| Title of Invention | BETA 2-ADRENOCEPTOR AGONISTS |
|---|---|
| Abstract | Compounds of formula (I) in free or salt or solvate form, where Ar is a group of formula (II) Y is carbon or nitrogen and R<sup>1</sup, R<sup>2</sup, R<sup>3</sup, R<sup>4</sup, R<sup>5</sup, R<sup>6</sup, R<sup>7</sup, R<sup>8</sup, R<sup>9</sup, R<sup>10</sup, X, n, p, q and r are as defined in the specification, their preparation and their use as pharmaceuticals, particularly for the treatment of obstructive or inflammatory airways diseases. The compounds of formula (I) in free, salt or solvate form, have $g(b)2-adrenoreceptor agonist activity. |
| Full Text | This invention relates to organic compounds, their preparation and their use as pharmaceuticals. The invention provides in one aspea a compound of formula R' is hydrogen, hydroxy, or alkoxy, R2 and R2 are each independently hydrogen or alkyl, R2, R1, R1 and R' are each independently hydrogen, halogen, cyano, hydroxy, alkoxy, aryl, alkyl, alkyl substituted by one or more halogen atoms or one or more hydroxy or alkoxy groups, alkyl interrupted by one or more hetero atoms, alkcnyl, trialkylsilyl, carboxy, alkoxycarbonyl, or -CONR11R12 where R1 and R'2 are each independently hydrogen or alkyl, or R2 and R2, R2 and R2, or R1 and R' together with the carbon atoms to which they are attached denote a carbocyclic or heterocyclic ring, R» is halogen, -OR14, -CH2OR11 or -NHR12 where R13 is hydrogen, alkyl, alkyl interrupted by one or more hetero atoms, -COR2'1, where R'2 is hydrogen, -N{Ri2)R'1, alkyl or alkyl interrupted by one or more hetero atoms, or aryl and R12 and R21 are each independendy hydrogen, alkyl or alkyl interrupted by one or more hetero atoms, or R is -C(=NH)R, -SOR'2 or -SOJR'2 where R2' is alkyl or alkyl interrupted by one or more hetero atoms, and R' is hydrogen, or R' is -NHR where -NHR21 and R', together with the carbon atoms to which they are attached, denote a 5- or 6- membered heterocycle, R' is -OR'2 or -NHR2' where R is hydrogen, alkyl, alkyl interrupted by one or more hetero atoms, or -COR2, where R2 is -N(R2')R, alkyl or alkyl interrupted by one or more hetero atoms, or atyl, and R2' and R are each independently hydrogen, alkyl or alkyl interrupted by one or more hetero atoms, X is halogen or halomethyl or alkyl, Y is carbon or nitrogen, n is 1 or 2, p is zero when Y is nitrogen or 1 when Y is carbon, q and r are each zero or 1, the sum of q+r is 1 or 2; and the carbon atom marked with an asterisk1 has the R or S configuration, or a mixture thereof, when R2 is hydroxy or alkoxy. Terms used in this specification have the following meanings: Alkyl denotes straight chain or branched alkyl, which may be, for example, Q to Qo alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, straight or branched heptyl, straight or branched nonyl or straight or branched decyl. Preferably aikyl is C1 to C4 alkyl. Alkyl substituted by one or more halogen atoms or one or more hydroxy or alkoxy groups may be any of the above C1 to Cio alkyl groups substituted by one or more halogen, preferably fluorine or chlorine, atoms, by one or more hydroxy groups or by one or more C1 to Cjo , preferably Q to C4, alkoxy groups. Alkyl interrupted by one or more hetero atoms denotes straight chain or branched alkyl e.g. Cito Cio alkyl, in which one or more pairs of carbon atoms are hnked by -0-, -NR-,-S-, -S(=0)- or -SO2-, where R is hydrogen or C1 to Cio (preferably C] to C4) alkyl. Preferred such groups are alkoxyalkyl groups, preferably C]-C4-alkoxy-C1-C4-alkyl groups. Alkoxy denotes straight chain or branched alkoxy and may be, for example, C1 to Cio alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tcrt-butoxy, or straight or branched pentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy. Preferably alkoxy is C1 to c4 alkoxy. Alkenyl means straight chain or branched alkenyl, which may be unsubstituted or substituted, for example by one or more halogen atoms or one or more alkoxy groups, and which may be, for example, C2 to C10 alkenyl such as vinyl, l-propenyl, 2-propenyl, 1-butenyl, isobutenyl, or straight or branched pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl. Preferred alkenyl is C2 to C4 alkenyl. Aryl denotes unsubstituted or substituted aryl, e.g. unsubstituted phenyl or naphthyl, or phenyl or naphthyl substituted by one or more, e.g. 1 to 4, substituents selected from C]-C4-alkyl, hydroxy, C1-C4-alkoxy, halogen, or halo-C1-C4-alkyI. Preferably, aryl is unsubstituted phenyl or phenyl substituted by 1 or 2 substituents selected from C1-C4-alkyl or halogen. Alkylene denotes straight chain or branched alkylene which may be, for example, C1-C50-alkylene such as methylene, ethylene, 1,2-propylene, 1,3-propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene. Preferably alkylene is C1-C4-alkylene. Alkenylene denotes straight chain or branched alkenylene which may be, for example, C2-Cio-alkenylene such as vinylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene or decenylene. Preferably alkenylene is C2-C4-alkenylene. In formula I, n is 1 ot 2, i.e. there are 2 or 4 CH2 groups in the ring fused to the indicated benzene ring, so that ring is either a 5-membered or 7-membered ring. The group Ar in formula n in which R' is -NHR'1 and -NHR and R1 together denote a 5-or 6- membered heterocycle may be, for example, a group in which Y is carbon, R1 is -NHR1 and -NHR11 and R' together denote a group of formula -NH-CO-R- where R1 is an alkylene, alkenylene or alkyleneoxy group, a group of formula -NH-S02-R11 where R11 is an alkyleneoxy group, a group of formula -NH-R(COOR1)- where R25 is an alkylene or alkenylene group and R1 is alkyl, ot a group of formula -NH-CO-NH- or -NH-CO-S-, R'° is -OR1' where R19 is as hereinbefore defined, X is alkyl, p is 1, q is 1 and i is zero or 1. The alkylene, alkenylene and alkyleneoxy groups preferably have 1 to 4 carbon atoms. Preferred groups At of formula n in which R2 is -NHR, and -NHR12 and R1 together denote a 5- or 6- membered heterocycle, include groups in which Y is carbon, R2 is -NHR and -NHR and R1 together denote a group of formula -NH-CO-C(R11)sC(R12)- or -NH-CO-CHz-O- or -NH-CO-CHj- or -NH-SOi-CHi-O- or -NH-C(COOR1)=CH- or -NH-CO-NH- or -NH-CO-S- where R11 and R=2 are each independently hydrogen or C1-C4-alkyl and R is C1-C4-alkyl, R'° is -OH, X is C1-C4-alkyi, p is 1, q is 1 and r is zero or 1. More preferred groups Ar of formula 11 where R2 is -NHR, and -NHR and R2 together denote a 5- or 6- membered heterocycle include those of the formulae in which R , R and R are each independently hydrogen or C1-C4-alkyl, IV VI VII in which Z is -0-, -NH- or -S-. The group Ar of formula II in which R2 is halogen and R' is hydrogen may be, for example, a group of formula II in which Y is carbon, R2 is halogen, preferably chlorine, R' is hydrogen, R2 is -NHR1' where R is hydrogen or C1-C1-alkyi, preferably hydrogen or methyl, X is halogen or halomethyi, preferably chlorine or trifluoromethyl, and p, q and r are each 1. Preferred groups Ar among such groups include those of formulae CI. VIII The group Ar of formula II in which R2 is -OR'1 and R' is hydrogen may be, for example, a group of formula E in which Y is carbon, R2 is -OR where R is hydrogen, C1-C4-alkyI, C,-C4-alkoxy-C1-C4-alkyl. -COR where R'2 is C1-Q-alkyl, Q-Cio-aryl or -N(R'1)R'2 where R11 and R'2 are each independently hydrogen or C1-C4-alkyl, R is -OR or -NHR'1 where R'1 is hydrogen, C1-C1-alkyl, C1-C4-alkoxy-C1-C4-alkyl, or -COR1 where R1 is -N(R11)R, C1-C4-alkyl, C]-C4-alkoxy-C]-C4-a]kyl or Q-Cio-aryl and R11 and R are each independently hydrogen or C1-C4-aIkyl, p and q are each 1 and r is zero. Preferred groups Ar among such groups include those of formulae I XI CH, The group Ar of formula II in which R' is -CHaOR'1 may be, for example, a group of formula II in which Y is carbon, R' is -CH2OR where R is hydrogen, C]-C4-alkyl, or Cj-C4-alkoxy-C]-C4-alkyl, R' is hydrogen, R is -OR where R is hydrogen, Cj-Q-alkyl or C-Ct-alkoxy-C1-C-alkyl or R is -NHR where R is hydrogen, C,-C4-alkyl or -COR1 where R1 is C1-C4-aikyl, Q-C,o-aryl or -N{R2')R where R1' and R are each independently hydrogen or C1-C4-alkyl, p and q are each 1 and r is zero; or a group of formula in which Y is nitrogen, R' is -CH2OR where R'1 is hydrogen, C1-C4-alkyl or Cj-Q-alkoxy-C1-Q-alkyl, R1 is -OR where R is hydrogen, C1-C4-alkyl or CrC4-alkoxy- C,- XIII The group At of formula H in which R' is -NHR1 may be, for example, a group of formula n in which Y is carbon, R2 is -NHR11 where R1 is hydrogen, C,-Cio alkyl, C1-Cio alkyl interrupted by 1 to 3 hetero atoms, -COR'2 where R'2 is hydrogen, C]-C]o-aIkyl or C1-Cjo-alkyl interrupted by 1 to 3 hetero atoms, or R1 is -C(=NH)R'1 -SOR'1 or -SOjR1 where R1 is C]-Cio-alkyi or C1-C]o-alkyl interrupted by 1 to 3 hetero atoms, R' is hydrogen, R'° is -OR'2 where R'1 is hydrogen, C1-Q-alkyl or C]-C4-alkoxy-C]-C4 alkyl, p and q are each 1 and r is zero. Preferred groups Ar among such groups include those of formula i13 XV especially those where R'1 is hydrogen, C]-C4-alkyl, -COR'5 where R2 is hydrogen or Ci-C5-alkyl, or R2 is -SOjR1' where R1' is CrC4-alkyl. Especially preferred groups Ar are those of formulae EI, IV, V, XII and XV as hereinbefore defined. The group R' in formula I may be, for example, hydrogen, hydroxy or Ci-Q-alkoxy such as methoxy, ethoxy, isopropoxy, n-butoxy or tert-butoxy, Preferably, R' is hydroxy. When R' is hydroxy or alkoxy, the carbon atom in formula I marked with an asterisk 5 preferably has the R configuration. The groups R1 and R1 in formula I may be, for example, each independently hydrogen or Ci-C4-alkyl, e.g. methyl or ethyl. In most of the preferred embodiments of the invention, R1 is hydrogen and R1 is hydrogen or methyl. The groups R\ R1 R5 and R1 in formula I may be, for example, each independently hydrogen, chlorine, fluorine, chloiomethyl, trifluoromethyl, hydroxy, CrCio-alkoxy, Ci-Cio-alkyl, Ci-C]o-alkyl interrupted by one or more oxygen or sulfur atoms or one or more NH, SO or SO; groups, C2-C4-alkenyl, trimethylsilyl, triethylsilyl, phenyl, carboxy, CrC,-alkoxycarbonyl, -C0NR2R'1 (where R2 and R'1 are each independently hydrogen or Ci-C1-alkyl), or R25 and R1, R1 and R1 or R5 and R1, together with the carbon atoms to which they are attached, may denote a 5- or 6- membered carbocyclic ring, which is preferably a cycloaliphatic ring which is preferably saturated, or a 5- or 6- membered O- heterocyclic ring containing one or two oxygen atoms. Preferably, R1, R1, R5 and R1 are each hydrogen or are such that the benzene ring to which they are attached is symmetrically substituted, i.e. either (a) R5 and R' are identical and R5 and R1 arc identical or together denote a symmetrical ring, or (b) R1 and R1 together and R5 and R' together denote identical rings. More preferably, R1and R1are identical and are each hydrogen, C]-C4-alkyl or C1-C4-alkoxy, and either R1 and R5 are identical and are each hydrogen, Cj-C4-alkyl, Ci-C4-alkoxy or Ci-C4-aIkoxy-Ci-C4-alkyI, or R' and R1 together denote -(CHj),- or -0(CH2),0- where s is 3 or 4 and t is 1 or 2. Especially preferred compoimds of the invention include compounds of formula I in which Ar is a group of formula IH, IV, V, XH or XV, R' is hydroxy, R1 and R1 are hydrogen, and