IE980421A1 - Compounds - Google Patents

Abstract

In formula 1 wherein R1 to R9 are selected from one or more of the same or different of: H, halo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, aryl, acyl,alkyl carbonyl, aryl carbonyl, hydro carbonyl, amino, amido, 10 alkylamino, hydroxylamino, amine oxide groups, azo groups, cyano, hydrazino groups, hydrazide groups, hydrozone groups, imide groups, iminoether groups, ureyl groups, oxime, nitro, nitrate, nitrite, nitroso groups, nitrile, heterocyclic groups containing hetero atoms selected from one or more of N, O or S, 15 aralkyl groups, mono and polybenzoid aryl groups, substituted aryl groups, thiol, thioureyl, phenylthiol groups, sulphonic acid groups, sulphoxide groups, sulphone groups, alkyl containing 1 to 10 carbon atoms, substituted alkyl, carboxylic acid containing Ci to Cm which may be substituted or unsubstituted.

Description

The invention relates to indane compounds, processes for their production, compositions containing them and their pharmacological use.

More particularly, the invention relates to 3-aminoindanones as antiinflammatory agents and/or mast cell stabilising agents.

According to the invention, there is provided a compound of the formula 1 io Wherein R1 to R9 are selected from one or more of the same or different of: H, halo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, aryl, acyl, alkyl carbonyl, hydro carbonyl, aryl carbonyl, amino, amido, alkylamino, hydroxylamino, amine oxide groups, azo groups, cyano, hydrazino groups, hydrazide groups, hydrazone groups, imide groups, iminoether groups, ureyl groups, oxime, nitro, nitrate, nitrite, nitroso groups, nitrile, heterocyclic groups containing hetero atoms selected from one or more of N, O or S, aralkyl groups, mono and polybenzoid aryl groups, substituted INT CL b 2S5/3-L Zt»/eo> -2aryl groups, thiol, thioureyl, phenylthiol groups, sulphonic acid groups, sulphoxide groups, sulphone groups, alkyl containing 1 to 10 carbon atoms, substituted alkyl, carboxylic acid containing C, to C|0 which may be substituted or unsubstituted any of: R1 and R2; or R2 and R3 together may represent a double bond R1 or R2 or R1 and R2 together may represent oxo.

Preferred because of solubility, salt formation, pharmacological activity and /or ease of production are the following subsets.

In one embodiment of the invention R1 to R9 are selected from one or more of the same or different of: H, hydroxy, alkoxy, aryloxy, acetoxy, alkyl carbonyl, hydrocarbonyl, amino, amido, alkylamino, hydroxylamino, amine oxide, mono and polybenzid aryl groups, substituted aryl groups, alkyl, heterocyclic groups containing hetero atoms selected from one or more of N, O.

In a preferred embodiment of the invention R8, R9 are one or more of the same or different of alkyl, or aryl, each of which may be substituted with one or more of the same or different of: halo, oxo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, carbonyl, amino, amido, alkylamino, hydroxyamino, amine oxide groups, azo groups, cyano, hydrazino groups, hydrazide groups, hydrazone groups, imide groups, imino ether groups, ureyl groups, oxime, nitro, nitrate, nitrite, nitroso groups, nitrile, heterocyclic groups, aralkyl groups, mono and polybenzoid aryl groups, substituted aryl groups, thiol, thioureyl, phenyl thiol groups, sulphonic acid groups, sulphoxide groups and sulphone groups. -3Preferably one or both of R8, R9 is alkyl of C, to C]0.

Preferably alkyl is substituted by hydroxy.

Preferably the heterocyclic groups are selected from heteroatoms containing one or more ofN, O or S.

In one embodiment of the invention R3 to R7 are hydrogen.

Preferably R8 is H and R9 is COR10 in which R10 is alkyl, substituted alkyl, aryl or substituted aryl.

In a preferred arrangement R1 represents oxo.

Alternatively R1 represents H, OH.

Preferably R8 and R9 do not represent Me, PhMe, or PhEt.

