CA2239853C - Indane dimer compounds and their pharmaceutical use - Google Patents

Indane dimer compounds and their pharmaceutical use Download PDF

Info

Publication number
CA2239853C
CA2239853C CA002239853A CA2239853A CA2239853C CA 2239853 C CA2239853 C CA 2239853C CA 002239853 A CA002239853 A CA 002239853A CA 2239853 A CA2239853 A CA 2239853A CA 2239853 C CA2239853 C CA 2239853C
Authority
CA
Canada
Prior art keywords
groups
indan
compound
indanylamino
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA002239853A
Other languages
French (fr)
Other versions
CA2239853A1 (en
Inventor
John Walsh
Neil Frankish
Helen Sheridan
William Byrne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Venantius Ltd
Original Assignee
Venantius Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Venantius Ltd filed Critical Venantius Ltd
Publication of CA2239853A1 publication Critical patent/CA2239853A1/en
Application granted granted Critical
Publication of CA2239853C publication Critical patent/CA2239853C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/45—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing nine carbon atoms
    • C07C13/465—Indenes; Completely or partially hydrogenated indenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
    • C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
    • C07C35/32—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system being a (4.3.0) system, e.g. indenols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/48—Halogenated derivatives
    • C07C35/52—Alcohols with a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/188—Unsaturated ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
    • C07C49/665—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system
    • C07C49/67—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system having two rings, e.g. tetralones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
    • C07C49/683—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/34—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic
    • C07C65/36—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/013—Esters of alcohols having the esterified hydroxy group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Abstract

Indane dimer compounds of general formula 5, 6 or 9 and their pharma- ceutical use, particularly to achieve smooth muscle relaxing activity and/or mast cell stabilising activity and/or antiinflammatory activity are described, wherein in formulae 5 and 9, R1 and R3 to R15, and in formula 6, R1, R2 and R4 to R15, are selected from one or more of the same or different of H, halo, h y- droxy, alkoxy, aryloxy acetoxy, carboxy, alkyl carbonyl, hydro carbonyl, amino, amido, alkylamino hydroxylamino, amine oxide groups, azo groups, cyano, hy- drazino groups, hydrazide groups, hydrazone groups, imide groups, iminoether groups, ureyl groups, oxime, nitro, nitrate, nitrite, nitroso groups, nitril e, hete- rocyclic groups containing one or more heteroatoms selected from 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 or cycloalkyl groups containin g 3 to 8 carbon atoms which may be saturated or unsaturated, substituted alkyl or cycloalkyl groups which may be saturated or unsaturated. In formulae 5, 6 an d 9, X is O, NR (wherein R is acyl, alkyl or sulphonate groups), S, SO or SO2. In formulae 5, 6 and 9, any one or more of R1, 1R1; R2,1R2; R3 1R3; R9 1R9; R10 , 1R10 and R14, 1R14 may together represent oxo.

Description

WO 9'7/2D805 PGTlIE96100081 TNDANE DIMER COMPOUNDS AND THEIR PHARMACEUTICAL USE
The invention relates to.indane compounds, processes for their production, compositions containing them and their pharmacological use.
According to the invention there is provided a compound of any of the formulae:
Rs , pio ~ ~9 ~
l !~ R9 ~.p.~ ~~Pid It; R W .Pt 'p~f X ~ _ .w ~?:
~ n i;

/ZW
Rat R~a R ~ Ra .R~~ Rø ~ :!''~ lyc Rs ~ ~( ~. R n R6 ~'' ~' SQ' ~ v~ R,It R~ R~s SUBSTITUTc SHEET '(RULE 26) wherein in Formulae S and 9 RI and R3 to Ris in Formula 6 R1, RZ and R4 to Rls are selected from one or more of the same or different of:
H, halo, hydroxy, alkoxy, ~ryloxy, acetoxy, carboxy, alkyl carbonyl, hydr 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 one or more heteroatoms selected from N, O or S, aralkyl groups, mono and polybenzoid aryl groups, substituted aryl groups, thiol, thioureyl, phenylthioi groups, sulphonic acid groups, sulphoxide groups, suiphone groups, alkyl containing I to 10 carbon atoms or cycloalkyl groups containing 3 to 8 carbon atoms which may be saturated or unsaturated, substituted akyl or cycloalkyl groups which may be saturated or unsaturated in Formulae 5, 6 and 9 X is O, NR (wherein R is aryl, alkyl or , sulphonate groups ) , 5, SO or SO~ .
in Formula 5 any one or more of R1, ~R1; R3, 1R3; R9, 1R9; and R'o, iRio may together represent oxo, SUBSTITUTc SHEET (RULE 26) in Formula 6 any of Rt, iRi; R~, 1R2; R9, 1R9; and RI', iRi4 may together represent oxo, and in Formula 9 any of R1, iRl; R3, iR3; R9, 1R9~ and R", iRi' may together represent oxo pharmacologically acceptable salts, esters, amides, solvates and isomers thereof.
In one embodiment of the invention the alkyl or cycloalkyl are 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 Z5 containing one or more heteroatoms selected from N, O or S, aralkyl groups, mono and polybenzoid aryl groups, substituted aryl groups, thiol, thioureyl, phenyl thiol groups, sulphonic acid groups, suiphoxide groups and sulphone groups.
In one embodiment of the invention the heterocyciic groups contain one or more heteroatoms selected from N, O or S.
In Formulae 5, 6 and 9 R4 to R' may be hydrogen. In Formula 5 , R11 to R1'' and in Formulae 6 and 9 , R1° to R13 may also be hydrogen.
In Formula 5, 6 and 9 preferred particularly because of pharmacological activity are those compounds in which X
represents NR wherein R is acyl, alkyl or sulphonate groups.
SUBSTITUTE SHEET (RULE 26) Preferred particularly because of activity as anti-inflammatory agents are those compounds in which R
represents acyl.
Preferred particularly because of activity as mast cell stabilizing agents are those compounds in which R represents alkyl or sulphonate.
The invention relates to the compounds above for use particularly as smooth muscle relaxants and/or as mast cell stabilizing agents and/or as anti-inflammatory agents.
The invention also relates to pharmaceutical compositions containing the compounds and to their use in methods of prophylaxis or treatment particularly to achieve smooth muscle relaxant activity and/or mast cell stabilizing activity and/or anti-inflammatory activity.
The invention also relates to the compounds per se given in Appendix 2.
The invention also provides various processes for preparing the indane dimers as outlined in the claims. These processes are described in more detail below.
In a broad aspect, then, the present invention relates to a compound of Formula 5:
R' m Rt3 -4a-wherein R is H, acyl, alkyl, allyl or benzyl group R2, 1R2~
R9 to R8, R9, 1R9, Rlo, 1R1°; Rll to R15 are each independently selected from the group consisting of: H, halo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, alkyl carbonyl, hydro carbonyl, amino, amido, alkylamino, hydroxylamino, a sulfonic acid group, a sulfoxide group, a sulfone group, optionally substituted C1-C1° alkyl and optionally substituted C3 -Cg cycloalkyl; wherein any one or more of R2, 1R2 ; R9, 1R9 : and R'°, iR1° may together optionally represent oxo, and wherein Rl and '~Rl are =O or when one of Rl and '-Rl is H then the other is OH.
In another broad aspect, then, the present invention relates to a compound of Formula 6:
~IU R11 R9 yRi2 R$

NR

R2 Ria wherein R is H, acyl, alkyl, allyl, benzyl or a sulfonate group Rl, 1R'', R2, 1R2, Rq to R", R9, IR9, R1° to R13, R19, 1R'-4 and R15 are each independently selected from the group consisting of: H, halo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, alkyl carbonyl, hydro carbonyl, amino, amido, alkylamino, hydroxylamino, a sulfonic acid group, a sulfoxide group, a sulfone group, optionally substituted Cl-C1° alkyl and optionally substituted C3-C8 cycloalkyl;
wherein any one or more of R1, 1R1 ; R°'-, 1R2 ; R9, 1R9 ~ and R19~ 1_R19 may together optionally represent oxo:

-4b-In a further broad aspect, then, the present invention relates to a compound selected from the group consisting of 3-(N-1-indanylamino)-indan-1-one, 3-(N-1-indanylamino)indan-1-0l, 3-(N-methyl-N-1-indanylamino)-indan-1-one, 3-(N-prop-2-enyl-N-1-indanylamino)-indan-1-one, 3-(N-benzyl-N-1-indanylamino)-indan-1-one, 3-(N-1-indanylamino)-indan-1-one hydrochloride, N-1-indanyl-N-3-indan-1-onylethanamide, 3-(N-prop-2-enyl-N-1-indanylamino)-indan-1-one, hydrochloride, 3-(N-2-indanylamino)-indan-1-one, 3-(N-2-indanylamino)-indan-1-0l, 3-(N-methyl-N-2-indanylamino)-indan-1-one, 3-(N-prop-2-enyl-N-2-indanylamino)-indan-1-one, 3-(N-benzyl-N-2-indanylamino)-indan-1-one, 3-(N-2-indanylamino)-indan-1-one hydrochloride, N-2-indanyl-N-3-indan-1-onyl-p-toluenesulfonamide, N-2-indanyl-N-3-indan-1-onylethanamide, and 3-(N-prop-2-enyl-N-2-indanylamino)-indan-1-one hydrochloride.
general Reaction Procedures 1. Coupling of 1-amino and 2-amino indan derivatives to 3-bromo-indanone derivatives The general reaction procedure for this reaction is as follows: Either 1-amino indan or 2-amino indan was dissolved in dry DCM and to this an equivalent of 3-bromo indanone was added. The reaction solution was then cooled to 0°C and triethyl amine was added as the tertiary base.
The solution was allowed to stir at 0°C for 3 hours. The product was purified by flash column chromatography.
2. N-Alkylation of the products from reaction procedure no. 1 The 1 or 2-aminoindan dimer was dissolved in DCM and to this was added triethyiamine as the tertiary base. The desired alkylation agent was then added and the solution was allowed to stir at room temperature for 3 hours. The reaction mixture was then passed through a flash silica column and the product was eluted.
3. N-sulfonylation of the products from reaction procedure no. 1 1 or 2-aminoindan dimer was dissolved in DCM and to this was added p-toluenesuifonyl chloride and triethylamine.
The solution was allowed to stir at 0°C for 15 mins and then at room temperature for a further hour. Pyridine was then added to the reaction solution and the reaction was allowed to stir for a further 2 hours. The crude reaction mixture was passed through a flash silica column.
SUBSTITUTE SHEET (RULE 2$) l.
4. N-acylation of the products from reaction procedure no. 1 1 or 2 aminoindan dimer was dissolved in DCM and to this was added triethylamine and acetic'. anhydride. To this stirring solution DMAP was added. The reaction was allowed to stir at room temperature for 3 hours. To the reaction mixture was added a 2M solution of aqueous HC1 and the solvent was removed using toluene. To the crude material an aqueous solution of NaHC03 was added and the product was extracted into ether, the organic layers were combined and the solvent removed. The crude material was then passed through a flash silica column.
5. Sodium borohydride reduction of dimers This reduction is particularly applicable to the reduction of the ketone functional group of the compounds. The reduction procedure was as follows.
The required dimer was dissolved in ethanol and sodium borohydride was added to the reaction in small portions over 10 mins. The reaction was then stirred at room temperature for 3 hours. The reaction mixture was poured onto water (20 ml) and extracted into diethyl ether (3 x 20 ml). Flash column chromatography over silica gel afforded the product.
S. Cyanoborohydride reduction of dimers This reduction procedure is particularly applicable to the reduction of the ketone functional group of the compounds.
The reduction is as follows.
The required dimer was dispersed in 1,2-dichloroethane at room temperature. To this solution was added solid zinc SUBSTITUTE SHEET (RULE 26) iodide and sodium cyanborohydride. The reaction was ' stirred at reflux for 20 hours. The product was added to water and extracted into ethyl acetate. Flash column ' chromatography (eluent: petroleum ether: ethyl acetate, 9:1) was used to isolate the pure product.
7. Hydrolysis of an ester The required ester was dissolved in a solution of 1.45 M
NaOH in THF:MeOH:HZO (6:3:2), which was then refluxed.
After 20 minutes, TLC showed that the hydrolysis of the ester was complete. After cooling the reaction mixture, a saturated solution of aqueous ammonium chloride, aqueous HCl (2M) and ether was added. The organic layer was isolated and the aqueous layer was extracted with ether.
The combined organic extracts were dried with Na2S04 and filtered. Evaporation of the solvent, left the acid.
8. Oxime synthesis This procedure is particularly applicable for the synthesis of oxime derivatives of ketonic indane dimers which have hydrogens to the ketone. Generally the procedure was as follows.
The ketonic indanone dimer was dissolved in a solution of methanol: pyridine (4:1) and to this solution was then added hydroxylamine hydrochloride. Depending on the specific ketonic indan dimer, the reaction was carried out either at room temperature or at reflux conditions.
9. O-alkylation of the oxime This procedure is particularly applicable to O-alkyiation of the oxime derivatives synthesised. Generally the procedure was as follows.
SUBSTITUTE SHEET (RULE 26) WO 97/20805 PCTlIE96100081 $ -A solution of the oxime indane dimer was dissolved in ether:tert-butanol 3:1. Benzyl bromide was generally set as the alkylating reagent and it was added to the reaction mixture. Potassium tert-butoxide 1 eq. was added dropwise to this solution at room temperature. After workup using aqueous ammonium chloride and ether the desired oxime ether was isolated after chromatography.
10. Indan ether dimers This procedure is particularly applicable for the self coupling of two 1-indanol molecules to give indan ether dimeric compounds with the loss of water.
The desired 1-indanol derivative was dissolved in DCM at 0°C and an equivalent of methane sulfonyl chloride or methane sulfonic anhydride was added to the reaction mixture. N,N-diisopropylethyl amine was added dropwise as the tertiary base. The reaction mixture was left stirring for either at 0°C or at room temperature, depending on the particular 1-indanol.
11. Acetylation of the hydroxyl indan-dimers Generally the procedure was to dissolve the compound for acetylation in DCM and to use acetic anhydride as the acetylating reagent with triethylamine as tertiary base and DMAP as the acylation catalyst.
SUBSTfTUTE SHEET (RULE 26) _ g _ ~vnthesis of 5C3 Coupling reaction.
Br EIjN
N
v :~'H ~_ {JoC H
O
~G3 To a solution of 3-bromo-indan-1-one (200 mg, 0.952 mmol) and 1-aminoindan (130 mg, 0.952 mmol) in dry DCM (10 ml) at 0°C was added triethylamine (0.19 g, 0.26 mi, 1.90 mmol). The solution was allowed to stir at 0°C for 3 hours. The crude reaction mixture was passed through a plug of silica, eluting with petroleum ether: ethyl acetate (4:i). 5C3 was isolated as a white solid (150 mg, 60~).
1H NMR (CDC13, 300 MHz) SH 1.7?-I.89 (1H, m, CH of CHCHZCHZ) , 2 .43-2 . 53 ( 1H, m, CH of CHCHZCH_2) , 2.58 { 1H, dd, J=3.4Hz & I8.5Hz, CH of CHCI-~Z) , 2. 79-2.89 ( 1H, m, CH of CHCH~CHZ) , 2.99-3 . 04 ( 1H, m, CH of CHC~i2CHZ) , 3.09 ( 1H, dd, J=6.7Hz & 18.7Hz, CH of CHCHz), 4.43 (1H, t, J=6.7Hz, CHCHzCHz), 4.65 (1H, q, J=3.SHz & 6.7Hz, C~CHZ), 7.21-7.27 (3H, m, 3 x Ar-I-~), 7.41-7.47 (2H, m, 2 x Ar-H), 7.65 (1H, dt, J=1.2, 7.7Hz, 1 x Ar-H), 7.75 (2H, 2 overlapping t, 2 x Ar-H).
SUBSTITUTE SHEET (RULE 26) WO 97/20805 PCTlIE96100081 isC NMR (CDC13, 7s.47 MHz) s~ 30.4, 36.0, 46.8 (3 x C_HZ), 52.2, 62.5 (2 x CH), 123.3, 124.1, 124.9, I26.Q, 126.3, 127.6, 128.6, 134.8 (8 x Ar-CH), 136.6, 143.4, 14s.3, 1s6.6 (4 x Ar-C), 204.6 (C=O).
SUBSTITUTE SHEET (RULE 26) Coupling of S-(+)-1-aminoindan to 3-bromoindanone to give ~ two diastereomers of 5C3 which are called 5C3 bottom S and SC3 top S
synthesis of 5C3 Bottom (S) and Tory (S} isomers Stereospecific coupling reaction Br O
/ - Et~
\ + \ E ----~ ~ \
v O \H. H~\. ~ H/ I
R,S
S.S
3-bromoindanone (780 mg, 3.73 mmol) was placed in a dry flask with DCM (10 ml). To this was added S (+}-I-aminoindane (500 mg, 3.78 mmol} and triethylamine (750 mg, 0.96 ml, 7.42 mmol). The solution was allowed to stir at 0°C for 2 hours . The crude reaction mixture was passed through a plug of silica, eluting the products with petroleum ether . ethyl acetate (7:3). The top diastereomer was obtained after evaporation of the eluent and was further purified by washing the solid with petroleum ether. The bottom diastereomer fraction was found to be insoluble in ether and this was used as a method of purification. Combined yield was recorded as ( 660 mg, 68 . 90 .
BOTTOM (S) diastereomer 5C3 bottom S
iH _NMR (CDC13, 300 MHz) 8H 1.63 (1H, s, NH), 1.76-I.88 {IH, m, 1H of CHC~ZCHZ) , 2.42-2.52 ( 1H, m, 1H of CHCHZCHZ) , 2.53 SUBSTITUTE SHEET (RULE 26) & 2. 60 ( 1H, 2 x d, J= 3. S Hz, H of CHCHZCO) , 2 . 78-2 . 88 ( 1H, q, J= 7.7 Hz, H of CHCHZC~Z), 2.98-3.04 (1H, m, H of CHCHzC,~2 ) , 3 . 06 & 3 . 1 I ( 1H, 2 x d, J= 6 . 6 Hz , H of CHC~-IZCO ) , 4 . 42 { 1H, t, J= 6 . 7 Hz , C~-iCHzCH2 ) , 4 . 61 ( 1H, q, -J =3 . 3 & 6 . 6 Hz , CHCHZCO) , 7 . 2I-7 . 28 ( 3H, m, 3 x Ar-~) , 7.41-7.46 (2H, superimposed t, J= 0.9 & 7.9 Hz, 2 x Ar-H_), 7 .65 ( 1H, 2 x t, J= 0 . 9 & 7 . 9 Hz, 1 x Ar-I~- } , 7 . 72-7 . 82 ( 2H, m, 2 x Ar-~) .
13C NMR (CDC13, 75.47 MHz) 8~ 30.3 (CHZCHZCHNH}, 36.0 ( CHZ~HZCHNH ) , 4 6 . 7 ( NHCHCHZCO } , 55 . 1 ( NHCHCH~CO ) , 6 2 . 4 (CHZCHZ~HNH), 123.1, 124.0, 124.8, 126.0, I26.2, 127.5, 128.5, 134.7 (8 x Ar-~H), 136.5, 143.3, 145.3, 156.5 {4 x Ar-~,), 204.5 (~=O).
TOP (S) diastereomer 5C3 top S
IS 1H NMR ( CDC13, 300 MHz ) 8H 1 . 70 ( 1H, s , NIA-,) , I . 94-2 . 00 ( 1H, q, J= 7.1 z, H of CHCHZCHZ), 2.51-2.58 (IH, m, 1H of CHCHZCHZ), 2.61 & 2.67 (1H, dd, J= 2.8, 18.4 Hz, H of CHCHZCO) , 2.83-2. 93 ( 1H, q, J= 7 . 7 Hz, H of CHCHZCF~-Z) , 3.03 (1H, d, J=6.6 Hz, H of CHCHZCHZ), 3.10 (1H, d, J= 6.4 Hz, H of CHCHZCO), 4.39 (1H, t, J= 6.6 Hz, CHCH,CHZ), 4.64 (1H, t, J =2. 8 Hz, CfICH2C0) , 7. 19-7.31 (4H, m, 4 x Ar-Fi) , 7.44 (1H, t, J= 7.4 Hz, 1 x Ar-H), 7.58-7.69 (2H, m, 2 x Ar-H), 7.75-7.82 {1H, d, 1 x Ar-Fi).
isC NMR ( CDC13 , 7 5 . 4 7 MHz ) s~ 3 0 . 4 ( CHZCHZCHNH ) , 34 . 3 2 5 ( CHZ~HZCHNH ) , 4 5 . 8 ( NHCHCHZCO ) , S 4 . 0 ( NHCHCH~CO ) , 61 . 6 (CHZCHZ~HNH), 123.4, 123.9, 124.8, 125.8, 126.5, 127.7, 128.?, 134.9 (8 x Ar-~H), 136.9, 143.5, 144.8, 156.2 (4 x Ar-~), 204.7 (C=O).
SUBSTITUTc SHEET (RULE 26) incr of R-(-~)-1-aminoindan to 3-bromoindanone to give two d~.astereomers of 5C3 which are called 5C3 bottom R and ' ~C3 top R
~,y~thesis of 5C3 Bottom R and Too R
Stereospecific coupling reaction Bc ~ O
~ E~w ~ ~ ~
o y H~ r-t W /
R.R
S.R
3-bromoindanone (780 mg, 3.73 mmol) was placed in a dry flask with DCM {10 ml). To this was added R (-)-I-aminoindane (500 mg, 3.73 mmol) and triethylamine (750 mg, 0.96 ml, 7.46 mmol). The solution allowed to stir at 0°C
for 2 hours. The crude reaction mixture was passed through a flash silica column, eluting the products with petroleum ether . ethyl acetate {7:3). The top diastereomer was obtained after evaporation of the eluent and was further purified by washing the solid with petroleum ether. The bottom diastereomer fraction was found to be insoluble in ether and this was used as a method of purification of the bottom spot. Combined yield for these compounds (680 mg, 68.90 .
Bottom (R) diastereomer 5C3 bottom R
IH NMR (CDC13, 300 MHz) 8H 1.63 ( 1H, s, N~) , I.83-I.85 ( 1H, m, 1H of CHCH_ZCHZ) , 2.42-2 . 52 ( 1H, m, 1H of CHC_HZCHZ) , 2.53 SUBSTITUTE SHEET (RULE 26j WO 97/20805 PCTlIE96/00081 & 2.60 (1H, 2 x d, J= 3.5 Hz, H of CHCF~ZCO), 2.78-2.88 (1H, q, 3= 7.7 Hz, H of CHCHZCHZ), 2.98-3.04 (1H, m, H of CHCHZCHz) , 3.06 & 3. 11 ( 1H, 2 x d, J= 6.6 Hz, H of CHCHZCO ) , 4 . 42 ( 1H, t, J=6 . 7 Hz , CHCHzCH2 ) , 4 . 61 ( 1H, q, J=3 . 3 & 6 . 6 Hz , CSI-CHZCO ) , 7 . 2I-7 . 28 ( 3H, m, 3 x Ar-H ) , 7.4I-7.46 (2H, superimposed t, J=0.9 & 7.9 Hz, 2 x Ar-H), 7.65 {IH, 2 x t, J=0.9 & 7.9 Hz, 1 x Ar-H_}, 7.72-7.72 {2H, m, 2 x Ar-H).
13C NMR (CDC13, 75.47 MHz) 8~ 30.3 (CHZCH~CHNH}, 35.9 ( CH,CHZCHNH ) , 4 6 . 6 ( NHCHCHZCO } , 5 5 . 0 ( NHCHCH,CO ) , 6 2 . 4 (CH~CHZCHNH}, 123.0, 123.9, 124.7, 125.9, 126.1, 127.4, 128.4, 134.6 (8 x Ar-~H), 136.4, 143.2, 145.2, 156.4 (4 x Ar-~,), 204.4 (C=O).
Top {R) diastereomer 5C3 Top R
1H NMR (CDC13, 300 MHz ) sA 1 .70 ( 1H, s, NI-~) , 1.94-2.00 ( iH, q, J= 7.1 z, H of CHCH,CHZ), 2.5I-2.58 {1H, m, 1H of CHC -,~i2CH2 ) , 2 . 6 I & 2 . 6 7 ( IH , dd , J= 2 . 8 Hz , H o f CHC~-i2C0 ) 2.83-2.93 (1H, q, J= 7.7 Hz, H of CHCHZC~2), 3.03 (1H, d, J=6.6 Hz, H of CHCH,CH ), 3.10 (1H, d, J= 6.4 Hz, H of CHCHzCO), 4.39 (1H, t, J= 6.6 Hz, CHCHZCH~), 4.64 (IH, t, J =2.8 Hz, CHCHZCO}, 7.i9-7.31 {4H, m, 4 x Ar-~-I), 7.44 (1H, t, J= 7 .4 Hz, 1 x Ar-~,) , 7.58-7 .69 (2H, m, 2 x Ar-,~,) , 7.75-7.82 (1H, d, J=7.5Hz, 1 x Ar-~).
13C NMR (CDC13, 75.47 MHz ) 8~ 30. 3 (~HzCHZCHNH) , 34. 2 2 5 ( CHz~HZCHNH ) , 4 5 . 8 ( NHCH~HZCO ) , 5 3 . 9 ( NHCHCH~CO } , 61 . 6 (CHZCH~~HNH), 123.3, 123.8, 124.7, 125.7, 126.4, 127.6, ' 128.6, 134.8 (8 x Ar-~H), 136.8, 143.4, 144.8, 156.2 (4 x Ar-~), 204.6 (C=O).
SU8ST1TUTE SHEET (RULE 26) Synthesis of 5C4 Sodium borohydride reduction of 5C3 EtOAc: ~tOH N ~ H
+ NaBH.~
ON
O