R5 and R' are identical and arc each hydrogen, C1-C4-alkyl or Ci-CU-alkoxy, and either R1 and R5 are identical and are each hydrogen, Ci-Q-alkyl, Cj-Q-alkoxy or Ci-C4-alkoxy-Ci-C4-alkyl, or R5 and R together denote -(CH2)4- or -0{CH2)20-, in free or salt or solvate form. In such compounds, the carbon atom in formula I marked with an asterisk 5 preferably has the R configuration. Specific especially preferred compounds are those described in the Examples hereinafter. The compounds of formula (I) are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric actd phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, p-chlorobenzoic acid, diphenylacetic acid, triphenylacetic acid, l-hydroxynaphthaiene-2-carboxylic acid, 3-hydroxynaphthalene-2-carbo3cyIic acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxyhc acids such as fumaric acid, maleic acid or succinic acid, and sulfonic acids such as mcthanesulfonic acid or benzenesulfonic acid. These salts may be prepared from compounds of formula I by known salt-forming procedures. Suitable solvates are pharmaceutically acceptable solvates, preferably hydrates. The present invention also provides a process for the preparation of compounds of formula I in free oc salt or solvate form. They can be prepared by a process comprising: (a) for the preparation of a compound where R' is hydroxy, either (i) reacting a compound of formula /Ar' CH CH R2 XVI with a compound of formula where Ar is Ar as hereinbefore defined or a protected form thereof, R, R, R2, R, R, R and n are as hereinbefore defined and R is hydrogen, or an amine-protective group, or (ii) reducing a compound of formula where Ar', R R\ R1, R\ R and R' are as hereinbefore defined, to convert the indicated keto oup into -CH(OH)-; or (b) for the preparation of a compound where R' is hydrogen, reducing a corresponding compound of formula I where R is hydroxy; or {c) for the preparation of a compound of formula I where R is alkoxy, either (i) O-alkylating a corresponding compound of formula I where R' is hydroxy or (li) reacting a corresponding compound having a leaving moiety instead of R' with an alcohol of formula R'H where R' is alkoxy; and, optionally, converting a resultant compound of formula I in protected form into a corresponding compoimd in unprotected form; and recovering the resultant compoimd of formula I in free or salt or solvate form. Process variant (a)(i) may be carried out using known procedures for epoxide-amine reactions. It is conveniently carried out without a solvent or in an inert solvent, for example a hydrocarbon such as toluene or an alcohol such as n-butanol. The reaction temperature is conveniendy from 25°C to 200"C, preferably from 80°C to 150°C. The temperature may be achieved by conventional heating or by microwave irradiation. Process variant (a)(ii) may be carried out using conventional methods, for example by reaction with sodium borohydride under conventional conditions. Process variant {b} may be carried out using known procedures for reduction of secondary alcohols to hydrocarbons. Process variant (c)(i) may be carried out using known procedures for O-alkylation, for example by reaction with an alkylating agent such as an alkyl halide under known conditions. Process variant (c)(ii) may be effected using known procedures for benzylic displacement reactions, the leaving moiety being e.g. tosylate, mesylate, halogen or hydroxy. Compounds of formula I in free form may be converted into salt or solvate forms, and vice versa, in a conventional manner. Compounds of the invention can be recovered from the reaction mixture and purified in a conventional manner. Isomers, such as enantiomers, may be obtained in a conventional manner, e.g. by fractional crystallization or asymmetric synthesis from corresponding asymmetrically substituted, e.g. optically active, starting materials. Compounds of formula XVI are known compounds or can be prepared by processes analogous to those used for the preparation of the known compounds, for example the procedures described in Journal of Medicinal Chemistry 1987, 30, 1S63-1566. Compounds of foimula XVI in which the carbon atom indicated by the asterisk 1 is chiral may be prepared from a compound of formula 1 Ar1 CH CH L XIX OH R2 where Ar and R are as hereinbefore defined and L is a leaving atom or group, as described in"WO95A25104. where Ar' and R are as hereinbefore defined, using conventional procedures, such as those used in the Examples hereinafter. Compounds of formula XX are known or may be prepared by methods analogous to those used for the preparation of known compounds, for example those used in the Examples hereinafter. Compoimds of formula XVII are known or may be prepared by methods analogous to those used for the preparation of the known compounds. R as an aminc-protective group in formula XVH may be a known such group, for example as described in Protective Groups in Organic Synthesis, T.W.Greene, P.G.M. Wuts, John Wiley & Sons Inc, Second Edition, 1991, preferably benzy! or trifluoroacetyl. For example, compounds of fotmula XVH, where R is hydrogen, may be prepared by reducing an oxime of formula .4 where R1, R, R1, R' and n are as hereinbefore defined. The reduction may be carried out by conventional methods for reducing oximes to amines. For example, the reduction may be carried out by catalytic hydrogenation, preferably using palladium on charcoal as the catalyst. The hydrogenation may be effected using known procedures, for example as described byRX). Sindclar etal, J. Med. Chem. (1982), 25(7), 858-864. Oximes of formula XXI may be prepared as described by Sindclar et al, op.cit., or by analogous procedures. Compoimds of formula XVII where R1 and R are hydrogen can be prepared by reacting a compound of formula where R1, R3, R2, R11 and n are as hereinbefore defined. The reaction may be carried out in the presence of a catalyst such as tris(triphenyIphosphine)rhodium chloride. The reaction temperature may be, for example, from 60 to HO'C. The reaction is conveniently carried out in an inert solvent, for example ethanol, when the reaction temperature is conveniently about the reflux temperature of the solvent. The reaction may be carried out using known procedures, for example as described in WO96/23760. Where R1 and R1 are trialkylsilyl, the reaction between riie compounds of formulae XXE and XXDI may be carried out in the presence of a metal carbonyl complex catalyst, for example using the procedure described by K.P.C. Vollhardt and R. Hillard, J.Am.Chem. Soc. 1977, 99(12), 4058, or an analogous procedure. Compounds of formula XXII may be prepared as described in WO96/23760 or by analogous procedures. Compounds of formula XXHI are known or may be prepared by known procedures. Compounds of formula XVH where R' is alkyl, particularly methyl, and n is 1 may be prepared by amination of the corresponding 2-alkyl-indan-l-one using ammonia and KsFeCNfi, e.g. by the procedure of Fornum and Carlson, Synthesis 1972, 191. Compounds of formula XVII as hereinbefore defined where R1, R1, R1 and R1 are such that the benzene ring to which they are attached is symmetrically substituted are novel, other than the compounds where R1, R1, R1, R' and R'11 are each hydrogen, where R1 and R' are methyl or methoxy when R1, R1 and R1" are each hydrogen, and where R11, R1 and R1° are hydrogen when R1 and R1 are each hydroxy, fluorine or chlorine. In particular, preferred intermediates of formula XVH are novel where (i) R1 and R1 are each hydrogen and R' and R1 are either each C2-C4-alkyl, Q-Q-alkoxy, Ci-Q-alkoxy-C-Q-alkyl or R1 and R"1 together denote -(CH:),- or -0(CH2)tO- where s is 1 to 4 and t is 1 or 2; or (ii) R1 and R1 are each Ci-Ct-alkyl or C2-C4-alkoxy and R1 and R1 are either each hydrogen, C]-C4-alkyl, Ci-C4-alkoxy and R1 and R1are either each hydrogen, Ci-C4-alkyl, Ci-C4-alkoxy, or Cj-Q-alkoxy-C,-C4-alkyl or R1 and R1 together denote -(CHa).- or -0(CH2),O- where s is 1 to 4 and t is 1 or 2. Compounds of formula XVni are novel compounds which may be prepared by reaction of a compound of formula Ar' CO Hal XXIV where Ar' is as hereinbefore defined and Hal is a halogen atom, preferably chlorine or bromine, with a compound of formula XVn as hereinbefore defined. The reaction may be carried out using conventional procedures, for example those described by Yoshizaki et al, J. Med. Chem (1976), 19(9), 1138-42. Where desired, the protection of any reactive group may be carried out at any appropriate stage in the above processes. The protecting group is suitably one used conventionally in the art and may be introduced and removed using conventional procedure. For example, when a hydroxy group in Ar' is protected by a benzyl group, the latter may be removed by catalytic hydrogenation in the presence of palladium on charcoal using conventional procedures, such as those used hereinafter in the Examples. Compounds of formula I in free, salt or solvate form are useful as pharmaceuticals. Accordingly the invention also provides a compound of formula I in free, salt or solvate form for use as a pharmaceutical. The compounds of formula I in free, salt or solvate form, hereinafter referred to alternatively as "agents of the invention", have good P2-adrenoreceptor agonist activity. The p2 agonist activity, onset of action and duration of action of the agents of the invention may be tested using the guinea pig tracheal stip in vitro assay according to the procedure of R.A. Coleman and A.T. Nials, J.Pharmacol. Methods (1989), 21(1), 71-86. The binding potency and selectivity for the p2-adrenoreceptor relative to the pl-adrenoreceptor can be measured by a classical filtration binding assay according to the procedure of Current Protocols in Pharmacology (S.J.Enna(editor-in-chief) et al, John Wiley & Son, Inc, 1998), or by cAMP determination in cells expressing p2- or pi-adrenoceptor, according to the procedure of B. January et al, British J. Pharmacol. 123: 701-711 (1998). The agents of the invention commonly have a rapid onset of action and have a prolonged stimulating action on the P2-adrcnoreceptor, compounds of the Examples hercinbclow having Ki (P2) values of the order of 0.1 to 1000 nM, having durations of action of the order of 1 to greater than 12 hours, and having binding sclectivites for the P2-adrenoreceptor relative to the pl-adrenoreceptor from 1.5 to 500. For example, the compounds of Examples 1,2,4,5, 6, 8 and 27 have p2 and pi binding potencies, measured by cAMP determination in cells expressing p2- and pi- adrenoreceptors, represented by EC50 values 02/pl) (in nM) of 0.92/9.52, 0.23/1.25, 6.07/14.5, 0.79/6.10, 0.3/3.60,0.57/8.46 and 0.012/0.5 respectively. The compounds of Examples 2,4,5,27 and 29 have T(50%) times (in minutes) of >400 at 71nM concentration, 82 at 100 nM, 444 at lOOnM, 222 at l.OnM and 279 at lOnM respectively in the guinea pig tracheal strip assay, where T(50%) is the time for inhibition of contraction to decay to 50% of its maximum value. Having regard to their ^2 agonist activity, the agents of the invention are suitable for use in the treatment of any condition which is prevented or alleviated by activation of the ^2-adrenoreceptor. In view of their loi^ acting selective p2 agonist activity, the agents of the invention are useful in the relaxation of bronchial smooth muscle and the relief of bronchoconstricdon. Relief of bronchoconstriction can be measured in models such as the in vivo plethysmt^aphy models of Chong et al, J. Pharmacol.Toxicol. Methods 1998, 39, 163-168, Hammelmann et al, Am. J. Rcspir. Crit. Care Med., 1997,156, 766-775 and analogous models. The agents of the invention are therefore useful in the treatment of obstructive or inflammatory airways diseases. In view of their long duration of action, it is possible to administer the agents of the invention once-a- or early-phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".) Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti¬inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy. Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary or airways disease (COPD or COAD), including chronic bronchitis, or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. Having regard to their p2 agonist activity, the agents of the invention are also useful in the treatment of a condition requiring relaxation of smooth muscle of the uterus or vascular system. They arc thus useful for the prevention or alleviation of premature labour pains in pre^ancy. They are also useful in the treatment of chronic and acute urticaria, psoriasis, allergic conjunctivitis, actinitis, hay fever, and mastocytosis. The agents of the invention are also useful as co-therapeutic agents for use in conjunction with anti-inflammatory or bronchodilatory drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such dru^. An agent of the invention may be mixed with the anti-inflammatory or bronchodilatory dri^ in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the anti-inflammatory or bronchodilatory drug. Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone, fluticasone or mometasone, and dopamine receptor agonists such as cabergoline, bromocriptine or ropinirole. Such bronchodilatory drugs include anticholiner^c or anlimuscarinic agents, in particular ipratropium bromide, oxitropium bromide and tiotropium bromide. Combinations of agents of the invention and steroids may be used, for example, in the treatment of COPD or, particularly, asthma. Combinations of agents of the invention and anticholinergic or anlimuscarinic agents or dopamine receptor agonists may be used, for example, in the treatment of asthma or, particularly, COPD. In accordance with the foregoing, the present invention also provides a method for the treatment of an obstructive or inflammatory airways disease which comprises administering to a subject, particularly a human subject, in need thereof a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore described. In another aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore described for use in the preparation of a medicament for the treatment of an obstructive or inflammatory airways disease. The agents of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; pacenterally, for example intravenously; topically to the skin, for example in the treatment of psoriasis; intranasally, for example in the treatment of hay fever; or, preferably, by inhalation, particularly in the treatment of obstructive ot inflammatory airways diseases. In a further aspect, the invention also provides a pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt ot solvate thereof, optionally together with a pharmaceutically acceptable diluent or carrier therefor. Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus oral dosage forms may include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches. Compositions for inhalation may comprise aerosol or other atomizablc formulations or dry powder formulations. The invention also includes (A) a compound of formula I as hereinbefore described in free form, or a phacmaceutically acceptable salt or solvate thereof, in inhalable form; (B) an inhalable medicament comprising such a compound in inhalable form together with a pharmaceutically acceptable carrier in inhalable form; (C) a pharmaceutical product comprising such a compound in inhalable form in association with an inhalation device; and {D) an inhalation device containing such a compound in inhalable form. Dosages employed in practising the invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, siutabie daily dosages for administration by inhalation are of the order of from 1 to 5000jlg. The invention is illustrated by the following Examples. Compounds used in the Examples are prepared as follows: Intermediate 1 - S,6-Diethyl-inden-2-ylamine hydrochloride Preparation 1 - 3-chloro-l-(3,4-diethvlphenvl)- 1-propanone 1,2-Diethylbenzene (10.9 g, 74.6 mmol) and ptopionyl chloride (9.7 g, 74.6 mmol) are added dropwise to AICI3 (22.3 g, 167.8 mmol) in nitromethane (75 mL) over 30 min. The reaction mixture is stirred at room temperature for 2 hours, after which 70 g of ice and 14 mL concentrated sulphuric acid are added. The aqueous phase is extracted with ether, and the combined organic phases extracted with 2N HCI and saturated aqueous NaCl. The organic phase is further treated with activated charcoal, magnesium sulphate, and filtered, and the solvent removed m vacuo. IH-NMR (CDCI3) ppm: 7.8 (IH, s, Ar); 7.7 (IH, d, Ar); 7.2 (IH, d, Ar); 3.9 (2H, t, CHj); 3.4 (2H, t, CH2); 2.8 (4H. q, CHiCHa); 1.2 (6H, m, CH3). Preparation 2 - 2.3-dihvdro-5.6-diethvl-lH-inden-l-one 3-chloro-l-(3,4-diethylphcnyl)- 1-propanonc (15.5 g) is dissolved in 66 mL concentrated sulphuric acid and heated to 90 °C for 4 hours. The reaction mixtxure is cooled, ice (70 g) is added, and the aqueous solution extracted twice with toluene. The organic layer is washed with sodiimi bicarbonate, saturated aqueous NaCl, and treated with activated charcoal and magnesium suphate. After filtration, the solvent is removed in vacuo. The product is purified by flash column chromatography (silica, hexane / ethylacetate 10:1), and further crystallised in hexane. IH-NMR (CDC13) ppm: 7,6 (IH, s, Ac); 7,3 (IH, d, Ar); 3.1 (2H, m, CHi); 2.7 (6H, m, CH2+CH:CH3); 1.2 (6H, m, CH3). Preparation 3 - 5,6-Diethyl- 3-oxime-lH-indene-1.2f3H)-dione 2,3-Dihydro-5,6-diethyl-lH-inden-l-one (5 g, 26 mmol) in methanol (75 mL) is brought to 40 "C, n-butyl nitrite (3.0 g, 28.6 mmol) is added dropwise, followed by the addition of concentrated HCl (1.25 mL). After 1 hour, the reaction is brought to room temperature and the precipitated product filtered off, washed with ice-cold methanol and dried. IH-NMR (d6-DMSO) ppm: 12.6 (IH, s, OH); 7.4 (IH, s, Ar); 7.3 (IH, d, Ar); 3.6 (2H, s, CH2); 2.6 (4H, m, CH2CH3); 1.1 (6H, m, CHj). Preparation 4 - 5.6-Diethvl-indan-2-vlamine hydrochloride 5,6-Diethyl- 3-oxime-lH-indene-l,2(3H)-dione (4.5 g) is added to a mixture of acetic acid (150 mL), and concentrated sulphuric add (4.5 mL). Pd/C 5% (1.5 g) is added, the reaction mixture degassed with nitrogen, and hydrogenated for 5 hours. The catalyst is then removed by filtration, the pH brought to pH 10 with 4M NaOH, and the solution extracted with chloroform. The organic phase is dried with magnesium sulphate, and the solvent removed in vacuo. The residue is redisolved in a minimum amount of ether, and HCl saturated ether added. The white precipitate is filtered and dried to yield the HCl salt of 5,6-diethyl-indan-2-ylanune, a compound of formula XVD where R^, R** and R'^ are H, R^ and R^ arc each CHsCHz-, R^" is hydrogen and n is 1. IH-NMR (d6-DMSO) ppm: 8.7 (3H, bd s, NH3); 7.3 (2H, s, Ar); 4.2 (IH, bd s, CH); 3.5 (2H, dd, CH2); 3.3 (2H, dd, CHi); 2.8 (4H, q, CH2CH3); 1.4 (6H, t, CH3). Other compounds of formula XVU are prepared by procedures analogous to those used for Intermediate 1 or starring from available compounds and using procedures analogous to Preparations 3 and 4. These compounds of formula XVn arc shown in the following table, R^ being hydrogen and n being 1 for all compounds. Intermediate R" R^ R* R^ 2 CH3CH2 H H CHaCHa 3 H -{CH2)4- H 4 H -0(CH2)20- H 5 H CH5(CH2)3 CH,{CH2)3 H 6 H CH3(CHl)2 CH3(CH2)2 H 7 H CH3O CH3O H Intermediate 2 : ES + MS m/e {MH+) : 204 Intermediate 3 : IH-NMR (d6-DMSO) ppm: 8.1 (3H, bd s, NH3); 6.9 (2H, s, Ar); 3.9 (IH, bd s, CH); 3.2 (2H, dd, CHi); 2.8 (2H, dd, CHi); 2.7 (4H, m, CHiAr); 1.7 (6H, t, CHi). Intermediate 4 : IH-NMR (d6-DMSO) ppm: 8.3 (3H,bds, NH3); 6.85 (2H, s, Ar); 4.2 (4H, s,2CH2); 3.1 (2H, dd, CH2); 2.85 (2H, dd, CH2). Intermediate 5 : IH-NMR (d6-DMSO) ppm: 6.9 (2H, s, Ar); 3.8 (IH, m, CH); 3.1 (2H, dd, CH2); 2.6 (2H, dd, CHI); 2.5 {4H, I, 2CH2); 1.65 (2H, bds, NH2); 1.55 (4H, m, 2CH2); 1.4 (4H, m, 2CH2); 0.95 (6H, t, 2CH3). Intermediate 6 : IH-NMR (d6-DMSO) ppm: 8.1 (3H, bd s, NH3); 7.0 (2H, s, Ar); 3.9 (IH, bd s, CH); 3.2 (2H, dd, CH2); 2.8 (2H, dd, CH2); 2.5 (4H, q, EtCHjAr); 1.6 (4H, q, CH2), 0.9 (6H, t, CH3). Intermediate 7 : IH-NMR (d6-DMSO) ppm: 8.3 (3H, bd s, NH3), 6.9 (2H, s, H-Ar), 3.9 (IH, bd m, CHN), 3.7 (6H, s, CH3O), 3.2 (2H, dd, CH;), 2.9 (2H, dd, CH2). Interffiediate 8 - 2-(TfifluoroacetylaminD)-5,6-bisfmethoxvmethvnindane According to the procedure of Magnus et.al (Tetrabed. Lett., 34, 23-26 (1993)) a solution of commercially available l,4-dimethoxy-2-butyne (1.32 g, 11.5 mmoI)in nitrogen-degassed ethanol is heated to 80°C with stirring under a nitrogen atmosphere. Tris(triphenylphosphine)rhodium chloride (64 mg, 0.07 mmol) and a solution of 2,2,2-trif]uoro-N-[l-(2-propynyl)-3-butynyl]-acetamide (470 mg, 2.32 mmol; prepared from hterature procedure: Romero, Arthur G.; Leiby, Jeffrey A PCX Int. Appl. WO 9623760) in nitrogen-degassed ethanol (2 ml) are added in portions over 2 hours. The mixture is stirred under nitrogen at 80°C for a further 3 hours. The solvent is removed imder vacuo and the residue is purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) 'H-NMR (CDCI3) ppm: 2.9 (2H, dd), 3.35 (2H, dd), 3.45 (6H, s), 4.57 (4H, s), 4.85 (IH, m), 6.4 (lH,brs), 7.30 (2H,s). Intermediate 9 - 2-Amino-5.6-bisfmethoxvmethvnindane A solution of potassium hydroxide (150 mg, 2.60 mmol) in water {0.5 ml) is added to a solution of 2-(trifluoroacetylamino)-5,6-bis(methoxymethyl)indane (240 mg, 0.75 mmol) in methanol (3 mL) and the mixture is heated at reflux for 2.5 hours. The solvent was removed in vacuo and the residue is partitioned hetwcen aqueous sodium hydroxide (10 mL) and ethyl acetate (20 mL). The organic extract is dried (MgS04) and the solvent is removed in vacuo to leave the product as a dark oil. 'H-NMR (CDCI3) ppm: 2.60 (2H, dd), 3.10 (2H, dd), 3.33 (6H, s), 3.75 (IH, m), 4.42 (4H, s),7.17(2H,s). Intermediate 10 - 8-Hydroxy-5-[(indan-2-ylam4no)-acetyI]-lH-quinoUn-2-one 5-(Chloroacetyl)-8-hydroxy-2(lH)-quinolinone (25 mg, 0.105 mmol) prepared from literature procedure (Yoshizaki, Shiro; Tanimura, Kaoru; Tamada, Shigeharu; Yabuuchi, Youichi; Nakagawa, Kazuyuki. J. Med. Chem. (1976), 19(9), 1138^2) is reacted neat with indan-2-ylamine (205 mg, 1.21 mmol) at 25 °C for 2 hours. The reaction mixture is purified by flash chromatography (silica, CH2CI2/ methanol 9:1). ES+ MS m/e 335 (MH+). Intermediate 11 This compound of formula XVm where Ar is a group of formula IH, R^', R^* and R^' are hydrogen, R^, R^ R^ and R' are hydrogen, and R^ and R* are each methoxy, is prepared by a procedure analogous to that used for preparation of Intermediate 10. ES+MS ni/e(MH*):395. Intermediate 12 - 8-Benzvloxv-3-mcthyl-S-oxiranvl-lH-qmnoUn-2-one 8-Hydroxy-3-methyHH-qiiinoKn-2-one is prepared according to the procedure of Wang et al (T.