In one embodiment of the invention R8 = H and R9 = an acetyl group. Alternatively R8 and R9 both represent acetyl groups.

Particularly preferred are compounds wherein R8 represents ethyl and R9 represents an acetyl group.

The invention especially provides the following compounds: N-3-indan-l-onyl ethanamide (Compound I) N-indanyl ethanamide (Compound II) -4N-(tert-butyl-carbonate)-3-aminoindan-l-one (Compound IV) N-cyclopentyl-N-3-indan-l-onyI propanmaide (Compound Vj N-cyclopentyl-N-benzoyl-3-aminoindan-l-one (Compound VI) N-cyclopentyl-N-3-indan-l-onyl butanmaide (Compound VII) N-cydopentyl-N-3-indan-l-onyl heptanmaide (Compound VIII) The invention further provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.

The invention also provides the use of the compounds to achieve mast cell stabilising activity and/or anti-inflammatory activity.

In addition, the invention provides a method of prophylaxis or treatment to achieve mast cell stabilising activity and/or anti-inflammatory activity by administering to a patient an effective amount of a compound of the invention.

The invention also provides processes for preparing the compounds of the invention by the process described in claims 32 to 47.

It will be appreciated that the compounds include pharmacologically acceptable salts, esters, amides, isomers and solvates thereof.

It will also be appreciated that if the compounds have one or more chircal centres they may exist as a pair of enantiomers or as a mixture of diastereomers. This may have an effect on pharmacological properties. -5It will further be appreciated that for pharmaceutical purposes the active compounds may be formulated in any desired form using any suitable excipients and/or earners. For example, particularly in the case for use to achieve antiinflammatory activity the compound may be formulated in a pharmaceutical composition suitable for topical/transdermal application.

The invention will be more clearly understood from the following description thereof given by way of example only.

IO Detailed Description The preparation of some of the compounds of the invention are described in detail below. Some of the starting materials used are described in our earlier applications PCT/IE96/00080, PCT/IE96/00081 and PCT/IE96/00082 the contents of which are incorporated herein for reference. Other compounds within the scope of the claims can be prepared by analogy. -6Example 1 Preparation of I (Method A) X 150 mg (8.67 mmol) of 3-Azido-indan-l-one was dissolved in 10 ml of an ethanol/ethyl acetate mixture (1:1) and stirred at room temperature. 150 mg of % palladium on charcoal was added to the mixture followed by 176.5 mg (17.34 mmol) of acetic acid. The reaction mixture was then put under a hydrogen atmosphere using a Kips apparatus (40% Hydrochloric acid dropped onto Zinc granules) and monitered by TLC to completion (3 hours). The reaction mixture was filtered and evaporated to dryness to give a yellow oil. This oil was purified by eluting on a column of flash silica to give a yellow solid (9/1: petroleum spirit/ethyl acetate grading to 1/4: petroleum spirit/ethyl acetate) and subsequent recrystallisation from ethyl acetate yielding compound I as white needles, (80 mg, 61%) mp 152.1-152.8°C.

*H nmr (CDC13, 400 MHz) δΗ 2.02 (3H, s, CH,), 2.45 (1H, dd, J=3.4 & 19 Hz, CH of CH;), 3.14 (dd, J=7.6 and 19 Hz, CH of CH2), 5.61 (1H, m, NHCHCH2), 6.4 (1H, broad, NH), 7.417.68 (4H, m, aromatics). 13C nmr (CDC13, 75.47 MHz) 5C 22.7 (CHj), 44.3 (CH;), 46.9 (CH), 122.8, 125.6, 128.8, 135.0 (4 x Ar-CH), 136.2, 153.5, (2 x Ar-C), 202.9, (C=O). -7Example 2 Preparation of I (Method B) Nitronium tetrafluoroborate (250 mg, 1.88 mmol) was dispersed in a clean dry necked round bottomed flask at 0°C under nitrogen. To this was added 3bromoindanone (200 mg, 0.95 mmol) in clean dry acetonitrile (20 ml). The reaction was stirred at 0°C for 6 hours and quenched by the addition of water (20 io ml). The product was isolated by column chromatography over silica gel and petroleum spirit : ethyl acetate (1:4) and recrystallised from ethyl acetate to give compound I as white needles (90 mg, 50.2%). Ή nmr (CDClj, 400 MHz) δΗ 2.02 (3H, s, CHj), 2.45 (1H, dd, J=3.4 & 19 Hz, CH of CH2), 3.14 (dd, J=7.6 and 19 Hz, CH of CH2), 5.61 (1H, m, NHCHCH2), 6.4 (1H, broad, NH), 7.417.68 (4H, m, aromatics).