Dimer 5C3 (100 mg, 0.38 mmol) was dissolved in ethanol (4 ml) and ethyl acetate (8 ml). To this solution sodium borohydride (0.1 g, 2.63 mmol) was added to the reaction in small portions over 10 minutes. The reaction was stirred at room temperature for 3 hours. Evaporation of the solvent left a white solid and to this was added DCM.
Filtration followed by evaporation left a mobile oil which was taken up in the minimum amount of DCM and passed through a plug of silica, eluting with petroleum ether (b.p. 40-60°C):ethyl acetate, 98:2) afforded 5C4 as a mixture of diastereomers (25 mg, 25$).
LH NMR (CDC13, 300MHz) SH:

' 15 1.84-1.90 ( m, CH of CHCHZC~z) 1H, 1.93 ( IH, t, CH of CHCHZC~-i2) J=3.7Hz ' 2 .06-2. 37 ( m, CH of CHCHZCHZ) 1H, 2.48-2.68 {2H, m, CH of NHC~-IZ) 2.86 (1H, q, =8.5 CH of CHCHz) J Hz, 2.98-3.01 ( m, CH of CHCHzCHz) 1H , SUBSTITUTE SHEET (RULE 26) WO 97!20805 4 . 6 3 ( 1H , t , J=5 . 9 , C~iCHZCH2 ) 5.02-5. 31 ( 1H, 2 x m, CHZCI~-OH) 7.18-7.50 {8H, m, 8 x Ar-H) 13C NMR (CDCi3, 75.47 MHz) s~ 30.3, 34.3, 45.0, (~HZ) , 59. 1, 61.5, (~HNH), 74.5, (~HOH), 124.0, 124.1, 124.2, 124.3, 124.6, 124.7, 124.8, 126.3, 126.4, 127.3, 127.4, 127.5, 128.0, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6 (8 x Ar ~H), 143.2, 143.2, 143.3, 143.3, 143.5, 143.5, 144.1, 144.5, 144.5, 144.6, 144.7, 144.8, 144.8, 145.0, 145.3, 145.4, 145.6, 145.7 (4 x Ar-~).
SUBSTITUTE SHEET (RULE 26) WO 97/20805 PCTlIE96100081 Synthesis of 5C5 O
O
+ Et3N + CH zI D I
CM
N
/N
Nb To a solution of dimer 5C3 (200 mg, 0.76 mmol) in DCM (5 m1) was added triethylamine (0.09 g, 0.13 ml, 0.91 mmol) and methyiodide (1.08g, 0.48 ml, 7.61 mmol). The solution was allowed to stir at room temperature for 2 hours. The solvent was removed and the crude reaction mixture was passed through a plug of silica, eluting with petroleum ether: ethyl acetate {8:2) to yield dimer 5C5 as a yellow oil (0.80 g, 38$).
1H NMR {CDC13, 300 MHz) SH i.89 & 2.27 (3H, 2 x s, Ci-~3), 1.98-2.19 (2H, m, CHCHZCHZ), 2.55 & 2.69 (1H, dd J=6.9Hz, CH of CHC-~i2C0), 2.74-2.89 (2H, m, CH of CHCHZCO & CH of CHCHZCFj- Z ) , 2 . 91-3 . 05 ( IH, m, CH o f CHCHZCHZ ) , 4 . 34 & 4 . 63 ( IH, 2 x t, J=7.7Hz, NCH3C~-ICHzCHZ) , 4.55 & 4 .77 ( 1H, 2 x dd, J=6 . 9Hz, CIA-CHCO) , 7 .20-7.29 { 3H, m, 3 x Ar-~-I) , 7 .44 (1H, m, i x Ar-F~), 7.52 (IH, m, 1 x Ar-H), 7.67 (1H, d$bq, J=l.2Hz & 7.4Hz, 1 x Ar-I-~), 7.75 (1H, t, J=6.7Hz, 1 x Ar-F~-), 7.84 (1H, dt, J=0.9Hz & ?.7Hz, 1 x Ar-H).
SUBSTITUTE SHEET (RULE 26) F3C NMR (CDC13, 75.47 MHz) s~ 26.5, 27.1 {MHz), 30.4, 31.8 , (MHz) , 37.9, 38.8 (CHZ) , 27.9, 34 .2, {CH3) , 58.0, 61.7 (~H), 66.9, 69.9 (~H), 122.7, 122.8, 124.4, 124.5, 124.7, , 126.1, 126.2, 126.3, 126.3, 126.3, 127.3, 127.3, 128.3, 128.3, 134.7, 134.7 (8 x Ar-~H), 136.8, 136.9, 142.9, 143.1, 143.7, 143.9, 156.0, 156.3 (4 x Ar-~), 204.7, 204.7 ( ~,=O ) .
SUBSTITUTE SHEET (RULE 26) Synthesis of 5C6 O
" ' ~ Ei ~.'~1 t s/~/ ~ DCM
M
5c3 sc6 To a solution of dimer 5C3 (200 mg, 0.76 mmol) in DCM (5 ml) was added triethylamine (0.09 g, 0.13 ml, 0.91 mmol) and allyl bromide (0.90 g, 0.65 ml, 7.61 mmol}. The solution was allowed to stir at room temperature for 2 hours. The solvent was removed and the crude reaction mixture was passed through a plug of silica, eluting with petroleum ether:ethyl acetate (8:2) to yield dimer 5C6 as a yellow oil (I85 mg, 80$).
1H NMR (CDC13, 300 MHz ) 8H 2 .05 ( 2H, br m, CI_i2) , 2 . 47 ( 1H, dd, J=9.5Hz, CH of CHZ) , 2.72 (2H, m, CIA-ZCH=CHZ) , 3. i1 ( 3H, br m, CH of CHz's), 4.40, 4.50 (1H, 2 x t, J=3.OHz, NC~iCH~CH2) , 4.65 ( 1H, m, Cg-CHZCO} , 4.97, 5.00, 5. 10, 5. 11, 5.I4, 5.18, 5.27, 5.33 (2H, 8 x br m, CH2CH=CHz}, 5.80 (1H, br m, CHZCH=CHZ) , 7 .20 ( 3H, br m, 3 x Ar-H) , 7 .40, 7 . SO
(2H, 2 x br m, 2 x Ar-H), 7.64 (IH, br m, 1 x Ar-H), 7.74, 7.86 (2H, 2 x br m, 2 x Ar-~).
i3C NMR (CDCI3, 75.47 MHz) 8~ 27.9, 29.6 (~HZ), 30.1, 30.3, 30.6 (~HZ) , 40. 1, 41.3 (~HZ) , 49.5, 49.6 (MHz) , 55. 8 57.0 (~H), 63.6, 64.6 (~H), 116.2, 116.8 (C=CHZ}, 122.9, 123.0, 124.I, 124.6, 124.7, 124.9, 126.2, 126.2, I26.4, 126.6, 12?.3, 127.6, 128.4 (8 x Ar-~H & 1 x ~H=CHZ), 134.5, 134.9, 137.0, 137.2, 137.4, 143.0, I43.3, 144.0, 144.5, 156.7 (4 x Ar-~, ) , 2 0 4 . 9 ( ~=O ) .
SUBSTITUTc SHEET (RULE 26) Alkylation of 5C3 bottom R diastereomer with allyl bromide to vieid 5C6 bottom S diastereomer i W
N

Dimer 5C3 Bottom R ( 200 mg, 0 . 76 mmol ) was dissolved in DCM (2 ml} in a round bottomed flask and this was allowed to stir. To this solution was added triethylamine (0.09 g, 0.13 ml, 0.94 mmol) and allyl bromide (0.9I g, 0.65 ml, 7.38 mmol). The reaction was allowed to stir at room temperature for 8 hours. The crude reaction mixture was passed through a plug of flash silica, eluting with petroleum ether . ethyl acetate 7:3. On evaporation of the solvent a white solid 5C6 Bottom R was obtained (I93 mg, 83.50 .
1H NMR ( CDC13, 300 MHz } SH 1 . 95-2 . 15 ( 2H, br m, CHCIIZCHZ ) , 2.54 {2H, 2 x ab q, J=18.9 & 16.9 Hz, CHCHZ}, 2.74 & 2.94 ( 2H, m CHCHaCFi2 ) , 3 . 10 & 3 . 23 ( 2H, 2 x ab q, J= 14 . 7 , 16 . 0 , 1 . 5 & 1 . 3 Hz , CF~IZCHCHZ ) , 4 . 5 0 ( 1H , t , J= 7 . 2 Hz , CHCHZCHZ ) , 4.66 (1H, q, J=6.6 Hz, CIiCHZCO), 4.97 & S.I8 (1H, 2 x dd, J=1 . 7 & 59 . 3, CH of CHZCH=C~-I2) , 5 .01 & 5. 11 ( 1H, 2 x dd, J=
1. 5 & 32 . 0 Hz , CH of CHZCH=CHZ ) , 5 . 7 3 ( 1H, m, CHZC~iCH2 ) , 7.20 (3H, m, 3 x Ar-H), 7.39 (2H, m, 2 x Ar-H), 7.62 (1H, dt, J= 1.32 & 7.26 Hz, 1 x Ar-H), 7.74 {2H, m, 2 x Ar-~-I).
SUBSTITUTE SHEET (RULE 26) 13C NMR (CDC13, ?5.47 MHz) 8~ 30.1, 30.5, 41.3, 49.4, 116.1 (5 x ~HZ), 57.1, 64.6 (2 x C_H), 122.9, 124.8, 124.8, 126.2, 126.6, 127.5, 128.3, 134.4, 137.4 (8 x Ar-CH & 1 x CH=CHZ), 137.1, 143.3, 144.0, 156.6 (4 x Ar-C), 204.7 (C_=O).
SUBSTITUTE SHEET (RULE 26) ~lkvlation of 5r3 bottom S diastereomer with allyl bromide to yield 5C6 bottom S
O

