyclopentylene, or indanylene are also preferred.

Compounds of formula (Ia) in which Y represents carboxy are preferred.

A preferred group of compounds of the invention are compounds of formula (Ia) in which: R.sup.2 is hydrogen or lower alkyl (e.g. methyl); R.sup.3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C.sub.14 alkyl); R.sup.17 is hydrogen, chloro, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; L.sup.1 is methylene; L.sup.2 is NH; L.sup.3 is a straight C.sub.1-4 alkylene chain, especially methylene; X is O; Y is carboxy; the group ##STR22##

is attached at the benzoxazole ring 6a position; the nitrogen atom of the ##STR23##

linkage is attached to the indane ring 5 or 6 position; and the --L.sup.1 --Y group is attached to the indane ring 1 or 2 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

Another preferred group of compounds of the invention are compounds of formula (Ia) in which: R.sup.2 is hydrogen or lower alkyl (e.g. methyl); R.sup.3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C.sub.1-4 alkyl); R.sup.17 is hydrogen, chloro, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; L.sup.1 is methylene; L.sup.2 is NH; L.sup.3 is a straight C.sub.1-4 alkylene chain, especially methylene; X is NR.sup.18 (especially NH); Y is carboxy; the group ##STR24##

is attached at the benzimidazole ring 5a or 6a position; the nitrogen atom of the ##STR25##

linkage is attached to the indane ring 5 or 6 position; and the --L.sup.1 --Y group is attached to the indane ring 1 or 2 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

Another particular group of compounds of the invention are compounds of formula (Ib): ##STR26##

in which R.sup.2, R.sup.3, L.sup.1, L.sup.2, L.sup.3 and Y are as hereinbefore defined; X is O or NR.sup.18 (where R.sup.18 is hydrogen or lower alkyl); and R.sup.17 is hydrogen, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, --NY.sup.1 Y.sup.2, --CONY.sup.1 Y.sup.2, --SO.sub.2 NY.sup.1 Y.sup.2, --Z.sup.2 --C.sub.2-6 alkylene-NY.sup.1 Y.sup.2, --NY.sup.1 --(C.dbd.O)alkyl, --NY.sup.1 --SO.sub.2 alkyl or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or --NY.sup.1 Y.sup.2 (where Y.sup.1, Y.sup.2 and Z.sup.2 are as defined hereinbefore), and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

Compounds of formula (Ib) in which R.sup.3 represents optionally substituted aryl, especially monosubstituted or disubstituted phenyl, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro or chloro) and Y.sup.1 Y.sup.2 N--(e.g. dimethylamino). R.sup.3 especially represents phenyl substituted in at least the 2-position, for example by a C.sub.1-4 alkyl group such as methyl.

Compounds of formula (Ib) in which L.sup.2 represents NH are preferred.

Compounds of formula (Ib) in which R.sup.17 represents hydrogen, halo (e.g. chloro), lower alkyl (e.g. methyl or ethyl) or lower alkoxy (e.g. methoxy) are preferred.

Compounds of formula (Ib) in which L.sup.3 represents a straight or branched C.sub.1-6 alkylene chain, especially a straight C.sub.1-4 alkylene chain, more especially methylene, are preferred.

Compounds of formula (Ib) in which R.sup.2 represents hydrogen are preferred.

Compounds of formula (Ib) in which R.sup.2 represents lower alkyl, (e.g. methyl) are also preferred.

Compounds of formula (Ib) in which L.sup.1 represents an optionally substituted alkylene linkage (e.g. optionally substituted methylene, optionally substituted ethylene or optionally substituted propylene) are preferred. Preferred optional substituents include lower alkyl, aryl, heteroaryl, --ZH, --ZR.sup.13, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 and --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4 or alkyl substituted by carboxy (or an acid bioisostere), --ZH, --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4. In one preferred embodiment L.sup.1 is a group ##STR27##

[where R.sup.14 is hydrogen or lower alkyl (e.g. methyl) and R.sup.15 represents hydrogen or lower alkyl, or where R.sup.14 is hydrogen and R.sup.15 represents aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 or --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4, or alkyl substituted by carboxy (or an acid bioisostere), --ZH, --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ], and is more preferably a group ##STR28##

particularly ##STR29##

[where R.sup.15 represents hydrogen, lower alkyl, aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4 or --NY.sup.3 Y.sup.4 or alkyl substituted by carboxy, --OH, --OR.sup.13 or --C(.dbd.O)--NY.sup.3 Y.sup.4 ]. In another preferred embodiment L.sup.1 is a group ##STR30##

[where R.sup.14 is hydrogen or lower alkyl (e.g. methyl) and R.sup.16 represents lower alkyl, or where R.sup.14 is hydrogen and R.sup.16 represents aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4, --NY.sup.3 Y.sup.4 or --[C(.dbd.O)--N(R.sup.7)--C(R.sup.8)(R.sup.9)].sub.p --C(.dbd.O)--NY.sup.3 Y.sup.4, or alkyl substituted by carboxy (or an an acid bioisostere), --ZH, --ZR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ], and is more preferably a group ##STR31##

particularly ##STR32##

[where R.sup.16 represents --N(R.sup.6)--C(.dbd.O)--R.sup.4, or --N(R.sup.6)--SO.sub.2 --R.sup.4 ].

Compounds of formula (Ib) in which L.sup.1 represents a --L.sup.4 --L.sup.5 --L.sup.6 -- linkage, in which L.sup.4 and L.sup.6 are independently a direct bond or alkylene (e.g. methylene) and L.sup.5 is cycloalkylene, such as cyclopropylene or cyclopentylene, or indanylene are also preferred.

Compounds of formula (Ib) in which Y represents carboxy are preferred.

A preferred group of compounds of the invention are compounds of formula (Ib) in which: R.sup.2 is hydrogen or lower alkyl (e.g. methyl); R.sup.3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C.sub.1-4 alkyl); R.sup.17 is hydrogen, chloro, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; L.sup.1 is a ##STR33##

group particularly a ##STR34##

group, where R.sup.15 represents hydrogen, lower alkyl, aryl, heteroaryl, --N(R.sup.6)--C(.dbd.O)--R.sup.4, --N(R.sup.6)--C(.dbd.O)--OR.sup.4, --N(R.sup.6)--SO.sub.2 --R.sup.4 or --NY.sup.3 Y.sup.4, or alkyl substituted by carboxy (or an acid bioisostere), --OH, --OR.sup.13, --C(.dbd.O)--NY.sup.3 Y.sup.4 or --NY.sup.3 Y.sup.4 ; L.sup.2 is NH; L.sup.3 is a straight or branched C.sub.1-4 alkylene chain, especially methylene; X is O; Y is carboxy; the group ##STR35##

is attached at the benzoxazole ring 6a position; the nitrogen atom of the ##STR36##

linkage is attached to the indane ring 4 position; and the --L.sup.1 --Y group is attached to the indane ring 7 position; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.

Another preferred group of compounds of the invention are compounds of formula (Ib) in which: R.sup.2 is hydrogen or lower alkyl (e.g. methyl); R.sup.3 is optionally substituted phenyl (especially phenyl substituted in at least the 2-position, e.g. by C.sub.1-4 alkyl); R.sup.17 is hydrogen, chloro, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; L.sup.1 is a ##STR37##

group, particularly ##STR38##

[where R.sup.16 represents --N(R.sup.6)--C(.dbd.O)--R.sup.4, or --N(R.sup.6)--SO.sub.2 --R.sup.4 ]; L.sup.2 is NH; L.sup.3 is a straight C.sub.1-4 alkylene cha