I3C nmr (CDClj, 75.47 MHz) 5C 22.7 (CH3), 44.3 (CH2), 46.9 (CH), 122.8, 125.6, 128.8, 135.0 (4 x Ar-CH), 136.2, 153.5, (2 x Ar-C), 202.9, (C=O). -8Example 3 Preparation of I (Method C) O o PPh3 CHjCOOH Toluene (reflux) HN O 346 mg (2 mmol) of the 3-Azido-indan-l-one was dissolved in 10 ml of anhydrous toluene. To this stirring solution was added 262 mg (2 mmol) of triphenylphosphine and 57.6 mg (2.4 mmol) of acetic acid. The mixture was refluxed for 12 hours and then cooled to room temperature and washed with 10 ml of 5% NaHCO3 solution. The organic layer was separated and put on a column of flash silica and eluted with pet spirit : ethyl acetate (1:4) to give a yellow oil which was recrystallised from ethyl acetate to give compound I as white needles, 50 mg (15.3%). Ή nmr (CDClj, 400 MHz) δΗ 2.02 (3H, s, CHj), 2.45 (1H, dd, J=3.4 & 19 Hz, CH of CH2), 3.14 (dd, J=7.6 and 19 Hz, CH of CH2), 5.61 (1H, m, NHCHCH2), 6.4 (1H, broad, NH), 7.417.68 (4H, m, aromatics). ,3C nmr (CDClj, 75.47 MHz) δσ 22.7 (CH3), 44.3 (CH2), 46.9 (CH), 122.8, 125.6, 128.8, 135.0 (4 x Ar-CH), 136.2, 153.5 (2 x Ar-C), 202.9, (C=O). -9IE 980421 Example 4 Preparation of II O=\ 1-Aminoindan (lg, 7.5 mmol) was dispersed in clean dry DCM (15 ml) and triethylamine (2.1 ml, 1.53 g, 15.1 mmol). To this solution was added acetic anhydride (1.5 ml, 1.6 g, 16 mmol) and DMAP (0.92 g, 7.5 mmol). The mixture was allowed to stir at room temperature for 1 hour and passed through a plug of silica eluting with petroleum ether: ethyl acetate (1.4) (0.97 g, 74%). Compound ίο II was formed. Ή nmr (5CDC13, 400 MHz) 1.77-1.89 (1H, m, CH of CH2), 2.03 (3H, s, CH3), 2.55-2.64 (1H, m, CH of CH2), 2.83-2.91 (1H, m, CH of CH2), 2.95-3.03 (1H, m, CH of CH2), 5.47 (1H, qm, J=7.7Hz, CHNH), 5.85 (1H, bs, NH), 7.23-7.31 (4H, m, Ar-CH). 13C nmr (CDClj, 75.47 MHz) 22.9 (COCHj), 29.8, 33.6 (2 x CH2), 54.3 (CH), 123.6, 124.4, 126.3, 127.5 (4 x Ar-CH), 142.7, 143.0 (2 x Ar-C), 169.4 (COCH3). - ίοExample 5 Preparation of III %Pd/C. H, u W ΛΛ, EtOH.EtOAc o -Ao 3-Azido-indan-l-one (lOOmg, 0.578 mmol) was dispersed in EtOH:EtOAc (1:1, 3ml) and triethylamine (2.1 ml, 1.53 g, 15.1 mmol). To this solution was added 10% palladium over charcoal (100 mg), di-tert-butyl-dicarbonate (0.25 g, 1.16 mmol) and the mixture was stirred under hydrogen for two hours. The crude mixture was passed through a plug of silica eluting with petroleum ether: ether acetate (1:4) (0.12 g, 86%). Compound III was formed. Ή nmr (6CDC13, 400 MHz) 1.42 (9H, s, 3 x CH3), 2.45 (1H, d, J = 19.1 Hz, CH of CH:), 3.12 (1H, q, J 6.8Hz, 12.3 Hz, CH of CH2), 5.04-5.32 (2H, m, CHNH & NH), 7.26 - 7.67 (4H, m, Ar-CH). 13C nmr (CDC13, 75.47 MHz) 28.2 (3 x CH3), 44.9 (CH;), 48.6 (CH), 79.9 (qC), 123.1, 125.8, 128.9, 135.1 (4 x Ar-CH), 136.4, 154.1 (2 x Ar-C), 155.6, 203.3 (2 x CO). • 11 Example 6 Synthesis of IV Compound B (500mg, 0.232 mmol) was dissolved in DCM (10ml) and to this was added triethylamine (0.47g, 0.65ml, 4.65mmol) and propionic anhydride (0.61ml, 4.65mmol). Then to this stirring solution DMAP (catalytic quantities) was added.