SC3 Bottom S (200 mg, 0.76 mmoi) was dissolved in DCM (2 ml) in a round bottomed flask and this was allowed to stir. To this was added triethylamine (0.09 g, 0.13 ml, 0.94 mmol) and aliyl bromide (0.91 g, 0.65 ml, 7.36 mmol).
The reaction was allowed to stir at roam temperature for 8 hours. The crude reaction mixture was passed through a plug of flash silica, eluting with petroleum ether : ethyl acetate 7:3. On evaporation of the solvent a white solid 5C6 Bottom S was obtained as a yellow solid (205 mg, 88.7$).
1H NMR (CDC13, 300 MHz) EH 1.95-2. i5 (2H, br m, CHCHZCHz) , 2.54 (2H, 2 x ab q, J=18.9 & I6.9 Hz, CHCHz), 2.74 & 2.94 ( 2H, m, CHCHZCFiZ ) , 3 . 1 I & 3 . 25 ( 2H, 2 x ab q, J= 14 . 5 &
14 . 7 Hz , CFi2CHCH2 ) , 4 . 51 ( 1H , t , J= 7 . 2 Hz , CIiCHZCHZ ) , 4 . 6 ( 1H, m, Ci~-CHZCO) , 4 . 99 & 5. 15 ( 2H, 2 x dd, J=9 . 9 & 17 . 1 Hz,CHzCH=CHI) , 5. 73 ( 1H, m, CHZC~-i,CHz) , 7.20 ( 3H, m, 3 x Ar-7 . 41 ( 2H, m, 2 x Ar-I~-. ) , 7 . 63 ( 1H, t, J= 7 . 2 Hz, 1 x ' Ar-,~), 7.74 (2H, m, 2 x Ar--Vii) .
isC NMR (CDC13, 75.47 MHz) 8~ 30.1, 30.5, 41.2, 49.4, 116.1 (5 x ~,HZ), 57.0, 64.6 (2 x CH), 122.9, 124.8, 124.8, 126.2, SUBSTITUTE SHEET (RULE 26) a126.5, 127.5, 128.3, 134.4, 137.4 (8 x Ar-C_H & i x CH=CHz), 137.1, 143.2, 143.9, 156.6 (4 x Ar-~), 204.7 ).
SUBSTITUTE SHEET (RULE 26) PCT/iE96/00081 P~kylation of 5C3 Ton R diastereomer with allvl bromide to yield 5C6 Top R
O
N'~\, Dimer 5C3 Top R (200 mg, 0.76 mmol) was dissolved in DCM
(2 ml) in a round bottomed flask and this was allowed to stir. To this was added triethylamine (0.09 g, 0.13 ml, 0.94 mmol) and allyi bromide (0.9i g, 0.65 ml, 7.35 mmol).
The reaction was allowed to stir at room temperature for 8 hours. The crude reaction mixture was passed through a plug of flash silica, eluting with petroleum ether: ethyl acetate 7:3. On evaporation of the solvent a white solid 5C6 Top R was obtained {I89 mg 81.80 .
1H NMR ( CDC13, 300 MHz ) sA 1 . 87-2 . 16 ( 2H, br m, CHC -LizCHz ) , 2.72 (2H, m, CHC 'BIZ) , 2.72 ( IH, m, CH of CHCHZCHi) , 2.93 ( 1H, m, CH of CHCHZCI~Z) , 2 . 95-3 . 15 ( 2H, m, CHZCH=CHz) , 4 .41 ( IH, t, J= 7.7 Hz, C~iCH2CH2) , 4 .64 ( 1H, t, J=5.0 Hz, CHCHZCO), 5.13-5.29 (2H, 2 x dd, J=10.1 & 17.1 Hz, CHZCH=CHI) , 5. 85 ( 1H, m, CHZC-~iCH2) , 7 . 23 ( 3H, m, 3 x Ar-H) , ' 7.42 (IH, t, J= 7.3 Hz, 1 x Ar-I-~), 7.52 {IH, d, J= 7.0 Hz, 1 x Ar-~), 7.66 {1H, t, J=7.3 Hz, 1 x Ar-I-~), 7.73 {1H, d, J= 7.4 Hz, 1 x Ar-~I), 7.86 (1H, d, J= 7.4 Hz, 1 x Ar-~-I').
isC NMR (CDC13, 75.47 MHz) 8~ 27.9, 30.3, 40.1, 49.6, 116.8 (5 x ~HZ), 55.9, 63.7 (2 x ~H), I22.9, 124.2, I24.5, 126.2, SUBSTITUTE SHEET (RUIF 26) WO 97!20805 PCTJIE96/00081 126.4, 12?.4, 28.4, 134.9, 137.0 (8 x Ar-CH & 1 x CH=CHZ), 137.3, I43.0, I44.5, I56.7 (4 x Ar-~), 204.8 (~=O).
SUBSTITUTE SHEET (RULE 26) Alkvlation of 5C3 Toy S diastereomer with allyl bromide to yield SC6 Toy S diastereomer O
N

Dimer SC6 Top S (200 mg, 0.76 mmol} was dissolved in DCM
(2 ml) in a round bottomed flask and this was allowed to stir. To this was added triethylamine (0.9 g, O.I3 ml, 0.94 mmol) and allyi bromide (0.91 g, 0.65 ml, 7.35 mmol).
The reaction was allowed to stir at room temperature for 8 hours. The crude reaction mixture was passed through a plug of flash silica, eluting with petroleum ether : ethyl acetate 7:3. On evaporation of the solvent a white solid 5C6 Top S was obtained (197 mg, 85.30 .
1H NMR { CDC13, 300 MHz ) 8 1 . 91-2 . 15 ( 2H, br m, CHCHZCH~) , 2 .72 { 2H, m, CHC-BIZ) , 2.72 ( 1H, m, CH of CHCH.,CF~Z) , 2.93 ( 1H, m, CH of CHCH~C -~i2 ) , 2 . 95-3 . 15 ( 2H, m, CIA- ZCH=CHZ ) , 4 . 41 (1H, t, J= 7.7 Hz, CHCHzCHz), 4.64 (1H, t, J=5.0 Hz, CIA-CHZCO), 5.13-5.29 {2H, 2 x dd, J=9.9 & 17.1 Hz, CHZCH=CHZ ) , S . 84 ( IH, m, CHzCHCHz ) , 7 . 19-7 . 26 ( 3H, br m, 3 x Ar-H}, 7.41 (1H, t, J= 7.2 Hz, i x Ar-H), 7.73 (1H, d, J= 6.8 Hz, 1 x Ar-H), 7.73 (1H, d, J= 6.8 Hz, 1 x Ar-H), -7.86 (1H, d, J= 7.6 Hz, 1 x Ar-H).
13C NMR (CDC13, 75.4? MHz) s~ 27.9, 30.2, 40.1, 49.6, 116.7 (5 x ~HZ), 55.8, 63.6 (2 x ~H), 122.8, 124.1, 124.5, 126.1, SUBSTITUTE SHEET (RUL.E 26) 126.4, 12?.3, 128.4, 134.8, 137.0 (8 x Ar-CH & 1 x CH=CH2j, 137.2, 143.0, 144.4, 156.7 (4 x Ar-~), 204.7 (C=O).
SUBSTITUTE SHEET (Ruth 26) Synthesis of 5C7 + Et j N + ~ I DC7H
Br sc3 sc~
To a solution of dimer 5C3 (200 mg, 0.76 mmol) in DCM (5 ml) was added triethylamine (0.09 g, 0.13 ml, 0.91 mmol) and benzyi bromide (1.30 g, 0.90 ml, 7.61 mmol). The solution was allowed to stir at room temperature for 2 hours. The solvent was removed and the crude reaction mixture was passed through a plug of silica, eluting with petroleum ether:ethyl acetate (8:2) to yield 5C7 as a yellow oil (I75 mg, 76$).
'H NMR (CDC13, 300 MHz) 8H 2.45, 2.76 (1H, 2 x dd, J=7.lHz & 19.3Hz, CH of COCA-ZCH), 2.63, 2.89 (1H, 2 x dd, J=3.7Hz & 19.3Hz, CH of COCH~CH), 2.10, 2.78, 2.95 (4H, 3 x br m, 2 x CHZ), 3.60 (1H, ab q, J=12.8Hz & 17.9Hz, H of PhCH_Z), 3.75 ( 1H, ab q, J=14 .4Hz & 52. 8Hz, CH of PhCH2) pair of diastereomers, 4.37, 4.42 (1H, 2 x t, J=8.2Hz & 7.3Hz, NCI-~CHZCH2) , 4.58, 4 .64 ( 1H, 2 x dd, J=7.OHz & 4.OHz, 3.8Hz, 7 . OHz, NCFiCHZCO) , 7 . 35, 7 .65 ( 12H, 2 x br m, 12 x Ar-H_) , 7.83 & 7.98 (1H, 2 x dd J= 0.9 & 7.7 Hz, 1 x Ar-H).
isC NMR ( CDC13, 75 . 47 MHz ) 8~ 27 . 2 ( 29 . 6 ) , 30 . 3 ( 30 . 6 ) , 39 .

(41.3), 50.6 (50.7), (4 x ~HZ), 55.6 (56.1), 63.4 (63.2), (2 x ~H), I22.8, 124.0, 124.5, 126.2, 126.3, 126.3, 126.8, 128.0, 128.0, 128.2, 128.2, 128.4, 134.7 (13 x Ar-C_H), SUBSTITUTE SHEET (RULE 26) 137.2 (I37.2), 139.6 (139.3), 143.4 (I43.1), 144.2 (I43.6), 156.5 (156.2), (5 x Ar-C), 204.6 (204.8), (C=O).
SUBSTITUTE SHEET (RULE 26) WO 97!20805 PCT/IE96/00081 synthesis of 5C8 p p H.FiCI
~. H
v IeOt I

SC3 (200 mg, 0.76 mmol) was dissolved in methanol and to this was added a 2M aqueous HCl (5 ml). Toluene was then added and the solvent evaporated to dryness to afford a yellow solid. The solid was then dissolved in water and ethyl acetate was added to remove any organic impurities which were present. The water phase was extracted and was evaporated to dryness. The solid was then dissolved in the minimum amount of methanol and ethyl acetate was added. The product was then allowed to crystallise out.
5C8 was then afforded as a white powder (205 mg, 90.310 .
SUBSTITUTE SHEET (RULE 26) Svnthesis of ~ _9 o l +c~-t ,c =o ( ~O-CI~K'1-! , E4 \ ~ O
~~ H
'.
_ D!1L-1P
~f v .l SC3 (200 mg, 0.76 mmol) was dissolved in DCM (5 ml) and to this was added triethylamine (1.54 g, 2.11 ml, 15.2 mmol) S and acetic anhydride (1.55 g, 1.43 ml, IS.2 mmol). Then to this stirring solution DMAP (460 mg, 0.38 mmol) was added. The reaction mixture was allowed to stir at room temperature for 3 hours. To the reaction solution was added 2M aqueous HC1 (5 ml) and 10 ml DCM. The organic layer was obtained and washed with water. To the organic was added to a 10~ solution of NaHC03 (30 ml). The organic phase was collected and the aqueous layer was washed with DCM. All the organic layers were combined and dried over NaZS04. 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 SC9 was obtained as a brownish solid (145 mg, 62.70 , SUBSTITUTE SHEET (RULE 26) synthesis of 5CI0 'I Et,~~ ~( 1 + p-TsCT
P5~ ~ / N
tar ~ ~ ~o C

To a stirring solution of 5C3 (200 mg, 0.76 mmol) and p-toluenesulfonyl chloride (1.45 g, 7.60 mmol) in DCM (10 ml) was added triethyiamine (0.09 g, 0.13 ml, 0.91 mmol).
The solution was allowed to stir at 0°C for 15 mins. The solution was allowed to stir at roam temperature for a further hour then to this solution was added pyridine (0.26 mi) and the reaction was allowed to stir for a further 2 hours. The crude reaction mixture was passed through a flash silica column, eluting with petroleum ether . ethyl acetate 1 . 4. 5C10 was isolated as a yellow solid (284 mg, 89.30 .
SUBSTITUTE SHEET (RULE 26) Synthesis of SC11 HC! gas N ~ MeOH
I~

Compound 5C6 (100 mg) was dissolved in dry methanol (5 ml ) , dry HCI gas was bubbled through the solution for S
mins. The methanol was then evaporated off and a white solid remained. The solid was then partioned between water and ether. The aqueous layers were combined and evaporated to dryness. The white solid 5CI1 which remained was dried on the vac line (97$).
SUBSTITUTc SHEET (RULE 26) WO 97/20805 1'CT/IE96/00081 Synthesis of SC12 methanesulphonic anhydride -~' o ipr2NEt OH
DCM
0°C