-C. Wang, Y.-L. Chen, K.-H. Lee, C.-C. Izeng Synthesis 1997, 87-90.). 'H-NMR (d4-CH30H) ppm: 2.14 (s, 3H), 6.84-6.89 (m, IH), 6.95-7.03 (m, 2H), 6.90 (s, IH), 7.71 (s, IH). 8-Benzyloxy-3-aiethyl:-l H-quinofinr2-one Benzyl bromide (1.28 mL) is added to a suspension of potassium carbonate (2.98 g) in a solution of 8-hydroxy-3-methyl-lH-quinoIin-2-onc (1.26 g) in acetone {36 mL) at room temperature. The reaction mixture is refluxed for 18 hours, filtered, evaporated and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane. 'H-NMR (CDCI3) ppm: 2.11 (s, 3H), 5.13 (s, 2H), 6.92-6.98 (m, IH), 7.02-7.08 (m, 2H), 7.29-7.40 (m, 5H), 7.57 (s, IH). 9.23 (s, IH). 8-Benzyloxy-5-bronio-3-inethyI-1 H-quinofin-2-one A solution of bromine (0.57 g) in acetic acid (2 mL) is added dropwisc to a solution of 8-benzyloxy-3-mcthyHH-quinolin-2-one (0.94g) and sodium acetate (0.96 g) in acetic acid (12 mL) at room temperature. The reaction mixture is stirred at room temperature for 3 hours, evaporated, the residue partitioned between water (5 mL) and ethyl acetate (5 mL), extracting a further 2x with ethyl acetate (5 mL). Combined oi^nic extracts are dried over magnesium sulphate and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane. 'H-NMR (CDCI3) ppm: 2.27 (s, 3H), 5.18 (s, 2H), 6.83 (d, IH), 7.39 (d, IH), 7.37-7.41 (m, SH), 7.91 (s, IH), 9.08 (s, IH). 8-Ben2yloxy-3-roctfiyl-5 -viiiyl-lH-quinolin-2-one Palladium terakis(triphenylphosphine) (30 mg) is added to a solution of 8-benzyloxy-5-bromo-3-methyl-lHKiuinohn-2-one (239 mg) and tributylvinyltin (203 pL) in toluene (7 mL) at room temperature. The reaction mixture is heated for 2 hours at 100 °C, cooled to room temperature, evaporated and the product purified by flash column chromatography on silica gel, eluting with 2% ethyl acetate in dichloromethane. 'H-NMR (CDCI3) ppm: 2.24 (s, 3H), 5.18 (s, 2H), 5.32-5.39 (m, IH), 5.61-5.68 (m, IH), 6.95 (d, :H), 7.09-7.20 (m, IH), 7.21-7.26 (m, 2H), 7.31-7.43 (m, 4H), 7.89 (s, IH), 9.20 (s, IH). S-Benzyloxy-S-mcthyl-S-oxiranyl-l H-quinoBn-2-one To 8-ben2yloxy-3-methyl-5-vinyl-lH-quinolin-2-one (300 mg) is added to a O.IM solution of dimethyldioxirane in acetone (12.4 mL), Aitec stirring at room temperature for 2 hours, the solvent is removed m vacuo to yield the product. 'H-NMR (CDCI3) ppm: 2.23 (s, 3H), 2.77-2.81 (m, IH), 3.18-3.23 (m, IH), 4.17-4.21 (m, IH), 5.18 (s, 2H), 6.91 (d, IH), 7.01 (d, IH), 7.93 (s, IH), 9.10 {s, IH). Jntermetjjate 13 - 8-Benzvloxv-5-B-(5f6-diethvl-indan-2-vlaminol-l-hv methyl-lH-quinohn-^-pne A solution of Intermediate 12 (65 mg) and 5,6-diethyl-indan-2-ylaminc (120 mg) in DMSO (1.5 mL) is heated for 18 hours at 90 °C. The solvent is removed in vacuo, and the product purified by flash chromatography on silica gel, eluting with 10% methanol in dichloromethane. "C-NMR (d4-CH30H) ppm: 15.96, 17.14,26.33, 36.77, 53.34, 59.82, 67.33, 71.73, 112.09.118.98,121.73,125.42,128.74,129.24,129.47,129.61,131.84. 134.56,137.52, 137.64, 142.29, 145.94, 164.02. Intermediate 14 - 8-Mcthoxymethoxv-6-methyl-5-oxiranyl-lH-quinolin-2-one 8-Hydroxy-6-niethyl-lH-qmno]in-2-one is prepared according to the procedure of Wang et al (T.-C. Wang, Y.-L. Chen, K.-H. Lee, C.-C. Izeng Synthesis 1997, 87-90.). 'H-NMR (d6-DMS0) ppm: 2.26 (s, 3H), 6.45 {d, IH), 6.79 (s, IH), 6.90 (s, IH), 7.78 (d, IH). S-Broino-8-hydroxy-6-niethyl-lH-qumolin-2-one A 45% solution of hydrobtomic acid in acetic acid (324 pL) is added dcopwise to a solution of 8-hydroxy-6-methyl-lH-quinoIin-2-one (316 mg) in dimethylsulphoxide (9 mL) at room temperature. The reaction mixture is allowed to stand for 18 hours at room temperature and the solvent removed in vacuo. 'H-NMR (d6-DMSO) ppm: 2.33 (s, 3H), 6.58 (d, IH), 6.92 (s, IH), 8.03 (d, IH), 10.44 (s, IB), 10.67 (s,br,lH). 5-Broino-8-meihoxymethoxy-6-m(rihyl-lH-qmnoBn-2-one Methoxymethyl chloride (410 \iL) was added to a suspension of potassium carbonate (1.24 g) in a solution of 5-bromo-8-hydroxy-6-methyl-lH-quinoUn-2H3ne (480 mg) in dimethylformamide (9 mL) at 0 °C. The reaction mixture is stirred for 18 hours at room temperature, filtered, the solvent removed in vacuo, and the product purified by flash column chromatography on sihca gel, eluting with 2% methanol in dichloiomethanc. ^^C-NMR (CDCI3) ppm: 23.42, 56.52, 95.07, 115.78, 116.19, 119.32, 123.30, 128.13, 132.14, 139.78, 141.78, 161.32. 8-Methoxyinethoxy-6-niethyl-5-vinyl-l H-quinoKn-2-one Bis-(triphcnylphosphine)palladium (H) chloride (98 mg) is added to a solution of 5-bromQ-8-methoxymethoxy-6-methyl-lH-quinolin-2-one (410 n^) and tributylvinyltin (603 \lL) in dimethylformamide (14 mL) at room temperature. The reaction mixture is heated for 24 hours at 90 "C, evaporated and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane. 'H-NMR (CDCI3) ppm: 2.19 (s, 3H). 3.41 (s, 3H), 5.18 (d, IH), 5.20 (s, 2H), 5.60 (d, IH), 6.52 (d, IH), 6.63-6.69 (m, IH), 6.96 (s, IH), 7.95 (d, IH), 9.78 (s, IH). 8-Methoxymethoxy-6-inethyl-5-oxiranyl-l H-quinoBn-2-one is obtained from 8-methoxymeth oxy-6-methyl-5-vinyl-lH-quinolin-2-one (186 mg) according to the last step of the procedure for Intermediate 12. 'H-NMR (CDCU) Ppm: 2.38 (s, 3H), 2.68-2.72 (m, IH), 3.19-3.23 (m, IH), 3.43 {s, 3H), 3.97-4.01 (m. IH), 5.21 (s, 2H), 6.60 (d, IH), 6.98 (s, IH), 8.22 (d, IH), 9.09 (s, IH). Intermediate 15, (R)-2-(4-benzyloxy-3-nitrophenyl)-oxirane, is prepared according to the procedure of R. Hett et al, Tetrahedron Lett. (1997), 38(7), 1125-1128. Intermediate 16 - (5)-8-Benzylo}fy-5-oxiranvl-lH-quinolin-2-oqe 8-BenzyIoxy-5-{(S)-2-chloro-l -bydroxy-ethy])-1 H-quinoHii'2-one (S)-2-methyl-CBS-oxazaboroUdine, IM in toluene (0.30mL, 0.30mmol) is added to dry THF (tetrahydrofuran) (lOmL) in an oven dried flask. Borane-THF complex, IM in THF (3.05mL) is then added dropwise and the solution is stirred at room temperature for 15 minutes and then cooled to 0°C. 8-BenzyIoxy-5-chloroacetyl-lH-quinohn-2-one (l.OOg), prepared as described in WO95/25104, is then added in small portions over a period of 30 minutes. The reaction mixture is stirred at 0°C. The reaction is shown to be complete by TLC (thin layer chromatography) after 15 minutes. The reaction mixture is quenched with methanol (ImL), the solvent is removed m vacuo and the residue is partitioned between 0.2M H2SO4 (lOOmL) and CHCb (lOOmL). The organic layer is dried over MgSO,, filtered and the solvent is removed in vacuo. Crystallised from ethyl acetate. TLC (silica, dichloromethane / methanol 25:1 R^ = 0.30). {S)-8-Benzyloxy-5-oxiranyl-l H-quinoEn-2-one 8-Benzyloxy-5-((S)-2-chloro-l-hydroxy-etbyl)-lH-quinolin-2-one (0.55g) is dissolved in acetone (20mL). K2CO3 (0.58g) is added and the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 18 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (lOOmL) and water (lOOmL). The organic layer is dried over MgSO^, filtered and the solvent is removed in vacuo. The product is triturated with diethyl ether, filtered and dried. TLC (silica, dichloromethane / methanol 25;1 R^ = 0.45). Intermediate 17 - 6.7,8.9-Tctrahydro-.5i-L-Denzocycloftgpten-y-vlaminc Benz)'l-(6,7,8,9-tetrahydro-SH-bcnzocyclohepten-7-yl)-aimne 5,6,8,9-Tetrahydro-ben2ocycIohcpten-7-one (3.00g) and benzylamine (2.00g) are dissolved in ethane] (50mL). A catalytic amount of 10% palladium on charcoal is added and the reaction mixture is placed under an atmosphere of hydrogen. The reaction mixture is stirred at r.t. The reaction is shown to be complete by TLC after 24 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (siUca, n-hexane/ethyl acetate 1:2 R^= 0.50). 6,7,8,9-TetTahydro-5H-bcnzocycloliepten-7-ykmine Benzyl-(6,7,8,9-tetrahydro-5H-benzocycIohepten-7-yl)-aniine (2.80g) is dissolved in methanol (lOOmL) and the compound is deprotected by adding a catalytic amount of 10% palladium on charcoal and placing the solution under an atmosphere of hydrogen. The reaction is shown to be complete by TLC after 24 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, dichloromethane / methanol 25:1 R/ = 0.15). Intermediate 18 - Beqzyl-(5.6-dicthvl-indan-2-Yn-anune N-(5,6-Diethyl-indan-2-yl)-benzainide 5,6-Diethyl-mdan-2-ylaminc (4.10g) is dissolved in dichloromethane (DCM) (ISOmL) and triethylamine (2.4Ig) is added. Benzoyl chloride (3.20g) is then added dropwise and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 1 hour. The solution is washed with 0.2MHC1 (lOOmL), water (lOOmL) and brine (lOOmL). The organic layer is dried over MgS04, filtered and the solvent is removed in vacuo. Crystallised from ethyl acetate. TLC (siUca, dichloromethane / methanol 10:1 R/- s 0.85). Beiizylr(S ,6-diethyI-indan-2-yl)-ainine N-(5,6-Diethyl-indan-2-y])-bcnzamide (3.30g) is dissolved in dry THF (lOOmL). Lithium aluminium hydride, IM in THF (22.52ml) is then added dropwise. The reaction mixture is stirred at 50°C. The reaction is shown to be complete by TLC after 6 hours. The reaction mixture is allowed to cool, poured slowly into ice-water (200mL) and extracted with diethyl ether (2 x 150mL). The oi^nic layer is dried over M^OA, filtered and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane / ethyl acetate 2:1 R/= 0.20). Intermediate 19 - fRl-l-f3-Aniino-4-ben2vlQXv-phenvl)-2-fbenzvl-f5.6-diethvl-indan-2-vn-amiqo]-ethanol (R)-2-[Ben2yl-(S,6-diethyVmdan-2-yl)-ainino]-l-(4-benzyloxy-3-iiitro-phcnyl)-ethanol) The title compound is prepared from Intermediate 15 (3.01g) and Intermediate 18 (3.10g) by an analogous procedure to that used to prepare (S)'8-Benzyloxy-5-I2-(5,6-diethyl-indan-2-ylanuno)-l-hydroxy-ethyI]-lH-quinolin-2-onein Example 19. The reaction is shown to be complete by TLC after 24 hours. The product is purified by flash column chromatography (silica, n-hexane / ethyl acetate 4:1). TLC (silica, n-hexane / ethyl acetate 4:1 Rf= 0.25). (R)-l-(3-Aaiino-4-benzyloxy-phcnyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-ainino]-ethanoI {R)-2-[Benzyl-(5,6-diethyl-i ndan-2-yl)-amino] -1 -(4-benzyloxy-3 -nitro-phenyl)-ethanol (3.00g) is dissolved inTHF (50mL) and toluene (50mL). A catalytic amount of PtOi is added and the solution is stirred under an atmosphere of Hj. The reaction is shown to be complete by TLC after 6 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane / ethyl acetate 1:1 R/ = 0.75). Intermediate 20 - l-(3-Aniino-4-benzYloxy-phenyl)-2-[benzyl-(5T6-diethyl-indan-2-yl)-amino]-ethanone 2-[BeniyH S ,6-diethyl-mdanr2-yl)-aininol-l-(4-benzyloxy-3-mtro-phenyl)-ethafione l-(4-Ben2yloxy-3'nitro-phenyl)-2-bromo-ethanone (2.00g) (Prepared following procedure; Hett, Robert; Fang, Qun Kevin; Gao, Yun; Hong, Yaping; Butler, Hal T.; Nie, Xiaoyi; "^aldy Stephen A. Tetrahedron Lett. 1997, 38, 1125-1128.) is dissolved in methymethylketone (lOOmL). Triethylamine (0.64g) is added followed by benzyI-{5,6-diethyl-indan-2-yl)-amine (1.60g). The reaction mixture is then refluxed. The reaction is shown to be complete by TLC after 3 hours. The solvent is removed in vacuo and the product is purified by flash column chromato^aphy (silica, n-hexane / ethyl acetate 4:1). TLC (silica, n-hexane / ethyl acetate 2:1 R^ = 0.75). l-{3-AiiMno-4-benzyloxy-pheiiyl)-2-n»n2yl-(5,6-diethyI-indaii-2-yl)-aiiiino]-ethanoneis prepared from 2-[benzyi-{5,6-diethyl-indan-2-yl)-aniino]-l-(4-benzyloxy-3-mtro-phenyl)- 2,2,2-Trifluoro-.N.