The reaction mixture was allowed to stir at room temperature for 3 hours. To the reaction solution was added 2M aqueous HCl (5ml) and 10ml DCM. The organic layer was obtained and washed with water. To the organic was added to a 10% solution of NaHCO3 (30ml). The organic phase was collected and the aqueous layer was washed with DCM. All the organic layers were combined and dried io over Na2SO4.. The crude reaction was then passed through a plug of flash silica, eluting with petroleum ether 100% and grading to petroleum ether: ethyl acetate 1:4. The product Compound IV was obtained as a white solid (217mg, 34.8%). Ή nmr (bCDC13, 400 MHz) 0.93 (3H, bs, CEL), 1.6 - 2.96 (12H, m, 6x CH,), 4.49 (1H, s, CH), 4.88(lH,s, CH),7.38 - 7.61 (4H, m, Ar - CH) Low resolution mass Spectrum CitHijNO, requires M+271, found M+271 13C nmr (CDC13, 75.47 MHz) 9.3 (CH3), 24.2, 24.2, 27.6, 30.6, 31.1, 43.1 (6 x CH;), 56.4, 57.2 (2 x CH), 122.8. 124.2, 129.5, 134.6 (4 x Ar - CH), 137.5, 156.6 (2 x Ar - C), 172.6, 203.1 (2 x C=O) - 12Example 7 Synthesis of V NH O 0 o Compound B (500mg, 0.232 mmol) was dissolved in DCM (10ml) and to this was added triethylamine (0.47g, 0.65ml, 4.65 mmol) and benzoic anhydride (1,05g, 4.65mmol). Then to this stirring solution DMAP (catalytic quantities) was added.