To a solution of 1-indanol 90.25 g, 1.87 mmol) in DCM (15 ml) at 0°C was added methane sulphonic anhydride (0.325 g, 1.87 mmol) and diisopropyethylamine (0.24 g, 1.87 mmol).
The solution was left stirring at 0°C for 5 hrs. The solvent was then evaporated to leave a mobile oil. The oil was then passed through a plug of silica. Evaporation of the relevant eluent gave a compound as a mobile oil which slowly crystallised overnight to give white crystals (0.20 g).
1H NMR ( CDC13, 300 MHz ) aA 2 . 21 ( 2H, m, CHZ ) , 2 . 53 ( 2H, m, CIA-2), 2.92 (2H, m, CI-~z), 3.2I (2H, m, CHZ), 5.28 (2H, br m, CHZCHOC~CH2) , 7 . 32 ( 6H, br m, 6 x Ar--~I) , 7 .51 ( 1H, d, J=6.8Hz, 1 x Ar--~I), 7.55 (1H, d, J=7.OHz, 1 x Ar-H).
13C NMR (CDC13, 75.47MHz) a~ 29.9, 29.9, 32.2, 33.8 (~HZ), 81.6, 82.2 {CHZ~HOCHCHZ), 124.6, 124.6, 124.7, 124.9, 126.2, 126.3, 127.9, 128.0 (8 x Ar-H), 143.3, 143.3 (2 x Ar-C), 143.5, 143.6 (2 x Ar-C).
SUBSTITUTE SHEET (RULE 26) WO 97!20805 PCT/IE96/00081 Synthesis of 6G4 Coupling reaction Bt Et3N
\ ~ ~' ~ ~ ~.HCI ~' H
\ DCM l O OoC ~ I
0 6c 4 To a solution of 3-bromo-indan-1-one (200 mg, 0.952 mmol) and 2-aminoindan hydrochloride (160 mg, 0.952 mmol) in dry DCM ( 10 ml ) at 0°C was added triethylamine ( 0 . 19 g, 0 . 26 ml, 1.90 mmol). The solution was allowed to stir at 0°C
for 3 hours. The crude reaction mixture was passed through a plug of silica, eluting with petroleum ether:ethyl acetate (4:1). Salt formation 6C4 was isolated as a brown solid {150 mg, 60$).
1H NMR (CDCi3, 300 MHz) sH 2.54 (1H, dd, J=3.2Hz & 18.7Hz, CH of CHC~ZCO), 2.81 (1H, dd, J=6.8Hz & 45.1Hz, CH of CHC~) , 2 .86 ( IH, dd, J=6 . 9Hz & 14 . !Hz, CH of CHCHZ) , 3.0 { 1H, dd, J=6 .7Hz & 18 . SHz, CH of CHCHzCO) , 3. 18 ( IH, dd, J=6 . 9Hz & 19 . !Hz, CH of CHCI-~2) , 3.22 ( IH, dd, J=6 .9Hz &
19 . 3Hz, CH of CHC~-IZ} , 3. 81 ( 1H, quip, J=7.OHz, CHCHZ) , 4 .51 {1H, q, J=3.iHz & 6.7Hz, CHCHZCO), 7.14-7.29 (4H, m, 4 x Ar-~), 7.42-7.45 (1H, m, 1 x Ar-H), 7.59-7.75 (3H, m, 3 x Ar-~, ) 13C NMR (CDC13, 75.47 MHz ) s~ 39 . 5, 40. 1, 45.0 ( 3 x ~HZ) , 54.1, 57.8 (2 x CH), 122.7, 124.0, 124.1, 125.4, 125.9, I25.9, 128.1, I34.2 (8 x Ar-CH), 136.1, 140.7, 140.9, 155.5 (4 x Ar-~), 203.9 (C=O).
SUBSTITUTt SHEET (RULE 26) WO 97/20805 PC"T/IE96/00081 Synthesis of 6C5 Sodium borohydride reduction of 6C4 ~'~ i-t + NaH~, ~~~c:~tOH

o toH
6G~ 6c s' Dimer 6C4 (100 mg, 0.38 mmol) was dissolved in ethanol (4 ml) and ethyl acetate (8 ml). To this sodium borohydride (0.1 g, 2.63 mmol) was added to the reaction in small portions over ZO minutes. The reaction was stirred at room temperature for 3 hours. Evaporation of the solvent left a white solid and to this was added DCM. Filtration followed by evaporation left a mobile oil, which was then taken up in the minimum amount of DCM and passed through a plug of silica, eluting with petroleum ether (b.p. 40-60°C) :ethyl acetate, 98:2) afforded dimer 6C5 (39 mg, 39~) .
1H NMR {CDC13, 300 MHz) 8A 1.90 & 1.94 (1H, 2 x t, J=3.5Hz, CH of CHZCHOH), 2.55 & 2.59 (1H, 2 x t, J=5.9Hz, CH of C~iZCHOH), 2.77-2.87 (2H, m, CHCHZ), 3.18-3.29 (2H, m, CHC~-IZ), 3.78-3.85 (1H, quin, J=6.7 Hz, CH_CHZ), 4.25 (1H, q, J=3.5Hz & 5.7Hz, CHCHZCHOH), 5.03 (1H, q, J=3.4Hz & 6.OHz, CHZC-~iOH), 7.I5-7.26 (4H, m, 4 x Ar-H), 7.29-7.38 (3H, m, 3 x Ar-F~,) , 7 .47-7.49 ( 1H, m, 1 x Ar--~i) .
SUBSTITUTc SHEET (RULE 26) ~vnthesis of 6 -~

o ~~ + cH~r N
He~N '' 6CS 6c6 To a solution of dimer 6C5 (200 mg, 0.76 mmol) in DCM (S
ml) was added triethylamine (0.09 g, O.I3 ml, 0.91 mmol) and methyl iodide (1.08 g, 0.48 ml, 7.61 mmol). The S solution was allowed to stir at room temperature for 2 hours. The solvent was removed and the crude reaction mixture was passed through a flash silica column, eluting with petroleum ether: ethyl acetate (8:2) to yield dimer 6C6 as a yellow oil (0.80 g, 38~).
iH NMR ( CDC13, 300 MHz ) sH 2 . 03 ( 3H, s , NCH3 ) , 2 . 57 ( 1H, dd, J=7.OHz & 18.9Hz, CH of CHCHi) , 2.77 ( 1H, dd, J=3.8Hz, &
18. 9Hz, CH of CHCHz) , 2 . 93-3 . 17 ( 4H, m, 2 x C~-IZ) , 3.46-3. 57 ( IH, quin, CHCHZ ) , 4 . 78 ( 1H, q, J=3 . 5 Hz , CIiCH2 ) , 7 . 13-7 . 21 (4H, m, 4 x Ar-#~), 7.43 (IH, t, J=7.OHz, 1 x Ar-~-I), 7.61 (IH, dt, J=I.OHz & 7.8Hz, 1 x Ar-H), 7.72 (2H, t, J=6.OHz, 2 x Ar-~-I ) .
13C NMR (CDClj, 75.47 MHz) s~ 33.1 (~H3), 35.8, 37.7, 38.0 (3 x ~HZ), 59.6, 65.1 (2 x CH), 123.0, 124.3, 124.4, 126.3, 126.4, 126.4, 129.0, 134.7 (8 x Ar-~H), 137.2, 141.2, 141~4, 155.3 (4 x Ar-C), 205.0 (C=O).
SUBSTITUTc SHEET {RULE 26) synthesis of 6C7 , l~
+ ~ 3N + ~B~ ~ DGM

6cS
To a solution of 6C4 (200 mg, 0.76 mmol) in DCM (5 ml) was added triethylamine (0.09 g, 0.13 ml, 0.91 mmol) and allyl bromide (0.90 g, 0.65 ml, 7.61 mmol). The solution was allowed to stir at room temperature for 2 hours. The solvent was removed and the crude reaction mixture was passed through a plug of silica, eluting with petroleum ether:ethyl acetate (8:2) to yield 6C7 as a yellow oil (0.80 g, $ yield).
1H NMR (CDC13, 300 MHz) 8H 2.58 (IH, dd, J=6.7Hz & 18.8Hz, CH of CHCHZCO), 2.68 (1H, dd, J=4.2Hz & I8.8Hz, CH of CHC~ZCO), 2.9-3.09 (6H, m, 3 x CHZ), 3.72-3.82 (1H, quin, J=7 . 6Hz , CIiCH2 ) , 4 . 67 ( IH, dd, J=6 . 7Hz & 4 . 2Hz , C -~iCHZCO ) , 5.05 & 5.08 (2H, 2 x dd, J=10.2Hz & l.BHz & l.3Hz, CHZCH=CF,~2 ) , 5 . 80 ( IH, m, CHZCHCH2 ) , 7 . I I-7 . 21 ( 4H, m, 4 x Ar--~I), 7.42 (1H, dt, J=7.8Hz, 1 x Ar-H), 7.64 (1H, dt, J=7.7Hz & l.2Hz 1 x Ar-I~-), 7.74 (2H, dt, J=7.6Hz, 2 x Ar-~i ) i3C NMR {CDC13, 75.47 MHz) s~ 36.0, 38.7, 39.2, 50.2, 116.3 (5 x ~HZ), 57.4, 61.0 (2 x CH), 122.9, 124.2, 124.6, 126.3, 126.4, 128.5, 134.8, 137.2 (8 x Ar-~H), 126.4, 141.4, 141.6, 156.4 (4 x Ar-~), 204.? {C=O).
SUBSTITUTE SHEET (RULE 26) WO 97!20805 PCT/IE96l0008i Synthesis of 6C8 ~ ,N + ~ 1 oorc .
a~

6cs 6~ 8 To a solution of dimer 6C4 (200 mg, 0.76 mmol) in DCM (5 ml) was added triethyiamine (0.09 g, 0.13 ml, 0.91 mmol) and benzyl bromide {1.30 g, 0.90 ml, 7.61 mmol). The solution was allowed to stir at room temperature for 2 hours. The solvent was removed and the crude reaction mixture was passed through a plug of silica, eluting with petroleum ether:ethyl acetate (8:2) to yield 6C8 as a yellow oil (0.80 g, 30~).
I0 1H NMR (CDC13, 300 MHz) SH 2.63 (1H, dd, J=7.0Hz & 18.8Hz, CH of CHCFi~CO), 2.81 (1H, dd, J=3.$Hz & 18.8Hz, CH of CHCHZCO), 2.95-3.13 (4H, m, 2 x CHZ), 3.58-3.71 (2H, m, CSI Ph) , 3 . 76 { 1H, t, J=7 . 6Hz, CHCH~CO) , 4 . 65-4 .68 ( 1H, m, C~CHZ), 7.14-7.48 (!OH, m, IO x Ar-H), 7.67 {1H, dt, J=I.2Hz, 7.68Hz, 1 x Ar-H), 7.76 (1H, d, J=7.7Hz, 1 x Ar-7.87 (1H, d, J=7.7Hz, 1 x Ar-H).
1'C NMR (CDC13, 75.47 MHz) 8~ 35.2, 38.6, 38.7, 50.9 (4 x ~HZ), 56.9, 60.4 (2 x CH), 122.8, 124.0, I24.5, 126.2, 126.3, 126.8, 128.0, 128.2, 128.2, 128.4, 128.6, 128.8, 134.7 (13 x Ar-CH), 137.1, 139.9, 141.2, 141.4, 156.1 (5 x Ar-~), 204.5 (C=O).
SUBSTITUTE SHEET (RULE 26) WO 97/20805 PCT/IE96l0008I

SLrnthesis of 6C9 O
O
+ aq HCI
C1.HV1 1~
6~ ' ~ 6C9 6C4 (100 mg, 0.38 mmol) was dissolved in methanol. To this was added a 2M aqueous HC1 solution (5 ml), the flask was stirred vigorously and toluene was added to the flask and it was evaporated to dryness. The salt of this dimer was then extracted into water and evaporation of the water left 6C9 as a yellow solid. This was then partitioned between ethyl acetate and water. The aqueous layer was isolated and washed with ethyl acetate. Evaporation of the aqueous layer left the BRA 128 as a white solid, which was then recrystallised from water and methanol to yield white crystals of 6C9 (84 mg, 72.40 .
1H NMR ( D20, 300 MHz ) 8g 2 . 89 ( 2H, d, J= 19 . 4 Hz, CHCHZCO) , 3.07 & 3.14 (IH, d, J= 6.2 Hz, CH of CHZCHCH~), 3. I8 & 3.26 ( 1H, d, J= 5.5 Hz, CH of CHZCHCHZ) , 3 .22 ( 1H, d, J= 8. 1 Hz, CH of CHZCHC~Z), 3.31-3.42 (1H, q, J= 8.1 Hz, CH of CHZCHCHZ) , 4 .26 ( IH, t, J= 6 . 8 Hz, CHZCHCH~) , 5. 18 ( 1H, d, J= 6.4 Hz, C-~ICHZCO) , 7 . 17 ( 2H, m, 2 x Ar-~-I) , 7 .59 ( 1H, superimposed d, J= 7.1 & 6.4 Hz, 1 x Ar-H), 7.76 (1H, d, J= 6.8 Hz, 1 x Ar-H).
13C NMR (D20, 75.47 MHz) 8~ 38.4, 38.8, 42.6 (~HZ), 56.8, 60.0 (~H), 127.2, 127.6, I27.7, 129.7, 130.2, 130.3, 134.1, 139.4 (8 x Ar-CH), 141.5, 141.6, 142.0, 150.3 (4 x Ar-~), 207.3 (~=O).
SUBSTITUTc SHEET (RUf..E 26) Bvnthesis of 6 -,t~n n / o E~ ~ /
+ p-'1'sCt Fi pyridine p 1t j DC~ I
0"C r- O