-(2-meth)']-l-oxo-indan-2->'l)-acetamide (3.41 g) in acetic acid {25 mL) and H2SO4 (0.5 mL) is stirred under hydrogen in the presence of 10% Pd/C at room temperature for 18 hours. The mixture is filtered throi^ celite and the filtrate is concentrated m vacuo. After diluting with water the mixture is extracted with diethyl ether. The organic phase is removed, washed several times with aqueous sodium bicarbonate and dried (NajS04). The solvent is removed to give an oil which soHdifies. 'H-NMR (CDCI3) ppm: 1.55 (s, 3H), 3.05 (d, 2H), 3.28 (d, 2H), 6.28 (br.s, IH), 7.12 {s, 4H). 2-Methyl-indan-2-ylainine A stirred solution of 2,2,2-trifluoro-.N.-{2-methyl-indan-2-yl)-acetamide (6.70 g) and NaOH (4,0 g} in methanol (100 mL) and water (1 mL) is heated at 70°C foe 2 hours. The solvent is removed and the residue is partitioned between aqueous HCl (100 mL, 2M) and ethyl acetate (100 mL). The aqueous extract is separated, basified with aq. NaOH, and extracted with ethyl acetate. The organic phase is separated, dried (MgS04), and the solvent is removed to give an orange oil which solidifies. 'H-NMR (CDCU) ppm: 1.19 (s, 3H), 1.5 (br.s, 2H), 2.65 (d, 2H), 2.79 (d, 2H), 6.97 (m, +H}. nterfnediate 24 - 2-Methvl-2.3.5,6,7.8-hexahydro-lH-cvclopenta[b)naphthaleii[-2-vlamine I -(5,6,7,8-Tetrahydro-naphthalen-2-yl)-propan-1 -one *ropionyl chloride 17.5 mL) and 1,2,3,3-tetrahydronapthalene (27.5 mL) ate added slowly iver 1 hour to a stirred solution of AlCla (61.3 g) in nitromethane (200 mL) at 0°C. After tirring at room temperature for 18 hours the reaction is cautiously added to a mixture of :c and concentrated HCl. The product is extracted with ethyl acetate, washed with brine nd dried (NajSO*). 'H-NMR (CDCI3) ppm: 1.15 (t, 3H), 1.72 (m, 4H), 2.72 (m, 4H), 2.88 (q, 2H), 7.04 (d, H), 7.60 (m. IH), -Mcthyl-2,3,5,6,7,8-hexahydro- ccordingto the procedure of Bhattacharya e(.j/(Sy?. Commun 1996., 26, 1775-1784.) a lixture of l-(5,6,7,8-tetrahydro-naphthalcn-2-yl)-propan-l-one (37.6 g), examethylenetetramine (44.9 g) and acetic anhydride (38.8 mL) is heated with stirring at for 23 hours. The mixture is allowed to cool, and added slowly to a stirred mixture F ethyl acetate (200 mL) and aqueous sodium hydroxide (200 mL, 2M). The layer is separated, washed with aqueous HCl, brine, and dried (Na2S04). The solvent is removed to give a brown oil. This is added cautiously to concentrated sulfuric acid (120 mL) and the resulting mixture is heated at 55°C for 5 hours followed by room temperature for 18 hours. The reaction is diluted with water and extracted with dichloromethane. After drying (NazSO^) the solvent is removed to give an oil. The product is purified by chromatography (sihca, ethyl acetate / hexane) to give a geometrical mixture of isomers containing 2-Methyl-l,2,6,7,8,9-hexahydro-cyclopenta[.a.]naphthalen-3-one and the title compound. 'H-NMR (CDCli) ppm (mixtuie): 1.4 (m, 3H), 1.9 (m, 4H), 2.5-3.0 (m, 6H), 3.35 (m, IH), 7.15 (m, IH), 7.55 (m, IH). 2,2,2-Trifluoro-N-(2-methyl-l-oxo-2,3,5,6,7,8-hexahydro-l H-cyclopenta[b]naphthalen-2-yl)-acetaiiiide This compound is prepared from an isomeric mixture, containing 2-methyl-2,3,5,6,7,8-hexahydro-cyclopenta[b]naphthalen-l-one, according to the procedure used for the preparation of 2,2,2-trifluoro-.N.-(2-methyl-l-oxo-indan-2-yl)-acetamide. The isomeric mixture of products is recrystalhsed from ethyl acetate/hexane to give a 4:1 mixture in favour of the title compound. 'H-NMR (CDCI3) ppm (major component): 1.55(s, 3H), 1.85 (m, 4H), 2.87 (m, 4H), 6.88 (br.s, IH), 7.18 (s, IH), 7.57 (s, IH). TOFMSES" m/e 310 (M-H) 2-Meihyl-2,3,S,6,7,8-hexaliydro-lH-cyclopenia[b]naphthaleii-2-ylaniine A 4:1 mixture of geometrical isomers, containing predominantly 2,2,2-trifluoro-.N.-(2-methyl-l-oxo-2,3,5,6,7,8-hexahydro-lH-cyclopenta[b]naphthalen-2-yl)-acetamide, is hydrogenated over Pd/C in acetic acid/H2S04 and the products are saponified with NaOH according to the procedures described for the preparation of 2-methyl-indan-2-ylaimne. The resulting product mixture is recrystalhsed repeatedly from hexane to give the title compound, a single isomer. 'H-NMR (CDCI3) ppm: 1.40 (s, 3H), 1.6 {br.s, NHj), 1.75 (m, 4H), 3.75 (m, 4H), 2.78 (d, 2H), 2.94 (d, 2H), 6.93 (s, 2H). Intermediate 25 - 2-Ethyl-indan-2-ylamine 2-Ethyl-indaii-l-one is prepared from benzene following analogous procedures to those used for 2-methyl-2,3,5,6,7,8-hcxahydro-cyclopenta[b]naphthalen-l-one. ^H-NMR (CDCI3) ppm: 0.97 {t, 3H), 1.50 (m. IH), 1.90 (m, IH), 2.55 (m, IH), 2.75 {dd, IH). 3.25 (q, IH), 7.29 (t, IH), 7.39 (d, IH), 7.50 (t, IH), 7.69 (d, IH). 2-Ethyl-indan-2-ylamine is prepared from 2-ethy]-indan-l-one by procedures analogous to those used for Intermediate 23, 'H-NMR (CDCI3) ppm: 1.05 (t, 3H), 1.5 (br.s, NHi), 2.70 (q. 2H), 2.75 (d, 2H), 3.01 (d,2H), 7.20 (m, 4H). Intermediate 26 - 2r5f6-Trimethyl-indan-2-vlamine 2,S,6-Trimethyl-indan-2-ykmine is prepared from 1,2-dimethylbenzene by procedures analogous to those used for 2-methyl-2,3,5,6,7,8-hexahydro-lH-cyclopenta|>]naphthaIen- 2-ylamine. 'H-NMR (CDCla) ppm: 1.29 (s, 3H), 2.16 (s, 6H), 2.69 (d, 2H), 2.84 (d, 2H), 2.89 (s, 2H). Intermediate 27 - Acetic acid (R)-l-(3-amino-4-benzyloxv-phenvl)-2-fben2vl-(2-methyl-in The title compound is prepared from (R)-2-(4-benzyloxy-3-nitro-phenyl)-oxirane (2.52g) and ben2yl-(2-methyl-indan-2-yi)-amine (2.20g) by an analogous procedure to that used to prepare (S)-8-Benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-lH-quinolin-2-one in Example 19. The reaction is shown to be complete by TLC after 24 hours. The product is purified by flash column chromatography (siUca, n-hexane / ethyl acetate 4:1). TLC (sihca, n-hexane / ethyl acetate 4:1 Rf = 0.30). iH NMR [CDCI3, 400MHz] d 1.20 (3H, s), 2.65 {IH. m), 2.75 (IH, m), 2.90 (2H, m), 3.25 (2H, m). 3.60 {IH, d), 3.70 (IH, broad), 3.80 (IH, d of d), 4.10 (IH, d), 5.20 (2H, s), 7.00 (IH, d), 7,20 (4H, m), 7,35 (IIH, m). 7.60 (IH. d). Acetic add (RV2-ibenzyM2-incthyl-indaiv-2-yl)-ainiiiol-l-(4-baKyloxy-3-mtra-phenyl)-ethyl ester (R)-2-IBenzyl-(2-methyl-indan-2-yl)-ainino]-l-{4-benzyloxy-3-nitro-phenyl)-ethanol (2.75g) is dissolved in pyridine (15niL). Acetic anhydride {1.66g) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 18 hours. Water (lOmL) is added to quench the reaction. Ethyl acetate(250niL) is added and the solution is washed with IMKHSO4 (3 x 1 OOmL), saturated NaHCOi (lOOmL), water (lOOmL) and brine (lOOmL). The organic layer is dried over MgS04, filtered and the solvent is removed m vacuo. The product is not purified further. TLC (silica, n-hexane / ethyl acetate4:lR,-=0.40). IHNMR [CDCI3, 4OOMH2] d 1.20 (3H, s), 1.90 (3H, s), 2.80 (3H, m), 3.00 (IH, d), 3.10 (IH, m), 3.20 (IH, d), 3.75 (IH, d), 3.90 (IH, d), 5.20 (2H, s), 5.25 (IH, m), 6.95 {IH, d), 7.10 (4H. m), 7.30 (IIH, m), 7.55 (IH, d). Acetic add {R)-l-(3-aiiiino-4-ben2yloxy-phcnyI)-2-[beiizyl-(2-inethyI-indan-2-yl)-ainino]-ethyl ester The title compound is prepared from acetic acid (R)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-l-{4-benzyloxy-3-nitro-phenyl)-ethyI ester (2.90g) by an analogous procedure to that used to prepare {R)-l-(3-amino-4-bcnzyloxy-phenyl)-2-[benzyI-{5,6-diethyl-indan-2-yl)-arnino]-ethanol in Example 19. The reaction is shown to be complete by TLC after 6 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane / ethyl acetate 2:1 Rf = 0.60). ^H NMR [CDCI3 , 400MHz] d 1.10 (3H, s), 1.80 (3H, s), 2.70 (3H, m), 3.05 (2H, m), 3.15 (IH, d), 3.65 (2H, broad), 3.75 (IH, d), 3.90 (IH, d), 4.95 (2H, s), 5.20 (IH, m), 6.40 (2H, m), 6.65 (IH, d), 7.20 (14H, m). Intermediate 28 - Benzyl-(2.5.6-trimethyl-indan-2-vl)-amine N-(2,5,6-TriiiiethyI-indan-2-yl)-benzamde Intermediate 26 is treated with benzoyl chloride in dichloromethane / triethylamine for 1 hour. The mixture is washed with IN HCI, then with saturated NaHCOs solution, dried (Na2S04) and evaporated. The residue is triturated with ether / hexane to give white crystals. 'H-NMR (CDCI3) ppm: 1.60 (s, 3H), 2.18 {s, 6H), 3.02 (d, 2H), 3.30 (d, 2H), 6.17 (br.s, NH), 6.90 {s, 2H), 7.34 {m, 2H), 7.40 (m, IH). 7.63 (d, IH). Benzyl-(2,5,6-triinethyl-indaii-2-yI)-aiiBne To a solution of N-(2,5,6-trimethyl-indan-2-yl)-benzamide in THF under nitrogen is added LiAlH4 and the mixture refluxed for 48 hours. Quenched at O^C with ice / water and extracted with ether, dried (Na2S04) and solvent removed in vacuo. Purification by chromatography (sihca, ethyl acetate / hexane 1:4) gives a colourless oil. "■H-NMR (CDCI3) ppm: 1.58 (s, 3H), 1.79 (br.s., NH), 2.40 (s, 6H), 3.00 (d, 2H), 3.20 (d, 2H), 3.99 (s, 2H), 7.15 (s, 2H1, 7.37 - 7.53 (m, 5H). Intermediate 29 - Acetic acid (R)-l-f 3-ami^o-4-benzyloxv-phenvll-2-fbe^^vl-(2.5f6-t^imethy^~indan-2-yl)-am^^o]-ethyl ester (R)-1 -(4-Benzyloxy-3-nitro-phenyl)-2-[benEyl-(2,5,6-triinethyl-indan-2-yl)-aniino]-ethanol A mixture of 2-{4-methyl-3-nitro-phenyl)-oxirane and bcnzyI-(2,5,6-trimethyl-indan-2-yl}-amine is heated at llO'^C for 48 hours. The material is used without further purification. ES*MSm/c538(MH*) Acetic add (R)-l-(4-bcnzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trunethyl-indan-2-yl)-anunol-etbyl ester To a solution of (R)-l-(4-Benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yI}-aminoj-ethanol in pyridine is added acetic anhydride and the mixture stirred for 18 hours. The reaction mixture is quenched with water and after addition of ethyl acetate washed twice with aqueous KHSO4 solution, twice with aqueous NaHCOi and once with brine. The product is purified by chromatoghaphy (silica, ethyl acetate / hexane 1:4). ES* MS m/e 579 (MH') Acetic acid (R)-l-(3-anano-4-benzyloxy-phenyl)-2-[bciHyl-(2,S,6-triinethyl-indan-2-yl)- aorinol-ethyl ester Acetic acid (R)-l-(4-benzyloxy-3-nitro-phenyl)'2-[benzyl-(2,5,6-trimethyl-indan-2-yI)-amino]-cthyl ester in a mixture of THF and toluene is stirred under hydrogen in the presence of PtOa at room temperature for 15 hours. The mixture is filtered through celitc and the filtrate is concentrated in vacuo. ES* MS m/e 549 (MH*) Intermediate 30 - 5.6-Dicthvl-2-methvl-indan-2-ylamine N-(5-Acetyl-2-niethyl-indan-2-yl)-benzaiiide Aluminium chloride (3.7g) is dissolved in nitromethane (12ml) under nitrogen followed by N-(2-methyl-indan-2-yl)-benzaniide (3.0g) at O'C. Acetyl chloride (0.85ml) is added dropwise over 30 minutes. After 4 hours at room temperature the mixture is quenched with ice and concentrated HCI, extracted with DCM. The organic layers are washed with dilute HCl and brine. Evaporation of the solvent yielded the desired product. ES* MS m/e 294 (MH*) N-{S-Ethyl-2-meihyl-indaii-2-yl)-benzamide A solution of N-(S-acetyl-2-methyl-indan-2-yl)-benzamide (3.4g) in ethanol (200ml) and cone. HCl (2ml) is stirred under hydrogen in the presence of 10% Pd/C at room temperature for 48 hours. The mixture is filtered through celite and the fihrate is concentrated in vacuo to give the title compound. 