The reaction mixture was allowed to stir at room temperature for 3 hours. To the reaction solution was added 2M aqueous HC1 (5ml) and 10ml DCM. The organic layer was obtained and washed with water. To the organic layer was added a 10% solution of NaCHO3 (30ml). The organic phase was collected and the aqueous layer was washed with DCM. All the organic layers were combined and dried over Na2SO4. The crude reaction was then passed through a plug of flash silica, eluting with petroleum ether 100% and grading to petroleum ether : ethyl acetate 1:4. The product Compound V was obtained as a white solid (339mg, 45.8%). Ή nmr (5CDC13, 400MHz) 0.88 - 1.99 (8H, m, 4 x CH,), 2.87 - 3.06 (2H, m, CH,), 3.38 (1H, s, CH), 4.77 (1H, s, CH), 7.41 - 8.00 (9H, m, Ar - CH) Lower resolution mass Spectrum C2iH2iNO2 requires M+319, Found M+319 -1313C nmr (CDC13, 75.47 MHz) 23.4, 23.5, 31.0, 31.7, 42.3 (5 x CH2), 53.8, 57.3 (2 x CH), 123.5, 126.8, 127.9, 127.9 129.3, 129.6, 129.6, 131.7, 134.9 (9 x Ar - CH), 133.2, 136.7, 151.8 (3 x Ar -C), 171.3, 202.3 (2 xC=O) IC I - 14Example 8 Synthesis of VI Compound B (1.5g, 0.696 mmol) was dissolved in DCM (10ml) and to this was added triethylamine (0.19g, 0.14ml, 1.39 mmol) and butyric anydride (0.23ml, 1.39 mmol). Then to this stirring solution DMAP (catalytic quantities) was added. The reaction mixture was allowed to stir at room temperature for 3 hours. To the reaction solution was added 2M aqueous HC1 (5ml) and 10ml DCM. The organic layer was obtained and washed with water. To the organic was added to a 10% solution of NaHCO3 (30ml). The organic phase was collected and the aqueous layer was washed wi± DCM. All the organic layers were combined and dried over Na2SO4. The crude reaction was then passed through a plug of flash silica, eluting with petroleum ether 100% and grading to petroleum ether : ethyl acetate 1:4. Compound VI was formed.

*H nmr (8CDCl3,400 MHz) 0.96 (3H, t, J=7.52Hz, CHj), 0.89 - 2.16 (10H, m, 5 x CH,), 2.30 (2H, t, J=7.04Hz, COCiLCHz), 2.88 (1H, bs, 1 each CHCOIT), 3.08 (1H, bs, 1 each CHCOCH,), 4.35 (1H, bs, CH), 4.66 (1H, bs, CH), 7.28 - 7.76 (4H, m, Ar - CH) Low resolution mass Spectrum Ci8H23 NO; requires M+ 291, Found M+ 291 -1513C nmr (CDC13, 75.47 MHz) 13.3 (CH3), 18.5, 23.6, 25.1, 25.5, 29.1, 29.6, 30.3, 30.5, 35.4, 36.0, 36.6, 36.8, 41.9, 42.4 (7 x CH2), 51.7, 55.7, 56.7, 58.6, (2 x NCH), 122.6, 123.0, 123.3, 125.1, 127.4, 128.9, 134.0, 134.9 (4 x Ar - CH), 136.1, 154.7 (2 x Ar - C), 178.2, 202.8, (2 x C=O) Compound B (1,5g, 0.696 mmol) was dissolved in DCM (10ml) and to this was added triethylamine (0.19g, 0.14ml, 1.39mmol) and heptanoic anhydride (0.36ml, 1.39mmol). Then to this stirring solution DMAP (catalytic quantities) was added.

The reaction mixture was allowed to stir at room temperature for 3 hours. To the reaction solution was added 2M aqueous HC1 (5ml) and 10ml DCM. The organic layer was obtained and washed with water. To the organic was added to a 10% solution of NaHCO3 (30ml). The organic phase was collected and the aqueous io layer was washed with DCM. All the organic layers were combined and dried over Na2SO4. The crude reaction was then passed through a plug of flash silica, eluting with petroleum ether 100% grading to petroleum ether : ethyl acetate 1:4.

The product Compound VII was obtained as a white solid.