To a stirring solution of 6C4 (200 mg, 0.76 mmol) and p-toluenesulfonyl chloride ( 1 . 45 g, 7 . 60 mmol ) in DCM ( IO
ml) was added triethylamine (0.09 g, O.I3 ml, 0.91 mmol).
The solution was allowed to stir at 0°C for 15 mins. The solution was allowed to stir at room temperature for a further hour then to this solution was added pyridine (0.26 ml) and the reaction was allowed to stir for a i0 further 2 hours. The crude reaction mixture was passed through a flash silica column, eluting with petroleum ether . ethyl acetate 1:4. 6CI0 was isolated as a yellow solid (284 mg, 89.30 .
13C NMR (CDC13, 75.47 MHz) 8~ 21.2 (~H3), 37.4, 37.4, 38.0 (3 x ~H2), 54.8, 57.9 (CH), 123.1, 124.0, I24.2, 125.0, 125.6, 126.5, 126.9, 127.9, I28.7, 128.9, 129.5, 134.6 (I2 x Ar-~H), 136.9, 137.5, 138.2, 138.3, 139.7, 139.9, 143.3, 151.9 (6 x Ar-~ & 2 x qC), 201.8 (C=O).
SUBSTITUTE SHEET (RULE 26) Svnthesis of 6 11 N
/ t + cH~-cco~-o-c(o)-cH~ .~ Ec sc4 DMAP
DC1~I
N

O
To a solution of 5C4 (200 mg, 0.76 mmol) in DCM (5 ml) was added triethylamine (0.15 g, 0.20 ml, 1.48 mmol) and acetic anhydride (0.12 g, 0.11 ml, 1.I7 mmol). To this stirring solution was added N,N-dimethylaminopyridine (0.10 g, 0.82 mmol). The reaction was allowed to stir at room temperature for 2 hours. Additional acetic anhydride (0.12 g, 0.11 ml, I.17 mmol) was added and the reaction was allowed to stir at room temperature for 1 hour. The solvent was removed and the crude reaction mixture was passed through a plug of flash silica, eluting with petroleum ether . ethyl acetate, 4:I. 6C11 was isolated as a solid (I10 mg, 47.50 .
SUBSTITUTE SHEET (RULE 26) - 42a -1H NMR ( CDC13, 300 MHz ) sH 2 . 09 - 5 . 50 ( 11H, br m, Cue, CHZ's and CH), 7.00-7.95 (8H, br. m, 8 x Ar-H) isC NMR (CDC13, 75.47 MHz) s~ 20.6, 20.9 (~H3), 23.0, 23.8, 29.5, 35.8, 36., 38.0, 42.1, 42.3, 43.9 (3 x ~HZ), 52.3, 55.9, 57.0, 58.7, 60.2, (2 x ~,H), 123.3, 123.8, 124.0, 124.2, 124.5, 124.6, 124.$, 125.3, 126.0, 127.2, 127.9, 129.5, 134.5, 135.4, 137.6, (Ar-~H), 139.6, 139.7, 141.1, 152.2, 154.3 (Ar-C) 170.1, 171.0 (CH3C~N), 201.5, 202.8 to (~o .l) SUBSTITUTE SNEET (RULE 26) Synthesis of 6C12 HC! gas N ~ Mep~..i _ H. HC!
r sc~
Compound 6C7 (100 mg} was dissolved in dry methanol (5 ml), dry HC1 gas was bubbled through the solution for S
mins. The methanol was then evaporated off and a white solid remained. The solid was then partioned between water and ether. The aqueous layers were combined and evaporated to dryness. The white solid 6C12 which remained was dried on the vac line (93~}.
SUBSTITUTE SHEET (RULE 26) It will be appreciated that the compounds include pharmacologically acceptable salts, esters, isomers and solvates thereof. One example of a possible ester is a salicylate in at least one and possibly several suitable positions on the compound. This opens up the possibility of a combination therapy using an indane dimer and aspirin in a single molecule. The weight ratio of the base indane dimer to aspirin may be selected by providing a salicylate at a number of selected positions on the dimer.
It will be appreciated most of the compounds have one or more chiral centres and hence exist as a pair of enantiomers or as a mixture of diastereomers. This may have an effect on the pharmacological properties.
It will be appreciated that for pharmaceutical purposes the active compounds may be formulated in any desired form using any suitable excipients and/or carriers. 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.
SUBSTITUTE SHEET (RULE 26) PHARMACOLOGY
Introduction The indane dimers according to the invention have potent mast cell stabilising activity, smooth muscle relaxing activity, and anti-inflammatory activity. Such compounds are, therefore, potential anti-asthmatic agents with bronchodilator activity. The mast cell stabilising activity of the compounds suggests their ~otentiai use in the treatment of allergic rhini~tis, allergic conjunctivitis and other anaphylactic or allergic conditions. The anti-inflammatory 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 include: atopic excema, weeping excemas psoriasis, chronic discoid lupus erythematosus, lichen simplex chronicus, hypertrophic lichen planes, 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 SUBSTITUTc SHEEP (RULE 26) 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.
The compounds were assessed for their ability to stabilize mast cell membranes in vitro. Mast cells treated with the compounds and un-treated mast cells were stimulated to release histamine. A reduction in histamine release by the treated cells compared to the un-treated cells indicates stabilisation of the membrane. The compounds were assessed for their ability to relax smooth muscle in vitro. Intestinal smooth muscle was stimulated to contract, using calcium chloride and subsequently treated IS with the compounds, relaxation of the contraction was measured for each compound. The effects of the compounds were also studied on relaxation of guinea-pig tracheal muscle. In the rat paw oedema test, the drugs were administered systemically prior to inducing inflammation by the injection of carageenan below the plantar aponeurosis of the hind paw. The volume of the paw was determined both before and after treatment as an index of oedema. In the mouse ear oedema test, the drugs were administered topically prior to inducing inflammation by the topical application of arachidonic acid. The width of the ear was determined both before and after treatment as an index of oedema.
There follows protocols of each of the assays used and a summary of the results.
ABBREVIATIONS
BSS buffered salt solution CaCl2 calcium chloride SUBSTITUTE SHEET tRULE 26) COz carbon dioxide DMSO dimethyl sulphoxide DSCG disodium cromoglycate dH20 distilled water HC1 hydrochloric acid HEPES N-2-hydroxyethylpiperazine-N-2-ethanesulphonic acid KC1 potassium chloride l~m emission wavelength IO lex excitation wavelength M Molar MgClz magnesium chloride min minutes u1 microliters I5 mM milli-molar NaCl sodium chloride NaHC03 sodium hydrogen carbonate NaH2P0 sodium hydrogen phosphate NaOH sodium hydroxide oxygen oPT o-phthaldialdehyde S.E.M. standard error of mean w/v wei ht g per volume v/v volume per volume Histamine Release Assay The buffered salt solution (BSS) was prepared in advance (NaCI I37 mM; KC1 2.7mM; MgClZ l.OmM; CaClz 0.5mM; NaHZP04 0.4mM; Glucose 5.6mM; HEPES 10 mM). This was dispensed 30 into test tubes and heated to 37°C, each test tube contained 4.5m1 BSS. The solvent blank was supplemented with 0.5~ (v/v) dimethyl sulphoxide (DMSO) or 0.5g (v/v) distilled water (dHzO). The two positive controls were SUBSTITUTE SHEET (RULE 26) WO 97!20805 PCT/IE96/OOOSI

supplemented with 0.5~ (v/v) dHzO / 2x10-SM disodium cromoglycate (DSCG) and 0.5~ (v/v) DMSO / 2x10-SM DSCG.
The test compounds' incubation tubes contained 2x10-SM test compound / 0.5~ (v/v) DMSO. The basal release, maximum release and total histamine content incubation tubes contained no additions.
Female Wistar rats (200-300g) were killed in an atmosphere of saturated CO2. Pre-warmed BSS (lOml) was injected i.p.
and the abdomen was massaged for 3 min. The BSS, with suspended mast cells and other cells, was aspirated following a mid-line incision. The aspirate was centrifuged for 5 min at 400g and the supernatant removed.
The cells were re-suspended in BSS, at 4°C, and centrifuged as before. the cells were washed in this manner a total of three times. Following the final wash, the pelleted cells were stored at 4°C, for use as soon as possible.
The cells were re-suspended in 7m1 BSS. From this, 0.5m1 aliquots were transferred to each of the incubation tubes.
After 10 min at 37°C with gentle agitation, Compound 48/80 was added to a final concentration of 2mg/ml, in order to stimulate histamine release. The cell stimulation was stopped after 2 min by the addition of 0.5m1 ice cold BSS, the incubation tubes were transferred to an ice bath. The cell suspensions were centrifuged for S min at 400 g. The "total histamine content" tube was placed at 100°C for 2 min prior to centrifugation. The supernatants were retained for histamine assay.
To 2 ml of supernatant from each tube was added 0.4 ml of 1M NaOH and O.lml oPT (1~ (w/v) in methanol). This was incubated at room temperature for 4 min. The reaction was stopped by the addition of 0.2 ml of 3M HCl. The supernatant from each incubation tube was assa~P~
duplicate and run simultaneously with a standard curve in SUBSTITUTE SHEET (RULE 26) the range 0-I000ng/ml. The presence of the fluorescent product of the reaction was measured using a Shimazu RF-1501 spectrofluorophotometer set at ~~r=360nm, ~em=450nm.
Each drug was tested on at least five animals {n - 5).
The results were expressed as a percentage of maximum, compound 48/80 induced, histamine release in the solvent blank sample. Each drug was compared to DSCG on the same tissues. The basal histamine release in untreated cells was noted, expressed as a percentage of the total histamine content of the cells in suspension. The maximum histamine released by the cells in response to compound 48/80, in the relevant solvent blank sample, was expressed in the same manner. Overall, the mean basal release was 9.60$ (S.E.M. - I.02) of total histamine content of the cells {n = 55). The maximum stimulated histamine release was 67.38 (S.E.M. - 2.90) in the present of 0.5$ (v/v) dH~O and 54.87 (S.E.M. - 2.69 ) on the presence of 0.5~
(v/v) DMSO of total histamine content of the cells (n -55).
Smooth Muscle Effects Guinea pigs (350g approx.), of either sex, were killed in an atmosphere of saturated CO2. The abdomen was opened by a mid-line incision and the small intestine was removed.
The trachea was removed and sectioned between the cartilage rings, which were then split through.
Segments of ileum (1-l.5cm) were suspended in a high potassium, no calcium Krebs buffer (NaCl 160.4mM); KC1 45mM; MgClz 0.54mM; NaH2P04 0.89mM; NaH,C03 24.9mM; Glucose ll.imM). Tracheal sections were suspended in normal Krebs buffer (NaCl 236.5mM; KC1 4.7mM; CaCl2 2.5mM; MgCl, 0.54mM;
NaH2P04 0.89mM; NaHC03 24.9mM; Glucose 11.1mM). The solutions were maintained at 37°C by a jacketed organ bath SUBSTITUTE SHEET (RULE 26) and gassed with 95$ O., and 5$ COZ. The tissues were ' anchored by thread to the bottom of the organ bath and suspended from force displacement transducers under a ' resting tension of 1g approx. in the case of ileum and 4g approx. in the case of trachea. Isotonic contractions were recorded using a MacLab/4e system in conjunction with the Chart 3.3.1 software package. Surplus tissue was stored at 4°C in Krebs buffer, for a maximum of 48 hours.
Four segments of tissue were suspended and observed concurrently. Contractions were initiated by the addition of 25~C1 of 1M CaClz (a final concentration of 2.5mM). The contractions stabilized with time, 10-15 min, and could be maintained for up to 45 min. from the addition of the CaClz. The tracheal sections were allowed to develop spontaneous resting tension over a period of 30 mins.
Stock solutions of drug were prepared at 10'3M in 50~ (v/v) DMSO. These were diluted to give; 10-4M in 5$ (v/v) DMSO
and 10-SM in 0.5~ (v/v) DMSO. In cases of poor solubility the 10-~M stock was made up in higher concentrations of DMSO. Solvent 'blank' solutions were prepared containing 50~, 5~ and 0.5$ (v/v) DMSO (or as appropriate). A
cumulative dose-response assay was carried out in the range 5x10-8M to 10'5M. A second cumulative dose-response assay was carried out using DMSO 'blank' solutions only.
Each drug was tested, in duplicate, on at least three different animals (n=3). The results were expressed as percentage inhibition of the CaCl2 induced contraction in the case of heal tissue and percentage relaxation in the case of tracheal tissue, for each tissue, at each concentration of drug in DMSO. The effect of DMSO, for each tissue at each concentration, was subtracted from the effect of the drug in DMSO, to give the effect of the drug alone. A log dose vs. response curve was plotted for each SUBSTITUTE SHEET {RULE 2fi) drug using the mean and the standard error of the mean for the cumulated results.
In vi vv Inflammation Models 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, indomethacin or dexamethasone (all at 300 1g ear in acetone) drug. After 30min, oedema was induced by the topical application of arachidonic acid (10 F.rl at 0.4g/ml in acetone). The thickness of each ear was measured, both before and 60min 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.
RESULTS
Mast Cell Stabilisation and Smooth Muscle Relaxation The findings of the histamine release and the smooth muscle effect assays are summarised in the accompanying tables of results. The results from some of the compounds are illustrated in the accompanying graphs. The results indicate that these compounds show a wide variety of smooth muscle relaxing and mast cell stabilising activity, and that these two effects are not related (i.e.
a good mast cell stabiliser is not necessarily a good ' smooth muscle relaxant and vice versa).
SUBSTITUTc SiiEET (RULE 26) Results for Histamine Release Assay and Smooth Muscle _.
Percentage Inhibition of H istamine CaCl2 Release Induced Contractions (t S.E.M.D (t S.E,M.) Conc. 3x10a 10'' 3x10' 10'~ 3x10 10~ 2x10 (M) 5C3 0.~3 2.61 3.78 7.21 15.0 29.99 32.77 --0.38 r0.77 -1.80 x.02 _2.90 _2.92 ~ 7.24 SC4 -0.86 -0.86 -0.99 1.15 5.08 19.I4 5.68 0.40 10.68 ~i.28 1.38 1.60 11.80 2.21 5C5 -0.26 0.28 0.43 1.56 3.56 10.50 58.68 0.27 t 0.44 0.54. t L16 1.00 x-1.54t 2.47 5C6 -1.00 0.02 0.36 1.31 8.84 20.94 77.77 t 0.89 t 0.90 0.69 L59 t 0.91 t 0.801.94 SC7 0.16 -0.44 -0.36 -1.72 0.00 2.06 24.12 10.24 10.50 10.88 10.69 11.25 11.75 4.41 Percentage Inhibition of Histamine CaCl2 Release Induced Contractions (t S.E.M.D ( S.E.M.) Conc. 3x10' 10'' 3x10'' 10'~ 3x10' I0d 2x10a (Ml _ 6C4 2.16 3.02 4.63 8.84 17.11 33.46 14.92 10.65 L10 tl.ll tL77 x.03 x-2.438.55 6C6 O.IS 2.75 4.64 9.01 12.62 22.95 68.05 037 1.92 12.60 x.48 3.55 4.32 t 6.96 6C7 1.16 3.I5 4.52 5.36 10.67 21.83 89.46 L(~6 1,57 1.60 L89 1.61 t 3.741.84 6C8 L97 2.94 3.26 4.69 11.29 31.14 88.59 t 1.58 t 1.62t 1.37 t 1.35 t 133 t 3.18t 0.61 6C9 0.31 0.61 -L76 -2.94 -0.86 L58 43.60 10.33 i-0.54i-0.72 f1.06 10.89 12.01 t 7.11 SUBSTITUTE 26) SHEET
(RULE