'H-NMR (CDClj) ppm: 1.20 (t, 3H), 1.60 (s, 3H), 2.55 (q, 2H), 3.05 (d, 2H), 3.35 (d, 2H), 6.35 (br.s, NH), 6.90-7.10 {m, 3H}, 7.39 (d, 2H), 7.65 (s, 2H) N-(5-Acetyl-6-ethyl-2-nicthyl-indail-2-yl)-beiizanidc is prepared from N'{5-ethyI-2-methyl-indan-2-yl)-benzaniide (2.6g) following the procedure used to prepare N-(5-acetyl-2-methyl-indan-2-yI)-ben2amide. The product is purified by chromatography {silica, hexane / ethyl acetate, 4:1) to ^ve the tide compound. ES* MS m/e 322 (MH*) N-(5,6-Diethyl-2-methylrindan-2-yl)-benzanMde is prepared from N-(5-acetyl-6-ethyl-2-methyI-indan-2-yI)-benzaniide (l.lg) following the procedure used to prepare N-(5-ethyI-2-methyl-indan-2-yl)-benzamide. ES* MS m/e 308 (MH*) Benzyl-(S,6-diethyl-2-niethyl-indan-2-yl)-aniine is prepared from N-(5,6-diethyl-2-methyl-indan-2-yl)-benzamide by an analogous procedure to that used to prepare benzyl-(5,6-diethyl-indan-2-yl)-amine in Intermediate 18. ES* MS m/e 294 (MH*) 5,6-Diethyl-2-iiiethyl-indan'2-ylamine A solution of benzyi-(5,6-diethyl-2-methyl-indan-2-yl)-amine (0.48g) in methanol (10ml) is stirred under an atmosphere of hydrogen in the presence of 10% Pd/C at room temperature for 18 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo to give the title compound. ES* MS m/e 204 (MH*) Example 1 (R)-8-Ben2yU)xy-5-[2-(4,7-Kliiiiethoxy-mdan-2-ylamino)-l-hydroxy-ethyl]-lH-^uinoKn-2-onc (R)-8-Benzyloxy-5HDxiranylcarbostycil (lOOn^, 0.34mmol), prepared from literature procedure (Beeley, Lee James; Dean, David Kenneth, PCT Int. Appl. WO 9525104) and 4,7-dimethoxy-indan-2-ylamine (66mg, 0.34nimol), prepared from literature procedure (Sindelar, R. D.; Mott, J.; Barfknccht, C. p.; Arneric, S. P.; Flynn, J. R.j Long, J. P.; Bhatnagar, R. K. J. Med. Chem. (1982), 25(7), 858-64), are dissolved in toluene (ImL). The reaction mixture was heated to 110°C and the solvent is allowed to evaporate. The residue is then stirred at 110°C for 4 hours. The reaction is shown to be complete by TLC. The product is purified by flash column chromatography (siUca, dichloromethane / methanol 20:1). TLC {sihca, dichloromethane/methanol 25:1 Rf= 0.10). ES+ MS m/e 487 (MH*). (R>-8-hy droxy 5 -[2^47-IMiiiethoxy-indan-2-ylanimo)-l-hydroxy-ediy 1]-1 H-quinoHn-2-one hydrochloride (R)-8-Benzyloxy-5-[2-{4,7-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-1 H-quinoIin-2-one (37n^, O.OSmmol) is dissolved in methanol (lOmL) and the compound is deprotected by adding a catalytic amount of 10% palladium on charcoal and placing the solution under an atmosphere of hydrogen. The reaction is shown to be complete by TLC after 4 hours. The catalyst is filtered off, IM HCl/diethyl ether (1.1 equivalent) is added and the solvent is removed m vacuo. TLC (sihca, dichloromethane / methanol 10:1 R^ s 0.15). ES+ MS m/e 397 (MH*). Other compounds of formula I are prepared from (R)-8-benzyloxy-5-oxiranylcarbostyril ((R)-2-{4-benzyIoxy-3-nitrophenyl)-oxirane (Intermediate 15) in Example 11) and the appropriate compound of formula XVII by procedures analogous to Example 1. These compounds, in which R* is OH, R^ and R^ arc H, Ar is a group of formula IH in which R^, R'° and R^' are H (except in Example 11, where Ar is a group of formula XV in which R^^ is H) and n is 1 (except in Example 9 where n is 2) are shown in the following table. 11 H CH3CH2 CH3CH3 H 341 Example 10: 'H-NMR (d4-MeOH) ppm: 2.78 (2H, m), 2.9 (2H, m), 3.15 (2H, m), 3.28 (6H, s), 3.7 (IH, m), 4.55 (IH, br s), 5.15 (IH, m), 6.58 (IH, d), 6.9 (IH, d), 7.11 (2H, s), 7.15 (lH,s),8.25(lH,s). Example 12 8-Hydroxy-5-[l-hydroxy-2-(indan-2-ylaiiBno )-etfayI]-l H-quinolin-2-one Intermediate 10 {18 mg, 0.054 mmol) is dissolved in methanol (2 mL) and cooled on ice. Sodium borohydride (6 mg, 0.12 mmol) is added over 2 hours. Concentrated HCi is then added until pH reaches 1, and the reaction mixture filtered. The filtrate is washed with methanol. The combined liquid phases are evaporated and redisolved in methanol twice. After removal of the methanol in vacuo, the residue is redisolved in water and the pH brought to 12 wirh IN KOH. The solvent is removed in vacuo and the residue coevaporated twice with toluene. The residue is purified by flash chromatography (silica, CHiClj/methanol 8:2). ES+ MS m/e 337 (MH+). Example 13 5-[2-(5,6-Diiiiethoxy-indan-2-ylamino)-l -hydroxy-ethyI]-8-hydroxy-l H-quinolm-2-one This compound is prepared from Intermediate 11 by a procedure analogous to that of Example 12. ES+MS m/e 397 (MH*) Example 14 S-[2-(5,6-Diethyl-indaii-2-ykniino )-l-hydroxy-ethyfl-8-hydroxy-3-methyl-l H-quinoKii-2- one This is prepared from Intermediate 13 (21mg) by the hydrogenation procedure for removal of the benzyl group used in Example 1. 'H-NMR {d4-CH30H) ppm 1.11 (t, 6H), 2.11 (s, 3H), 2.58 (q, 4H), 3.01-3.37 {m, 6H), 4.10-4.16 (m, IH), 5.31-5.38 (m, IH), 6. 91 (d. IH), 7.00 {s. 2H), 7.21 (d, IH), 8.13 (s, IH). Example 15 S-[2-(5,6-Diethyl-indan-2-ykmino )-l -hydroxy-cthyI]-8-inethoxyinethoxy-6-niethyI-l H-quinolin-2-one This is obtained from Intermediate 14 (20 mg) and 5,6-diethyl-indan-2-ylamine (72 mg) according to the procedure used for preparation of Intermediate 13. ^H-NMR (CDCIj) ppm: 1.14 (t, 6H}, 2.30 (s, 3H), 2.51 (q, 4H), 2.64-3.16 (m, 6H), 3.41 (s, 3H), 3.60-3.68 (m, IH), 5.18-5.25 (m, 3H), 6.50 (d, IH), 7.89-7.94 (m, 3H), 8.68 (d, 2H), 9.15 (s, br, IH). 5 -[2-(5,6-Diethyl-indan-2-ylanano )-1 -hydroxy-ethyI]-8-hydroxy-6-iiiethyl-l H-quinolin-2-one 3N Hydrochloric acid (ImL) is added to a solution of 5-[2-(5,6-Diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-8-methoxymethoxy-6-methyl-lH-quinolin-2-one (12 mg) in isopropanol (ImL) and tetrahydrofuran (ImL) at room temperature and the reaction mixture heated for 18 hours at 40'C. The solvent is removed in vacuo, and the product purified by preparative scale HPLC on a C8 column, eluting with a water/acetonitrile/trifluoroacetic acid gradient. "C-NMR (d4-CH30H) ppm: 15.97,20.09,26.34, 36.87,51.75, 59.72, 67.33, 118.41, 119.12,121.21,125.45,126.11, 128.60,133.35,137.52,137.55,142.32,142.50,145.69, 163.24. Example 16 8-hydroxy-5-[2-(5,6-diethyl-indan-2-ylanMno )-l -hydroxy-ethyl]-3,4-dihydro-l H-quinoIiii-2-one Hydrogenation of a methanol/ethanol solution of 8-hydioxy-S-[2-(S,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-lH-quinolin-2-one (Example 2) with a 10% palladium on carbon catalyst at 30*'C for 48 hours under one atmosphere of hydrogen gives the title compound after filtration and evaporation. Further purification is achieved via preparative HPLC (column: Phenomenex Luna 10\un 150 mm x 50 mm, eluent: gradient from 10% to 95% acetonitrile in water containing 0.1% trifluoroacetic acid, UV detection at 254 nm). "C-NMR (d6-DMS0) ppm: 15.77, 21.42, 25,01, 30.37, 37.73, 37.83, 53.88, 58.68, 67.37, 113.28, 120.21, 122.08, 124.31, 124.34, 131.01, 138.46, 138.52, 139.58, 143.12, 169.44. Example 17 (a) Acetic add (R)-l-(4-bcnzyIoxy-3-forniylainino-phenyI)-2-[benzyl-(2,5,6-trimethyI-indan- 2-yl)-ainino]-ethyl ester To Intermediate 29 in toluene / THF is slowly added an aged mixture of formic acid and acetic anhydride and the reaction is stirred for 5 hours at room temperature. Ethyl acetate is added and washed with saturated NaHCOs solution. Purification by chromatography (silica, ethyl acetate / hcxane 1:2) and trituration with ether gave off-while crystals. ES* MS m/e 577 (MH*) (b) N- phenyl)-foniiaiiiide The product of Example 17(a) is suspended in ethanol and a catalyic amount of NaOCHj in methanol is added. After two hours at 70°C the solvent is removed and the residue purified by chromatography (sihca, ethyl acetate / hcxane 2:3) to give white crystals. ES* MS m/e 535 (MH*) (c)N-{2-Hydroxy-5-[(R)-l-hydroxy-2-(2,5,6-trimethyl-indan-2-ylanino)-ethyl]-phenyl}-formanide is prepared from the product of example 17(b) by a procedure analogous to that of Example 34(c). ES* MS m/e 355 (MH*) (a) 8-Bcn2ykinino-S-[(R)-2-(5,6-dieihyl-2-inethyl-indan-2-ylamino)-l-hydroxy-ethyl]-lH-quinolin-2-one A mixture of S,6-diethyl-2-methyl-iiidan-2-ylamine (0.28g) and 8-benzyloxy-5-oxitanyHH-quinolin-2-one {0.42g) in n-butanol (0,7nil) is placed in a Prolabo microwave oven for 75 minutes, at lOO^C. The product is purified by chromatography (silica, DCM / ethanol, 5:1) to give the desired product. ES* MS m/e 497 (MH*) 5-[(R)-2-(5,6-Diethylr2-methyl-indan-2-ylainino)-1 -hydroxy-ethyI|-8-hydroxy-l H-qiiinoKn-2-one A solution of the product of Example 18(a) (0.20g) in methanol (20ml) is stirred under an atmosphere of hydrogen in the presence of 10% Pd/C at room temperature for 2 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo. Trituration with diethyl ether gave the desired product. ES* MS m/c 407 (MH*) Example 19 (a) (S^8-Benzyk}xy-5-[2-(5,6^ctfay^indaI^2-ylaIIi^o)-l-hydroxy•«tfayII-lH■4]uinoHn-2-OIle is prepared from Intermediate 16 (152n^) and Intermediate 1 (lOOmg) using a procedure analogous to that of Example 1(a). TLC (silica, dichloromcthane / methanol 10:1 Rf = 0.25). (b) (S)-5-[2-(5,6-Diethyl-indian-2-ylamino)-l-hydroxy-ethyl] 8-hydroxylH-quinolin-2-one hydrochloride is prepared from the product of Example 19(a) by a procediuc analogous to that of Example 1(b). TLC (silica, dichloromcthane/methanol 10:1 Rf=O.OS). ExamDle20 (a) 8-Benzyloxy-5-[(RVl-faydroxy-2-(ti.7.8>9-tctiabydro-5H-benzocydohepten-7-yUniiiio)-ethyl]-lH-quuiofiii-2-one is prepared from (R)-8-benzy]oxy-5-oxiranylcarbostyril {203a^) and Intermediate 17 (llOmg) by a procedure analogous to that of Example 1(a). TLC (silica, dichloromcthane / methanol 10:1 R^ s 0.30). *>> 5-I(RH-Hydroxy-2-(6,7,8,9-tctrahydro-5H-benaocydobepten-7-ylaiEiiK>)-ethyll- a-hydroxy-lH-quinofin-2-onc faydrocliloride is prepared from the product of Example 20(a) by a procedure analogous to that of Example 1(b). TLC (silica, t^chloromcthane / medianol 10:1 Rf s 0.05). (a) (R)- 8-be^2yIoxy-5^{S)-2-(beIlzyH5,fr^KethyI-indan-2-yl^aIIMlo]-l-lIyd^oxy-ethyl}-lH- quioofin-2-one A solution of (R)-8-benzyloxy-5-oxiranylcarbostyriI (5.00^ and 2-amino-5,6-diethylindan (3.87g) in n-butanol is heated for 4 hours at llO'C. After cooljng to room temperature toluene (lOOml) is added and the organic phase is washed with water (3 X 25ml), loaded onto a silica gel chromatography colunm and eluted with toluene followed by a mixture of toluene: cthanol: ethyl acetaw; fnnr. amm/\nin /it.in.ici^»« ™..» ru- .i*-!