’H nmr (6CDC13, 400 MHz) 0.86 (3H, t, J=3Hz, CH0, 1.18 - 2.29 (16H, m, 8 x CH,), 2.33 (2H, bs, COCH2CH2), 2.86 (1H, bs, 1 each CHCOCH2), 3.06 (1H, bs, 1 each CHCOCtT), 4.29 (1H, bs, CH), 4.64 (1H, bs, CH), 7.38 - 7.61 (4H, m, Ar - CH) Low resolution mass Spectrum C22H3i NO2 requires M+ 341, Found M+ 341 -18PHARMACOLOGY Introduction The indane compounds according to the invention have mast cell stabilising activity, smooth muscle relaxing activity, and anti-inflammatory activity. The compounds are, therefore, potential anti-asthmatic agents with bronchodilator activity. The mast cell stabilising activity of the compounds suggests their potential use in the treatment of allergic rhinitis, allergic conjunctivitis and other anaphylactic or allergic conditions. The anti-flammatory activity may have applications in gout, rheumatic diseases, ankylosing spondylitis, polymyalgia rheumatica, temporal arteritis, polyarteritis nodosa, polymyositis and systemic lupus arteriosis and other inflammatory conditions. Topical applications may includes: atopic excema, weeping excemas, psoriasis, chronic discoid lupus erythematosus, lichen simplex chronicus, hypertrophic lichen planus, palmar plantar pustulosis. They may also have potential in the treatment of some malignant diseases and as immunosuppressants.

The smooth muscle relaxing activity of the compounds may have potential in the treatment of hypertension and peripheral vascular disease, such as intermittent claudication and Reynaud’s syndrome, as well as other cardiovascular disorders, such as congestive heart failure, angina pectoris, cerebral vascular disease and pulmonary hypertension. Such compounds are also indicated for potential use in the treatment of certain disorders of the gastro-intestinal tract, such as diverticular disease and irritable bowel syndrome. Similarly, these compounds may have potential as agents for the treatment of disorders of the genito-urinary tract, such as premature labour, incontinence, renal colic and disorders associated with the passage of kidney stones. Members of this group of compounds may also have potential as diuretics analgesics, antipyretics, local anaesthetics, central nervous system depressants and hypoglycaemic agents. -19Mouse Ear Oedema Model The mouse ear oedema model was performed using Laca mice (25-35g), of either sex. The animals were sedated with fentanyl/fluanisone (Hypnorm, Janssen). One ear was treated by the topical application of one of a range of test compounds or dexamethasone (all at 300 /rg per ear in acetone). After 30 minutes, oedema was induced by the topical application of arachidonic acid (10 μ\ at 0.4g/ml in acetone). The width of each ear was measured, both before and 60 minutes after the induction of oedema, using a micrometer screw gauge. Ear oedema was calculated by comparing the ear width before and after induction of oedema and expressed as percentage normal.

Values are expressed as the percentage increase in ear thickness 1 hour after administration of arachidonic acid and solvent controls (n=6 except Compound II, n=4). -20Compound I Control (-ve) Dexamethasone I δ% 75.0 43.2 25.0 δ% 67.6 25.0 28.6 δ% 80.0 51.4 27.8 δ% 58.8 32.4 30.6 δ% 85.3 62.5 31.4 δ% 47.1 35.1 35.1 Mean 69.0 41.6 29.7 SEM 5.8 5.6 1.4 Compound II Control (-ve) Dexamethasone II δ% 75.0 43.2 25.0 δ% 67.6 25.0 27.9 δ% 80.0 51.4 32.4 δ% 58.8 32.4 36.8 δ% 85.3 62.5 δ% 47.1 35.1 Mean 69.0 41.6 30.5 SEM 5.8 5.6 2.6 io -21 Modified Protocol of Mouse Ear Oedema.

Arachidonic Acid-induced Mouse Ear Oedema Methods Male Laca mice (23 - 35g) were sedated with sagatal. The right ears of groups of mice were treated by the topical application of indomethacin, IV or V (300gg) in acetone. One group of mice received acetone alone (negative control) on their right ears. Compounds/acetone were applied in a volume of 1 Ομί (20μ1 total) each to the inner and outer aspects of the ear. One hour later, arachidonic acid (0.5mg) was applied to the right ears of the mice, in a volume of 10μ1 (20 μΐ total) each to the inner and outer aspects of the ear. One hour later, the mice were killed by cervical dislocation and 5mm biopsy punches were taken from both the right and left ears. Oedema was expressed as a percentage change in weight of arachidonic acid-treated ears versus untreated ears.

Results Compound Mean % SEM n (number) Indomethacin 14.1 3.9 10 IV 47.1 14.3 5 V 18.6 2.2 4 Solvent Control 101 15.9 9 Mast Cell: (Protoco as original) Compound % Inhibition of Histamine Release N (number) IV 92.5 ± 9.6 3 V 18.7 ±6.7 3 The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims (44)

1. A pharmaceutical compound of formula 1 wherein R 1 to R 9 are selected from one or more of the same or different of: H, halo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, aryl, acyl, alkyl carbonyl, aryl carbonyl, hydro carbonyl, amino, amido, alkylamino, hydroxylamino, amine oxide groups, azo groups, cyano, hydrazino groups, hydrazide groups, hydrozone groups, imide groups, iminoether groups, ureyl groups, oxime, nitro, nitrate, nitrite, nitroso groups, nitrile, heterocyclic groups containing hetero atoms selected from one or more of N, O or S, aralkyl groups, mono and polybenzoid aryl groups, substituted aryl groups, thiol, thioureyl, phenylthiol groups, sulphonic acid groups, sulphoxide groups, sulphone groups, alkyl containing 1 to 10 carbon atoms, substituted alkyl, carboxylic acid containing Ci to C U ' which may be substituted or unsubstituted. -23any of: R' and R 2 ; or R 2 and R 3 together may represent a double bond R’ or R 2 5 6 or R 1 and R 2 together may represent oxo. 5

2. A compound as claimed in claim 1 wherein R 1 to R 9 are selected from one or more of the same or different of: H, hydroxy, alkoxy, aryloxy, acetoxy, alkyl carbonyl, hydrocarbonyl, amino, amido, alkylamino, hydroxylamino, amine oxide, mono and io polybenzid aryl groups, substituted aryl groups, alkyl, heterocyclic groups containing hetero atoms selected from one or more of N, O.

3. A compound as claimed in claim 1 or 2 wherein R 8 , R 9 are one or more of the same or different of alkyl, or aryl, each of which may be substituted 15 with one or more of the same or different of halo, oxo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, carbonyl, amino, amido, alkylamino, hydroxyamino, amine oxide groups, azo groups, cyano, hydrazino groups, hydrazide groups, hydrazone groups, imide groups, imino ether groups, ureyl groups, oxime, nitro, nitrate, nitrite, nitroso groups, nitrile, 20 heterocyclic groups, aralkyl groups, mono and polybenzoid aryl groups, substituted aryl groups, thiol, thioureyl, phenyl thiol groups, sulphonic acid groups, sulphoxide groups and sulphone groups.

4. A compound as claimed in claim 3 wherein one or both of R 8 , R 9 is alkyl of 25 C, to Cio.

5. A compound as claimed in claim 4 wherein alkyl is substituted by hydroxy.

6. A compound as claimed in claim 3 wherein the heterocyclic groups are 30 selected from heteroatoms containing one or more of N, O or S. -247. A compound as claimed in any of claims 1 to 6 wherein R 3 to R 7 are hydrogen.

7. 8. A compound as claimed in any of claims 1 to 7, wherein R 8 is H and R 9 is COR 10 in which R 10 is alkyl, substituted alkyl, aryl or substituted aryl.

8. 9. A compound as claimed in any of claims 1 to 8, wherein R 1 represents oxo.

9. 10. A compound as claimed in any of claims 1 to 8 wherein R 1 represents H, OH.

10. 11. A compound as claimed in any of claims 1 to 8 wherein R 1 represents H.

11. 12. A compound as claimed in any preceding claim wherein R 8 and R 9 do not represent Me, PhMe, or PhEt.

12. 13. A compound as claimed in any preceding claim wherein R 8 - H and R 9 an acetyl group.

13. 14. A compound as claimed in any of claims 1 to 12, wherein R 8 and R 9 both represent acetyl groups.

14. 15. A compound as claimed in any of claims 1 to 12, wherein R 8 represents ethyl and R 9 represents an acetyl group.