- —— 1 (b) (R)-5-[2-(S,6-diethyl-in€lan-2-ylamino)-l-liydroxy- (a) N-(S^(R)-2-3en2y^-(S,6-dietltyI-indan-2-yl)-ami^oJ-l-hyd^oxy-ethyl}-2-ben2yloxy- pbenylHonnairidc is prepared from Intermediate 19 (l.OOg), formic acid {l55mg) and acetic anhydride (226mg) using a procedure analogous to that of Example 21(a). TLC {silica, n-hexane / ethyl acetate 2:1 R^ = 0.20). (b) N-{5-[(R)-2-(5,6-DictbyI-indan-2-ylamino)-l-hydroxy-ethyI]-2-hydroxy-phenyl}- formamide is prepared from the product of Example 22(a) by a procedure analt^ous to that of Example 1(b). TLC (silica, n-hexane / ethyl acetate 2:1 Rfs 0.05). Example 23 (a) (R)-2-[BeiizyH5.6-dictIvWiidaiK2-yI)-amiiM>]-l-(4-ben2yloxy-3-diiiiethyIain«no-pbc^ ethanol Intermediate 19 (0.37g) is dissolved in CH3OH (SOmL) and formaldehyde, 37% in water (SmL), dissolved in water (lOmL), is added. A catalytic amount of PtOa is added and the solution is stirred under an atmosphere of H2. The reaction is shown to be complete by TLC after 24 hours. The catalyst is filtered off, the solvent is removed in vacuo and the residue is partitioned between ethyl acetate (lOOmL) and water (lOOmL). The organic layer is dried over MgSO^, filtered and the solvent is removed m vacuo. The product is purified by flash column chromatography (sihca, n-hexane / ethyl acetate 4:1). TLC (silica, n-hexane / ethyl acetate2:lR^=0.65). (b) 4-[{R)-2-(5,6-Dicthyl-indan-2-ylaniinoJ-l-hydroxy-cihyl]-2-diiiiethylainino-phenol hydrochloride is prepared from the product of Example 23(a) by a procedure analogous to that of Example 1(b). ^H NMR [DMSO , 400MHzl 5 1.10(6H,t), 2.55 (4H, q), 3.05(2H,m), 3.10 {6H, s), 3.20 (4H, m), 4.00 (IH, m), 4.95 (IH, m), 7.00 (2H, s), 7.15 (IH, d), 7.35 (IH, d), 7.80 (IH, s), 9.20 (IH, broad), 9.75 (IH, broad), 11.40 (IH, broad). Example 24 {A) (Ry-2-lBenzyl-(5,6-diethyl-indan-2-yl>-aii]ino]-l-(4-benzyloxy-3-methyknBno-phcnyl)-ethanol The product of Example 22 (260mg) is dissolved jn dioxan (20niL). Sodium borohydride {90mg) is added followed by the dropwise addition of acetic anhydride (142mg). The reaction mixture is stirred at 90°C. The reaction is shown to be complete by TLC after 4 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (lOOmL) and water (lOOmL). The organic layer is dried over MgS04, filtered and the solvent is removed m vacuo. The product is purified by flash column chromatography (silica, n-hexane/ethyl acetate4:l). TLC (silica, n-hexane / ethyl acetate 2:1 R/-= 0.65). (b) 4-[(R}-2-{5,6-Diethyl-indan-2-ylaniino)-l-hydroxy-ethyl]-2-inethylaniino-phenol hydrochloride is prepared from the product of Example 24(a) by a procedure analogoios to that of Example 1(b). 1H NMR pMSO , 400MHz] 8 1.10(6H,t), 2J5 (4H, q). 2.85 (3H, s), 3.10 (6H, m), 4.00 (IH, m), 4.90 (IH, m), 7.00 (3H, m), 7.15 (IH, m), 7.40 (IH, m), 9.10 (IH, broad),.9.60 (IH, broad), 10.80 (IH, broad). Example 25 (a) N-(5-{[Benzyl-(S,6-diethylrindan-2-yl)-aiDino]-acetyll-2-benzyloxy-phenyl)- methanesutfonairide Intermediate 20 (240mg) is dissolved in dichloromethanc (lOmL). Triethylaminc (56mg) is added followed by methanesulfonyl chloride (58n:^). The reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 24 hours. The solvent is removed m vacuo and the product is purified by flash colimm chromatography (silica, n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane / ethyl acetate 2:1 R/^= 0.40). (b) N-(5-{2-[Benzyl-(5,6-diethyl-indan-2-yl)-ainino]-l-hydroxy-ethyl}-2-beiizyloxy-phenyl)- methanesulfonamide The product of Example 25(a) {120mg) is dissolved in ethanol (1 OmL). Sodium borohydride (9n^) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 3 hours. The reaction mixture is quenched with 2M HCl (ImL), the solvent is removed in vacuo and the residue is partitioned between ethyl acetate {50mL) and saturated NaHCOs {50mL). The organic layer is dried over MgS04, filtered and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hcxane / ethyl acetate 2:1 R/= 0.45). (c) N-{5-t2-(S,6-Diethyl-mdan-2-ylamino)-l-hydroxy-cthyI|-2-hydroxy-phenyl}- methanesulfonamide hydrochloride) is prepared from the product of Example 25(b) by a procedure analogous to that of Example 1 (b). iH NMR [CDCI3 , 4OOMH2] S 1.15(6H,t), 2.55 (4H, q) 2.95 t3H,s), 3.10 (6H,m), 4.00 (IH, m), 4.85 (IH, m), 6.10 (IH, broad), 6.90 (2H, d), 7.00 (2H, s), 7.10 (IH, d of d), 7.25 (IH, d),8.75 (IH, s), 8,95 (IH, broad), 9.25 (IH, broad), 10.00 (IH, s). Example 26 (a) (R)-8-Benzyloxy-5-{(S)-2-[beiizyl-(4,5,6,7-tetranicthyl-iiidan-2-yl)-aniino]-l-hydroxy- ethylJ-lH-qumolin-2-one (R)-8-Ben2yloxy-5-oxiranylcarbostyriI (204 mg) and Intermediate 21 (194 mg) are dissolved in n-butanol (0.5ml) under nitiogen. The reaction mixture is heated at 110°C for 22 hours. On cooUng the solvent is removed in vacuo. The product is purified by flash column chromatography (silica, ethyl acetate/heaxane 50:50). ES* MS m/c 573 (MH*) (b) (R)-8-Hydroxy-5-[(S)-l-hydroxy-2-(4,5,6,7-tetraiiiethyl-indan-2-ylanimo>-ethyI|-lH- quuio]in-2*one is prepared from the product of Example 26(a) by a procedure analogous to that of Example 1(b). 'H NMR (CDaOD) ppm: 8.55 (IH, d); 7.5 (IH, d); 7.25 (IH, d); 6.9 (IH, d); 5.6 (IH, m)} 4.3 (IH, ra); 3.7 {2H, q); 3.6 (2H, dd); 3.3 (2H, dd); 2.4 (12H, s) Example 27 (a)8-Benzytoxy-S-[(R)-l-hydroxy-2-(2-melhyHndan-2-ylaiiino)-ethyl]-lH-qiiinolin-2-one. A mixture of 8-benzyloxy-5-(R)-oxiranyl-lH-quinolin-2-one (500 n^) and 2-methyl-indan-2-ylamine {276 mg) in n-butanol (1 mL) is subjected to microwave irradiation, using a Prolabo Synthewavc 402 instrument, for 90 minutes at ilO°C. The residue is absorbed on silica and the product is purified by flash chromatography (silica, chloroform/ethanol 4:1). 'H-NMR (CDCls) ppm: 1.30 (s, 3H), 2.65 (s, IH), 2.95 (dd, 2H), 3.07 (m, 3H), 5.15 (m, IH), 5.18 (s, 2H), 6.66 (d, IH), 7.17 (m, 4H), 7.26 (d, IH), 7.45 (m, 5H), 8.07 (d, IH), 8.8-9.5 (br.d, IH) (b) 8-Hydroxy-S-[(R)-l-hydroxy-2-(2-inethyI-indan-2-ylaiiiino)-etIiyl]-lH-qiiinoHn-2-onc The product of Example 27(a) (100 mg, 0.22 mmol) is dissolved in methanol (20 mL) and is deprotected by adding a catalytic amount of 10% palladium on charcoal and stirring imder an atmosphere of hydrogen for 1 hour. The catalyst is removed and the solvent is evaporated to give a yellow solid. ^H-NMR (d4-CH30H) ppm: 1.20 (s, 3H), 2.75 (m, 4H), 2.95 (d, 2H), 5.03 (m, IH), 6.60 (d, IH), 6.82 (d, IH), 7.0 (m, 4H), 7.08 (d, IH), 8.20 (d, IH). Example 28 5-i;2-(5,6-Diethyl-indaii-2-ylanino)-ethyl]-8-hydroxy-lH-qmnolin-2-one This compound is prepared from the product of Example 2 according to the procedure of Temple et ai, J. Med. Chem., 19, 626-633 (1976). 'H-NMR (d4-CH30H) ppm: 1.08 (t, 3H), 2.55 (q, 4H), 2.96 (dd, 2H), 3.18 (m, 4H), 3.28 (dd, 2H), i.99 (m, IH), 6.60 (d, IH), 6.90 (d, IH), 6.97 (d, IH), 6.00 (s, 2H), 8.07 (d, IH). F.xample 29 (a) 8-BenzylQxy-5-[(R}-l-hydroxy-2-(2-niethyl-2,3,5,6,7,8-hexahydro-lH-cydopcma- [b]naphtbalen-2-ylaiiiino)-ethyl]-lH-quinoHn-2-one is prepared from 8-benzyloxy-5-(R)-oxiranyl-lH-quino!in-2-one (220 mg) and Intermediate 24 (150 mg) by procedures analogous to those of Example 27(a). 'H-NMR (CDCb) ppm: 1.37 {s, IH), 1.78 (m, 4H), 2.1 (br.s, 2H), 2.72 (m, 5H), 2.80 (dd, 2H), 2.95 (m, 3H), 5.08 (m, IH), 5.17 ( s, 2H), 6.65 (d, IH), 6.88 (s, 2H), 7.02 (d, 2H), 7.26 (d, IH), 7.4 (m, SH), 8.05 (d, IH). (b) 8-Hydroxy-5-[(R)-l-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexaliydro-lH-cyclopenta- [b]iiaphthalen-2-y]aniino)-ethyl]-lH-quinofin-2-one is prepared by hydrogenation of the product of Example 29(a) using a procedure analogous to that of Example 27(b). The product is purified by HPLC (H2O, CH3CN, CF3COOH, gradient elution). ^H-NMR (d4-CH30H) ppm (TPA salt): 1.65 (s, 3H), 1.85 (m, 4H), 2.85 (m, 4H), 3.15 (m, 2H), 3.4 (m, 4H), 5.48 (t, IH), 6.83 (d, IH), 7.03 (s. 2H), 7.15 (d, IH), 7.45 (d, IH), 8.40 (d. IH). Example 30 (a) 5-{(S)-2-fBen2yI-(2,3,5,6,7,8-hexahydi'o-lH-cydopcnta[b]naphthalen-2-yl)-aminQ]-l- hydroxy-ethyll-S-benzyloxy-l H-quinoKn-2-one A mixture of Intermediate 16 (150mg) and benzyl-(2,3,5,6,7,8-hexahydro-lH-cyclopenta[b]naphthalen-2-yl)-amine (142 mg) in toluene (1 mL) is heated at 80*^0 for 36 hours. The residue is purified by chromatography (siUca, CHCI3 / EtOH, 20:1) to give a yellow foam. 'H-NMR (CDCb) ppm; 1.77 (m, 4H), 2.72 (m, 6H), 3.01 (m, 4H), 3.70 (d, IH), 3.88 (d, IH), 4.82 (m, IH), 5.15 (s, 2H), 6.50 (d, IH), 6.8 - 8 (m, 13H), 9.05 (br.s, IH) (b) 5-[(S)-2-(2,3,5,6,7,8-H«{ahydro-lH-cyclopenta[b]naphthalen-2-ylanrino)-l-hydroxy- cthyl]-8-hydroxy-l H-quinolin-2-one A solution of the product of Example 30(a) (150 mg) in methanol (20 mL) is stirred under an atmosphere of hydrogen in the presence of 10% Pd/C (20 mg) at room temperature for 5 hours. The rection is filtered and the product is purified by chromatography (siUca, CHCI3 / EtOH, 20:1) followed by crystalHsation (CH3OH). 'H-NMR (d4-CHiOH) ppm: 1.65 (m, 4H), 2J7 (m, 4H}, 2.86 (dd, 2H), 3.1 (m, 4H), 3.82 (m, IH), 5.25 (m, IH), 6.55 (d, IH), 6.78 (s, 2H), 6.91 (d, IH), 7.19 (d, IH), 8.27 (d, IH). Example 31 (a) Acetic add (R)-2-[ben2yl-(2-methyl-mdan-2-yl)-ainino]-l-{4-benzyIoxy-3- inethanestJlfonylaniino-pheiiyl)-etfayl ester is prepared from Intermediate 27 (476mg), triethylamine (231mg) and methanesulfonyl chloride (210n:^) by a procedure analogous to that of Example 25(b). TLC (silica, n-hexane / ethyl acetate 2:1 R/ = 0.45). (b) N-(S-{(R)-2-[Benzyl-(2-inethyI-indan-2-yl)-aniino]-l-hydroxy-cthyl}-2-bcnzyIoxy-phenyl}- methanesulfonainide The product of Example 31(a) (200mg) is dissolved in CH3OH (8mL). K2CO3 (138mg) is added followed by the dropwise addition of water (2mL). The reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 24 hours. Ethyl acetate (lOOmL) is added and the solution is washed with watet (50mL) and brine (SOmL). The organic layer is dried over MgS04, filtered and the solvent is removed in vacuo. The ptodua is purified by flash column chromatography (silica, n-hexane / ethyl acetate 3:1). TLC (silica, n-hexane / ethyl acetate 2:1 R,-= 0.35). (c) N-{2-Hydroxy-5-[(R)-t-hydroxy-2-(2-methyI-indan-2-ykinino)-ethyI]-phenyl}- methanesulfonairide) is prepared from the product of Example 31(b) by a procedure analogous to that of Example 1(b). TLC (silica, dichloromethane / methanol 10:1 R^ = 0.10). Example 32 (a) Acetic add (R)-2-[benzyl-(2-niethyl-mdan-2-yl)-anBno]-t-(4-benzyloxy-3- etbanesutfonylaii]ino-phenyl)-etliyl ester is prepared from Intermediate 27, triethylamine (242mg) and ethanesulfonyl chloride (247mg) by a procedure analogous to that of Example 25(b). TLC (siUca, n-hexane / ethyl acetate 2:1 R/= 0.50). (b) Etbanesulfonic acid (5-{(R)-2-[benzyl-(2-iiietliyl-indan-2-yI)-anrino]-l-hydroxy-etbyI)-2-benzylDxy-phenyl}-aniide is prepared from the product of Example 32(a) by a procedure analogous to that in Example 31(b). TLC (silica, n-hcxane / ethyl acetate 2:1 R^ = 0.40). (c) Etbanesulfonic add {2-hydroxy-5-[(R)-l-hydroxy-2-(2-in«hyI-indan-2-ylaniino>-tthyfl-pbenylj-ainide is prepared from the product of Example 32(b) by a procedure analogous to that of Example 1(b). TLC (siUca, dichloromethane / methanol 10:1 R^ = 0.10). Example 33 (a) Acetic add (R>-2-[benzyl-(2-inethyl-indan-2-yl)-ainino]-l-[4-benzyloxy-3-(propane-l-suHonyl3inno)-pbenyl]-ed]yl ester) is prepared from Intermediate 27 (525mg), triethylamine (255mg) and l-propanesulfonyl chloride {288mg) by a procedure analogous to that of Example 25(a). TLC (sihca, n-hexane / ethyl acetate 4:1 R/= 0.25). (b) Propane-1-sulfonic acid (S-{(R)-2-[b€nzyl-(2-Inethy^i^dan-2-yl^a^lino]-l-hyd^oxy-ethyl}- 2-beiizyloxy-phenyl)-aiiBde is prepared from the product of Example 33(a) by a procedure analogous to of Example 31(b). TLC (silica, n-hexane / ethyl acetate 4:1 R/-= 0.15). (c) Propane-1-sulfonic add {2-hydroxy-5-[(R)-l-hydroxy-2-(2-niethyl-indan-2-yianiino)- etliylj-phenyll-aiiiide is prepared from the product of Example 33(b) by a procedure analogous to that of Example l(b}. TLC (silica, dichloromethane / methanol 10:1 R^ = 0.05). Example 34 (a) N-{2-Benzyloxy-5-l(2-elhyl-indan-2-yUnino)-acetyl]-phenyl}-methanesulfonaniide A mixture of 2-cthyl-indan'2-ylamine and N-(2-benzyloxy-5-bromoacetyl-phenyl)-methanesulfonamide is stirred in acetonltrile at room temperature for 20 hours. The product is isolated by filtration. ES* MS m/e 479 (MH*) (b) N-(2-Beiizyloxy-S-I2-{2-ethyl-indan-2-ylainino)-l-hydroxy-eihyl]-pheiiyll- methanesulfonamide The product of Example 34(a) is suspended in a mixture of ethanol and dichloromethane. Sodium borohydride is added at O°C and the mixture stirred at room temperature for 3 hours, then filtered and chromatographed (silica, ethylacetate / ethanol 4:1) to give a white foam. ES* MS m/e 480 (MtT) (c) N-{5-[2-(2-EthyI-indaii-2-ylamino)-l-hydroxy-ethyl]-2-hydroxy-pbeiiyl}- methanesulfonainde The pcoduct of Example 34(b) (0.29 g) in methanol (20 mL) is stirred under hydrogen in the presence of 10% Pd/C at room temperature for 18 hours. The mixture is filtered through cetite and the filtrate is concentrated m vacuo, then chromatographed (silica, ethyl acetate / ethanol 2:1). After trituration with ether / ethyl acetate off-white crystals (100 mg) are obtained. 