15. 16. N-3-indan-l-onyl ethanamide

16. 17. N-indanyl ethanamide

17. 18. N-(tert-butyl-carbonate)-3-aminoindan-1 -one -2519. N-cyclopentyl-N-3-indan-l-onyl propanmaide

18. 20. N-cyclopentyl-N-benzoyl-3-aminoindan-l-one 5

19. 21. N-cyclopentyl-N-3-indan-l-onyl butanmaide

20. 22. N-cyclopentyl-N-3-indan-l-onyl heptanmaide

21. 23. A compound of formula 1 substantially as hereinbefore described with 10 reference to the examples.

22. 24. A pharmaceutical composition comprising a compound of any of claims 1 to 23 and a pharmaceutically acceptable carrier. 15

23. 25. A pharmaceutical composition substantially as hereinbefore described with reference to the examples.

24. 26. Use of a compound as claimed in any of claims 1 to 23 to achieve mast cell stabilising activity and/or anti-inflammatory activity.

25. 27. Use of a compound as claimed in any of claims 1 to 23 to achieve mast cell stabilising activity.

26. 28. Use of a compound as claimed in any of claims 1 to 23 to achieve anti25 inflammatory activity.

27. 29. Use substantially as hereinbefore described with reference to the Examples.

28. 30. A compound of formula 1 as claimed in any of claims 1 to 23 to achieve 30 mast cell stabilising activity and/or anti-inflammatory activity. -2631. A method of prophylaxis or treatment to achieve mast cell stabilising activity and/or anti-inflammatory activity by administering to a patient an effective amount of a compound of formula 1 as defined in any of claims 1 to 23.

29. 32. A process for preparing a compound as claimed in any of claims 1 to 23 by reacting 3-bromo indanone with sodium azide and reacting the isolate 3azido-indan-l-one with 10% Pd/C under hydrogen in the presence of acetic anhydride.

30. 33. A process as claimed in claim 32 using alkyl or aryl anhydrides.

31. 34. A process for preparing a compound of any of claims 1 to 23 by reacting 3bromoindanone with nitronium tetrafluoroborate in acetonitrile followed by quenching with H 2 O.

32. 35. A process as claimed in claim 34 wherein 3-bromoindanone is reacted with nitronium tetrafluoroborate in the presence of alkyl or aryl nitriles.

33. 36. A process for preparing a compound of any of claims 1 to 23 by reacting 3azido indan-1-one with triphenylphosphine and acetic acid.

34. 37. A process as claimed in claim 36 wherein 3-azido indan-1-one is reacted with triphenylphosphine and alkyl or aryl carboxylic acids.

35. 38. A process for preparing compounds of any of claims 1 to 23 in which 3 bromoindanone is reacted with alkylamines (C 1-10) in the presence of triethylamine.

36. 39. A process as claimed in claim 38 wherein the reaction is carried out with alkyl or aryl anhydrides in the presence of DMAP. -2740. A process as claimed in claim 38 wherein the reaction is carried out with alkylhalides in the presence of strong base.

37. 41. A process for preparing a compound of any of claims 1 to 23 by reduction of a double bond and/or ketone functional groups, particularly using a catalyst, especially Palladium over activated charcoal which may also include a concentrated aqueous acid such as HC1.

38. 42. A process as claimed in claim 41 wherein the reduction of ketone functional groups is achieved by using sodium borohydride.

39. 43. A process as claimed in claim 41 wherein the reduction of ketone functional groups is achieved by using hydrazine hydrate.

40. 44. A process as claimed in claim 41 wherein the reduction of ketone functional groups is achieved by using sodium cyanoborohydride.

41. 45. A process as claimed in claim 41 wherein the reduction of ketone functional groups is achieved with lithium tritertbutoxyaluminohydride or by using lithium aluminium hydride as reducing agent.

42. 46. A process as claimed in any of claims 41 to 45 including the step of Nalkylation or N-acylation of the coupled products.

43. 47. A process substantially as hereinbefore described with reference to the examples.

44. 48. A compound of formula 1 whenever prepared by any of the process of any of claims 32 to 47.