'H-NMR (di-CHaOH) ppm: 0.85 (t, 3H), 1.65 (m, 2H), 2.75 (m, 2H), 2.85 (s, 3H), 2.95 (m, 4H), 6.80 (d, IH), 7.05 (m, SH), 7.30 (s,lH). Example 35 (a) Acetic add (R)-l-(4-benzyloxy-3-mclhanesutfonykinino-phenyl)-2-[ben2yl-(2,S,6- triniethyl-indan-2-yI)-ainno]-ethyl ester To a solution of Intermediate 29 in dichloromethane and triethylamine at room temperature is added tnethanesulfonyl chloride and the mixture stirred for 18 hours. It is then washed with 0.2 N HClj saturated NaHCOs solution and brine. The product is purified by chromatcgaphy (silica, ethyl acetate / hexane 1:4). ES' MS m/e 625 (M") (b) N-{2-Benzyloxy-5-{(R)-2-[benzyl-(2,5,6-trimethyl-indan-2-yI)-ainino]-l-hydroxy-ethyll- pbenyl}-iiiethanesulfonaniide The product of Example 3S(a) is stirred in methanol / water with K2CO3 for 3 days then solvents removed in vacuo. The product is purified by chromatography (silica, ethyl acetate / hexane 1:2). 'H-NMR (CDCI3) ppm: 1.21 (s, 3H), 2.22 (s, 6H), 2.63-2.82 {m, 4H), 2.84 (s. 3H), 3.20 (br.d, 2H), 3.61 (d,lH), 3.64 (br.s., IH), 3.83 (m, IH), 4.08 (d, IH), S.09 (s, 2H), 6.75 (br.s, NH), 6.90-7.05 (m, 4H), 7.25- 7.45 (IIH). (c) N-{2-Hydroxy-5-[(R>-l-bydroxy-2-(2,5,6-trimethyl-indan-2-ylamino)-ethyl]-phenyI}- methanesulfonanade is prepared from the product of Example 35(b) by a procedure analogous to that of Example 34(c). ES* MS m/e 405 (MH+) 1. A compound of formula I R1 is hydrogen, hydroxy, or CrCio-alkoxy; R2 and R-5 are each independently hydrogen or CrCio-alkyl; R'5, R2, R5 and R2 are each independently hydrogen, halogen, cyano, hydroxy, C1-Cio-alkoxy, phenyl, C1-Cio-alkyl, C1-Cio-alkyl substituted by one or more halogen atoms or one or more hydroxy or C1-Cio-alkoxy groups, C1-Cio-alkyl interrupted by one or more hetero atoms, C2- Cio-alkenyl, tri- C1-Cio-alkylsilyl, carboxy, C1-Cio-alkoxycarbonyl, or -CONR"Ri2, where Rn and R'2 are each independently hydrogen or CrCio-alkyl, or R2 and R2, R2 and R5, or R5 and R' together with the carbon atoms to which they are attached denote a 5- or 6-membered carbocyclic ring or a 5- or 6-membered O-heterocyclic ring containing one or two oxygen atoms; RB is -NHR13 where R" is hydrogen, C1-Cio-alkyl or -COR14 where R'2 is hydrogen, or R'2 is -SOzR'2 where R22 is C1-Cio-alkyI or C1-Cio-alkyl interrupted by one or more hetero atoms, and R5 is hydrogen, or R5 is -NHR'5 where -NHR18 and R', together with the carbon atoms to which they are attached, denote a 6-membered N-heterocycle; RIO is -ORi' where Ri2 is hydrogen; X is C1-Cio-alkyl; n is 1 or 2; q and r are each zero or 1, the sum of q+r is 1 or 2; and the carbon atom marked with an asterisk5 has the R or S configuration, or a mixture thereof, when R' is hydroxy or alkoxy. 2. The compound according to claim 1, in which R5 is -NHR'8 and -NHR18 and R9 together denote a group of formula -NH-CO-R"- where R" is an alkylene, alkenylene or alkyleneoxy group, q is 1 and r is zero or 1. 2- The compound according to claim 1, in which Ri is hydrogen or hydroxy; R2 is hydrogen; R2 is hydrogen or C1-Cio-alkyl; and R'5, R2 R5 and R' are each independently hydrogen, C1-Cio-alkoxy, C1-Cio-alkyl or C1-Cio-alkyl substituted by C1-Cio-alkoxy, 01 R5 and RS B.2 and R5, or R5 and R' together with the carbon atoms to which ihey are attached denote a 6-membered carbocyclic ring or a 6-membered O-heterocyclic ring containing one or two oxygen atoms. 4- The compound according to any one of the preceding claims, in which Ar is a group of wherein R'2 is hydrogen, C1-C4-alkyl, -COR'14 where R15 is hydrogen, or -S02Ri2 where R"' is C1-C4-alkyl. 6, The compound according to any one of the preceding claims, in which R2 and R' are identical and are each hydrogen, C1-C4-alkyl or C1-C4-a!koxy, and either R2 and R5 are identical and are each hydrogen, C1-Cn-alkyl, C1-Q-alkoxy or C1-C4-alkoxy-C1-C4-alkyl, or R5 and R5 together denote -(CH2),- or -0(CH2)iO- where s is 4 and t is 2, 7. The compound according to claim 1, in which Ar is a group of formula III or Ilia as specified in claim 3 or a group of formula XV as specified in claim 5, Ri is hydroxy, R2 and R2 are hydrogen, and R' and R2 are identical and are each hydrogen, C1-C4-aIkyl or C1-C4-alkoxy, and either R2 and R5 are identical and are each hydrogen, C1-O-alkyl, C1-C4-aIkoxy or C1-Q- alkoxy-C1-C4-alkyl, or R2 and R5 together denote -{CH2)4- or -0(CH2)20-. 8. The compound according to any one of the preceding claims, in which R' is hydroxy and the carbon atom in formula I marked with an asterisk 5 has the R configuration. 9. A compound of formula I A in which R", R2o and R2' are each H, R2 is OH, R2 and R2 are each H and (i) n is 1, and R" and K' are each CH3O- and R2 and R' are each H; or (ii) n is 1, and R2 and R' are each H and R8 and R8 are each CH3CH2-; or (iii) n is 1, and R"8 and R2 are each H and R2 and R8 are each CH3-; or (iv) n is J, and R" and R2 are each CHaCHz- and R2 and R8 are each H; or (v) n is 1, and R88 and R' are each H and R2 and R8 together denote -(CH2)4-; or {vi) n is 1, and R2 and R2 are each H and R2 and R8 together denote -0(CHi)20-; or (vii) n is 1, and R-8 and R2 are each H and R2 and R8 are each CH3{CH2)3"i or (viij) n is 1, and R2 and R2 are each H and R2 and R« are each CHj(CH2)2-; or (ix) n is 2, R2 R2 R8 and R' are each H; or (x) n is 1, and R8 and R2 are each H and R2 and R« are each CH3OCH2-; or (B) wherein Ar is a group of formula XV in which R" is H, R' is OH, R2 and R2 are each H, R" and R2are each H and R2 and R8 are each H and n is 1; or {C) which is a compound selected from 8 -hydroxy-5- [ 1 -hydroxy-2-(indan-2-yiamino) -ethyl] -1 H-quinolin-2-one, 5- [2- (5,6-dimethoxy-indan-2-ylamino)-1 -hydroxy-ethyl] -8-hydroxy-1 H-quinolin-2 -one, 5-f2-(5,6-diethyI-indan-2-ylamino)-l-hydroxy-ethyIj-8-hydroxy-3-methyl-lH-quinolin- 2-one, 5-(2-{5,6-diethyl-indan-2-yIamino)-l-hydroxy-ethyl]-8-methoxymethoxy-6-methyl-lH- quinolin-2-one, 5-[2-(5,6-diethyl-indan-2-yIamino)-l-hydroxy-ethyl]-8-hydroxy-6-methyl-lH-quinolin- 2-one, 8-hydroxy-5-[2-{5,6-diethyl-indan-2-yIamino)-l-hydroxy-ethylI-3,4-dihydro-lH- quinoIin-2-one, N-{2-hydroxy-5-[(R)-l-hydroxy-2-(2,5,6-trimethyl-indan-2-yIamino)-ethyl]-phenyl)- formamide, 5-I(R)-2-(5,6-diethyl-2-methyI-indan-2-ylamino)-l-hydroxy-ethyl]-8-hydroxy-lH- quinolin-2-one, {S)-5-12-(5,6-diethyl-indan-2-ylaniino)-l-hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-one hydrochloride, 5-[(R)-l-hydroxy-2-( 6,7,8,9-tetrahydro-JH-ben20cyclohepten-7-yIamino)-ethyl]- 8-hydroxy-1 H-quinolin-2-one hydrochloride, {Rl-5-[2-(5,6-diethyl-indan-2-ylatnino)-l-hydroxy-ethyn- 8-hydcoxy-lH-quinolin-2-one maleate, (R)-5-[2-(S,6-diethyl-indan-2-ylam!no)-l-hydroxy-ethyl]- 8-hydroxy-lH-quinolin-2-one hydrochloride, N-{5 - [(R}-2-(5,6-diethyl-indan-2-yIamino)-l -hy dr oxy-ethy 1] -2-hydroxy-pheny 1 }-formamide, 4-j(R)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxy-ethyl]-2-dimethylamino-phenol hydrochloride, 4- [{R)-2-( 5,6-diethyl-indan-2-ylamino)-1 -hydroxy-ethyl] -2-methylaniino-phenol hydrochloride, N-15-12-( 5,6 -diethyl-indan-2-ylamino) -1 -hydroxy-ethyl] -2-hydroxy-pheny t }-methanesulfonamide hydrochloride, (R)-8-hydroxy-5-[(S)-l-hydroxy-2-(4,5,6,7-tetramethy!-indan-2-ylamino)-ethylj-lH-quinoIin-2-one, 8-hydroxy-5-[(R}-l-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-lH-quinolin-2-one, 5-[2-(5,6-diethyl-indan-2-ylamino)-ethyl]-8-hydroxy-lH-quino!in-2-one, 8-hydroxy-5-[{R)-l-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-lH-cyclopenta [b}-naphthalen-2-y lamino)-ethyl)-1 H-quinolin-2-one, 5-[(S)-2-(2,3,5,6,7,8-hexahydro-lH-cyclopenta[b]naphthalen-2-yIamino)-l-hydroxy-ethyl] -8-hy droxy-l H-qutnolin-2-one, N-{2-hy droxy-5- [(R)-1 -hydroxy-2-(2-methyl-indan-2-ylamino )-ethyiI-phenyl} -methane¬sulfonamide), ethanesulfonicacid{2-hydroxy-5-[(R)-l-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]- phenylj-amide, propane-l-sulfonicacid(2-hydroxy-5-[{R)-l-hydroxy-2-(2-methyl-indan-2-yIamino)- ethyl]-phenyl}-amide, N-15-12-(2-ethyl-indan-2-ylamino)-l-hydroxy-ethyl]-2-hydroxy-phenyl)-methane¬sulfonamide, or N-12-hy droxy-5 -[(R) -1 -hydroxy-2-( 2,5,6-irimethyl-indan-2-y Iamino)-ethy 11-pheny I} - methanesulfonamide. 10. A pharmaceutical composition comprising a compound according to any one of the preceding claims, optionally together with a steroid, an anticholinergic or antimuscarinic agent, or a pharmaceutically acceptable carrier. 11. A process for the preparation of a compound of formula I as claimed in claim 1, the process comprising the steps of: (a) for the preparation of a compound where R' is hydroxy, either where Ar' is Ar as defined in claim 1 or a protected form thereof, and R2, R3, R4', R5, R6 and R' are as defined in claim 1, to convert the indicated keto group into -CH(OH)-; (b) for the preparation of a compound where R' is hydrogen, reducing a corresponding compound of formula I where R' is hydroxy; or (c) for the preparation of a compound of formula I where R' is Ci-Cio-alkoxy, either (i) O- alkylating a corresponding compound of formula I where R1 is hydroxy or (ii) reacting a corresponding compound having a leaving moiety instead of R' with an alcohol of formula R"H where R' is C1-C10-alkoxy; and io each case, optionally, converting a resultant compound of formula ! in protected form into a corresponding compound in unprotected form; and recovering the resultant compound of formula L J |
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in-pct-2001-1673-che abstract.pdf
in-pct-2001-1673-che claims-duplicate.pdf
in-pct-2001-1673-che claims.pdf
in-pct-2001-1673-che correspondence-others.pdf
in-pct-2001-1673-che correspondence-po.pdf
in-pct-2001-1673-che description (complete)-duplicate.pdf
in-pct-2001-1673-che description (complete).pdf
in-pct-2001-1673-che form-19.pdf
in-pct-2001-1673-che form-3.pdf
in-pct-2001-1673-che form-5.pdf
in-pct-2001-1673-che petition.pdf
| Patent Number | 222346 | |||||||||||||||
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| Indian Patent Application Number | IN/PCT/2001/1673/CHE | |||||||||||||||
| PG Journal Number | 47/2008 | |||||||||||||||
| Publication Date | 21-Nov-2008 | |||||||||||||||
| Grant Date | 05-Aug-2008 | |||||||||||||||
| Date of Filing | 28-Nov-2001 | |||||||||||||||
| Name of Patentee | NOVARTIS AG | |||||||||||||||
| Applicant Address | Schwarzwaldalle 215, CH-4058 Basel, | |||||||||||||||
Inventors:
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| PCT International Classification Number | C07C 215/80 | |||||||||||||||
| PCT International Application Number | PCT/EP2000/005058 | |||||||||||||||
| PCT International Filing date | 2000-06-02 | |||||||||||||||
PCT Conventions:
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