Perce ntage Inhibition of CaCtZ Induced Spontaneous Histamine Contractions Tone Release (t S.E.M.) (t S.E.M.) (= S.E.M.) Conc. ileum 3x10' 10'~ trachea 3x10 10a 2x10 (M) 4b.02 TS 4.65 5C3 -0.50 4.59 1.58 2.78 45.30 TR -_-0.93 y2.03 =1.3:I 1.15 ~- 2.42 67.47 Bs ~-3.6~

SC3 1.39 10.71 0.44 0.09 52.20 BR 0.99 tL67 1.55 1.88 3.35 5C6 5.29 19.41 1.63 2.71 75.15 TS t2.I6 4.22 10.93 t1 .39 t 5.42 5C6 1.50 4.97 79.98 TR t1.05 ti.03 t 3.I9 5C6 13.66 3L47 2.03 4.09 80.29 BS 6.91 19.12 L37 11.51 t 3.81 5C6 8.72 31.64 78.84 BR 1.02 3.38 t 3,g9 5~ I4.33 2.47 5C9 9.06 18.31 2.64 2.38 14.33 3.90 3.80 2.59 X1.72 t 2.47 5C10 4.0,75 t 8.05 5~1 90.27 t 2.70 (n=4) 6C10 -0.75 0.50 51.I2 11.43 11.66 t 8.40 6C11 8.00 12.49 4.26 15.62 16.40 t 6.80 _ t 2.I9 (n=4) ITUTE SHEET (RULE 26) Inflammation Model Mouse Ear Oedema Responses of the mouse ear to single doses of a range of compounds compared to the response to indomethacin and S dexamethasone, each at a dose of 300,ug per ear administered topically 30 min prior to administration of 400 ~.rg of arachidonic acid. Values are expressed as the percentage increase in ear thickness 1 hour after administration of arachidonic acid (all n=4, solvent controls (n=8)). The results suggest that anti-inflammatory activity is not linked to mast cell stabilising activity.
Compound Mean $ SEM
Dexamethasone 37.9 g.5 Indomethacin 39.6 5.8 6C7 71.5 15.7 6C6 73.0 8.7 5C6 52.0 20.3 6C11 26.0 6.3 Solvent Control 78.8 15.2 It will be appreciated that the compounds may have useful pharmacological properties other than those described above.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
SUBSTITUTE SHEET (RULE 26) LIST OF ABBREVIATIONS USED
A1C13835 aluminium chloride aq aqueous b.p. boiling point BrCH2C6H4CO~CH3 methyl 4 - ( bromomethyl ) benzoate BrCHzCO2CH3 bromomethyl acetate BSS buffered salt solution CaCl2 calcium chloride CZHSI iodoethane C6H3 ( CH3 ) Br bromo-m-xylene ( CH3 ) C6HSCHZBr benzyl bromide CDC13 chloroform-d CF3S03Si(CH3)3 trimethylsilyl trifluoromethanesulfonate (TMS triflate) CH(OCH3)s trimethylsilyl orthoformate CH3C6H4SO3H.HZ0 p-toluenesulfonic CH3I iodomethane CLCHZCHzCOCl !3-chloropropionylchloride COz carbon dioxide CSZ carbon disulfide [ ( CsHs ) 3P tris ( triphenylphosphine ) rhodium ( 1 ) ] sRhCl chloride (wilkinsons catalyst) [ ( CH3 ) 3C0 aluminium tri- tert-butoxide ] 3A1 DCM dichloromethane dH20 distilled water DMSO dimethyl sulphoxide DSCG disodium cromoglycate Et~O ether Et3N triethylamine EtOAc ethyl acetate EtOH ethanol HZC=CHCHZBr allyl bromide HZNNHZ . HZO hydrazine hydrate . monohydrate SUBSTITUTc SHEET (RULE 26) LIST OF ABBREVIATIONS USED CONTD.

' Hz0 water HzS04 sulphuric acid HC1 hydrochloric acid HEPES N-2-hydroxyethylpiperazine-N-2-ethanesulphonic acid HOCHZCHzOH ethylene glycol IR infra red KC1 potassium chloride LDA lithium diisopropylamide M Molar MgClz magnesium chloride min minutes J.~l microlitres I5 mM milii-molar mp melting point Nz nitrogen NaBH~ sodium borohydride NaCl sodium chloride NaCN(BH3) sodium cyanoborohydride NaHC03 sodium hydrogen carbonate NaHC03 sodium bicarbonate NaHZPO sodium hydrogen phosphate NaOH sodium hydroxide NazS04 sodium sulphate NH4C1 ammonium chloride NMR nuclear magnetic resonance Oz oxygen oPT o-phthaldialdehyde Pd palladium RT room temperature 'BuOH tert butanol 'BuOK potassium tert butoxide S.E.M. standard error of mean SUBSTITUTE SHEET (RULE 26) _ 57 _ LIST OF ABBREVIATIONS USED CONTD.
THF tetrahydrofuran TLC thin layer chromatography u1 microliters Triflic Acid trifluoromethanesulfonic acid TMS Triflate trimethyl silyl trifluoromethanesulfonate v/v volume per volume w/v weight per volume Znlz zinc iodide ~,~ emission wavelength ~2ex excitation wavelength SUBSTITUTE SHEET (RULE 26j WO 97!20805 PCT/IE96/00081 5C3 3-(N-1-indanylamino)-indan-I-one 5C4 3-(N-1-indanylamino)indan-I-of 5C5 3-(N-methyl-N-1-indanylamino)-indan-3-one 5C6 3-(N-prop-2-enyl-N-1-indanylamino)-indan-i-one 5C7 3-(N-benzyl-N-I-indanylamino)-indan-I-one .

5C8 3-(N-I-indanylamino)-indan-I-one. Hydrochloride 5C9 N-I-Indanyl-N-3-indan-I-onylethanamide 5C10 N-1-Indanyl-N-3-indan-1-onyl_p_ toluenesulfonamide 5C11 3-(N-prop-2-enyl-N-I-indanylamino)-indan-1-one hydrochloride 5C12 I-diindanyl ether 6C4 3-(N-2-indanylamino)-indan-1-one I5 6C5 3-(N-2-indanylamino)-indan-i-of 6C6 3-(N-methyl-N-2-indanylamino)-indan-I-one 6C7 3-(N-prop-2-enyl-N-2-indanylamino)-indan-1-one 6C8 3-(N-benzyl-N-2-indanylamino)-indan-1-one 6C9 3-(N-2-indanylamino)indan-I-one. Hydrochloride 2 0 6 C 1 N - 2 - I n d a n y 1 - N - 3 - l n d a n - 1 -0 o n y 1 - p -toluenesuifonamide 6CI1 N-2-Indanyl-N-3-indan-I-onylethanamide 6C12 3-(N-prop-2-enyl-N-2-indanylamino)-indan-1-one hydrochloride SUBSTITUTE SEiEET (RULE 26)

Claims (18)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of Formula 5:

wherein R is H, acyl, alkyl, allyl or benzyl group R2, 1R2, R4 to R8, R9, 1R9, R10, 1R10, R11 to R15 are each independently selected from the group consisting of:

H, halo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, alkyl carbonyl, hydro carbonyl, amino, amido, alkylamino, hydroxylamino, a sulfonic acid group, a sulfoxide group, a sulfone group, optionally substituted C1-C10 alkyl and optionally substituted C3 -C8 cycloalkyl;

wherein any one or more of R2, 1R2 ; R9, 1R9 : and R10, 1R10 may together optionally represent oxo, and wherein R1 and 1R1 are =O or when one of R1 and 1R1 is H
then the other is OH.
2. A compound as claimed in claim 1 wherein the alkyl or cycloalkyl are substituted with one or more of the same or different of:

halo, oxo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, carbonyl, amino, amido, alkylamino, hydroxylamino.
3. A compound as claimed in claim 1 wherein each of R4 to R7 is hydrogen.
4. A compound as claimed in claim 1 wherein each of R11 to R14 is hydrogen.
5. A compound as claimed in claim 1 wherein the R group in NR represents aryl.
6. A compound as claimed in claim 1 wherein the R group in NR represents alkyl.
7. A compound of Formula 6:

wherein R is H, acyl, alkyl, allyl, benzyl or a sulfonate group R1, 1R1, R2, 1R2, R4 to R8, R9, 1R9, R10 to R13, R14, 1R14 and R15 are each independently selected from the group consisting of:

H, halo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, alkyl carbonyl, hydro carbonyl, amino, amido, alkylamino, hydroxylamino, a sulfonic acid group, a sulfoxide group, a sulfone group, optionally substituted C1-C10 alkyl and optionally substituted C3-C8 cycloalkyl;

wherein any one or more of R1, 1R1 ; R2, 1R2 ; R9, 1R9 ;
and R14, 1R14 may together optionally represent oxo.
8. A compound as claimed in claim 7 wherein the alkyl or cycloalkyl is substituted with one or more of the same or different of:

halo, oxo, hydroxy, alkoxy, aryloxy, acetoxy, carboxy, carbonyl, amino, amido, alkylamino, hydroxylamino.
9. A compound as claimed in claim 7 wherein each of R4 to R7 is hydrogen.
10. A compound as claimed in claim 7 wherein each of R10 to R13 is hydrogen.
11. A compound as claimed in claim 7 wherein the R group in NR represents acyl.
12. A compound as claimed in claim 7 wherein the R group in NR represents alkyl or a sulfonate group.
13. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising a compound as defined in claim 7 and a pharmaceutically acceptable carrier.
15. A compound selected from the group consisting of:

3-(N-1-indanylamino)-indan-1-one, 3-(N-1-indanylamino)indan-1-ol, 3-(N-methyl-N-1-indanylamino)-indan-1-one, 3-(N-prop-2-enyl-N-1-indanylamino)-indan-1-one, 3-(N-benzyl-N-1-indanylamino)-indan-1-one, 3 -(N-1-indanylamino)-indan-1-one hydrochloride, N-1-indanyl-N-3-indan-1-onylethanamide, 3-(N-prop-2-enyl-N-1-indanylamino)-indan-1-one, hydrochloride, 3-(N-2-indanylamino)-indan-1-one, 3-(N-2-indanylamino)-indan-1-ol, 3-(N-methyl-N-2-indanylamino)-indan-1-one, 3-(N-prop-2-enyl-N-2-indanylamino)-indan-1-one, 3-(N-benzyl-N-2-indanylamino)-indan-1-one, 3-(N-2-indanylamino)-indan-1-one hydrochloride, N-2-indanyl-N-3 -indan-1-onyl-p-toluenesulfonamide, N-2-indanyl-N-3-indan-1-onylethanamide, and 3-(N-prop-2-enyl-N-2-indan,ylamino)-indan-1-one hydrochloride.
16. A pharmaceutical composition comprising a compound as defined in claim 15 and a pharmaceutically acceptable carrier.
17. Use of an effective amount of a compound as defined in claim 1 as a prophylaxis for achieving smooth muscle relaxing activity, mast cell stabilising activity, or anti-inflammatory activity.
18. Use of an effective amount of a compound as defined in claim 7 as a prophylaxis for achieving smooth muscle relaxing activity, mast cell stabilising activity, or anti-inflammatory activity.
CA002239853A 1995-12-06 1996-12-06 Indane dimer compounds and their pharmaceutical use Expired - Fee Related CA2239853C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IE950922 1995-12-06
IE950922 1995-12-06
IE960762 1996-10-31
IE960762 1996-10-31
PCT/IE1996/000081 WO1997020805A1 (en) 1995-12-06 1996-12-06 Indane dimer compounds with smooth muscle relaxing and/or mast cell stabilising and/or antiinflammatory activity

Publications (2)

Publication Number Publication Date
CA2239853A1 CA2239853A1 (en) 1997-06-12
CA2239853C true CA2239853C (en) 2006-11-28

Family

ID=26319864

Family Applications (2)

Application Number Title Priority Date Filing Date
CA002239853A Expired - Fee Related CA2239853C (en) 1995-12-06 1996-12-06 Indane dimer compounds and their pharmaceutical use
CA002239694A Expired - Lifetime CA2239694C (en) 1995-12-06 1996-12-06 Indane dimer compounds and their pharmaceutical use

Family Applications After (1)

Application Number Title Priority Date Filing Date
CA002239694A Expired - Lifetime CA2239694C (en) 1995-12-06 1996-12-06 Indane dimer compounds and their pharmaceutical use

Country Status (13)

Country Link
US (3) US6297399B1 (en)
EP (3) EP0874800B1 (en)
JP (3) JP2000502328A (en)
KR (2) KR19990071978A (en)
AT (3) ATE246670T1 (en)
AU (3) AU1169197A (en)
CA (2) CA2239853C (en)
DE (3) DE69629390T2 (en)
DK (1) DK0865419T3 (en)
GB (3) GB2322858A (en)
IE (1) IE960865A1 (en)
IL (3) IL124756A0 (en)
WO (3) WO1997020802A1 (en)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997038693A1 (en) 1996-04-18 1997-10-23 Alcon Laboratories, Inc. Calcium channel blockers as human conjunctival mast cell degranulation inhibitors for treating ocular allergic conditions
AU8031698A (en) * 1997-06-05 1998-12-21 Venantius Limited Indane compounds and their pharmaceutical use
JP2001064202A (en) * 1999-08-25 2001-03-13 Kissei Pharmaceut Co Ltd Prophylactic and therapeutic agent of cardiac failure
DE10142660A1 (en) 2001-08-31 2003-03-20 Aventis Pharma Gmbh Use of derivatives of C2-substituted indan-1-ol systems for the preparation of medicaments for the prophylaxis or treatment of obesity
DE10142663B4 (en) * 2001-08-31 2004-08-19 Aventis Pharma Deutschland Gmbh C2-Disubstituted indan-1-ol systems
DE10142668A1 (en) * 2001-08-31 2003-03-20 Aventis Pharma Gmbh Use of C2-substituted indan-1-one systems for the preparation of medicaments for the prophylaxis or treatment of obesity
DE10142661B4 (en) 2001-08-31 2004-06-09 Aventis Pharma Deutschland Gmbh Poly-substituted indan-1-ol systems and their use as pharmaceuticals
DE10142665B4 (en) 2001-08-31 2004-05-06 Aventis Pharma Deutschland Gmbh C2-Disubstituted indan-1-ones and their derivatives
DE10142667B4 (en) 2001-08-31 2004-06-09 Aventis Pharma Deutschland Gmbh C2-substituted indan-1-oles and their derivatives and their use as medicines
DE10142662B4 (en) 2001-08-31 2004-07-08 Aventis Pharma Deutschland Gmbh Derivatives of C2-substituted indan-1-ol systems and their use as pharmaceuticals
DE10142659A1 (en) * 2001-08-31 2003-03-20 Aventis Pharma Gmbh Use of multiply substituted indan-1-ol. Systems for the preparation of medicaments for the prophylaxis or treatment of obesity
DE10142666A1 (en) 2001-08-31 2003-03-20 Aventis Pharma Gmbh Use of C2-substituted indan-1-ol systems for the preparation of medicaments for the prophylaxis or treatment of obesity
DE10142722A1 (en) * 2001-08-31 2003-03-27 Aventis Pharma Gmbh C2-substituted indan-1-ones and their derivatives, processes for their preparation and their use as medicaments
US10517839B2 (en) * 2008-06-09 2019-12-31 Cornell University Mast cell inhibition in diseases of the retina and vitreous
US9260376B2 (en) 2011-07-22 2016-02-16 Venantius Limited Compounds for use in the treatment of immune related inflammatory disease
CA2839606A1 (en) 2011-07-22 2013-01-31 Venantius Limited Indene derivatives for use in the treatment of inflammatory bowel disease
EP2734497A1 (en) * 2011-07-22 2014-05-28 Venantius Limited Indane dimers for use in the treatment of autoimmune inflammatory disease
US20150141506A1 (en) * 2012-05-24 2015-05-21 Venantius Limited Indane dimers for use in the treatment of autoimmune inflammatory disease
EP2864279B1 (en) 2012-05-24 2016-11-02 Venantius Limited Compounds for use in the treatment of autoimmune inflammatory disease
CN113660932A (en) * 2019-03-29 2021-11-16 景凯生物科技股份有限公司 Phenyl derivatives with pendant alkyl and alkenyl extensions and pharmaceutical compositions comprising the same
CN111533764B (en) * 2020-05-12 2023-06-06 杭州师范大学 Method for preparing siloxyindene derivative by utilizing domino reaction

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1205537B (en) * 1961-08-19 1965-11-25 Thomae Gmbh Dr K Process for making new steroid esters
US3668258A (en) * 1969-03-17 1972-06-06 Uniroyal Inc Sulfur-containing polyaryl polyphenolic compounds and process
SE421305B (en) * 1973-10-12 1981-12-14 Merck & Co Inc PROCEDURE FOR PREPARING 1-HYDROXY-5-INDANYLOXYETIC ACIDS

Also Published As

Publication number Publication date
GB2322859A (en) 1998-09-09
DE69631688D1 (en) 2004-04-01
GB9812216D0 (en) 1998-08-05
GB2322858A (en) 1998-09-09
EP0873301A1 (en) 1998-10-28
KR19990071978A (en) 1999-09-27
ATE260241T1 (en) 2004-03-15
DE69629387T2 (en) 2004-06-24
IE960865A1 (en) 1997-06-06
CA2239694C (en) 2008-05-06
EP0865419B1 (en) 2003-08-06
CA2239853A1 (en) 1997-06-12
US6297399B1 (en) 2001-10-02
JP2000502328A (en) 2000-02-29
DE69631688T2 (en) 2005-01-20
AU1169197A (en) 1997-06-27
US6300376B1 (en) 2001-10-09
EP0874800B1 (en) 2003-08-06
AU1169297A (en) 1997-06-27
WO1997020805A1 (en) 1997-06-12
EP0874800A1 (en) 1998-11-04
IL124756A0 (en) 1999-01-26
IL124756A (en) 2006-04-10
ATE246668T1 (en) 2003-08-15
DE69629390D1 (en) 2003-09-11
WO1997020806A1 (en) 1997-06-12
CA2239694A1 (en) 1997-06-12
IL124795A0 (en) 1999-01-26
DE69629387D1 (en) 2003-09-11
GB9812213D0 (en) 1998-08-05
WO1997020802A1 (en) 1997-06-12
EP0865419A1 (en) 1998-09-23
DE69629390T2 (en) 2004-06-24
DK0865419T3 (en) 2003-11-10
GB2323088A (en) 1998-09-16
GB9812215D0 (en) 1998-08-05
KR19990072007A (en) 1999-09-27
AU1169397A (en) 1997-06-27
JP2000506497A (en) 2000-05-30
EP0873301B1 (en) 2004-02-25
JP2000502072A (en) 2000-02-22
US6423752B1 (en) 2002-07-23
ATE246670T1 (en) 2003-08-15
AU724648B2 (en) 2000-09-28
IL124795A (en) 2001-01-28
US20020052530A1 (en) 2002-05-02

Similar Documents

Publication Publication Date Title
CA2239853C (en) Indane dimer compounds and their pharmaceutical use
US5650444A (en) Substituted biphenyl derivatives
US5604261A (en) Arylalkyl (thio)amides
HU198442B (en) Process for production of derivatives of substituated amin-5,6,7,8-tetrahydronaphtalin-oxi acetic acid and medical compositions containing them
JP2002528434A (en) N- (2-aryl-propionyl) -sulfonamides and pharmaceutical preparations containing them
PT99154A (en) PROCESS FOR THE PREPARATION OF INDOLE, UTEIS DERIVATIVES AS ANTI-ALLERGIC AND ANTI-INFLAMMATORY AGENTS
CA2355987C (en) Bicyclic amide derivatives and their use as muscle relaxants
HU224354B1 (en) Use of 2-aminoindan derivatives and pharmaceutical compositions containing them
US5708033A (en) Amide derivatives and their therapeutic use
WO2002022551A1 (en) Derivatives of naphthalene with comt inhibiting activity
WO1992015558A1 (en) Indian derivative and thromboxane antagonist containing the same
PL209113B1 (en) Novel cyclohexyl sulphones
US6433021B1 (en) Indane compounds and their pharmaceutical use
WO1998055447A1 (en) 3-aminoindane derivatives, process for their preparation and pharmaceutical compositions containing them
PT557787E (en) IMITAZOLYLPHENOL DERIVATIVES MEDICINES THAT CONTAIN THEM AS A PROCESS FOR THE PRODUCTION OF THESE COMPOUNDS AND MEDICINES
JP3124242B2 (en) New tricyclic compounds
JPS63502666A (en) Novel sulfonamide derived from diarylmethane, method for producing the same, and pharmaceutical composition containing the sulfonamide
DK155280B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF INCIDENTAL DERIVATIVES
JPS61277670A (en) Imidazole derivative
PT85547B (en) METHOD OF PREPARING PHARMACEUTICAL COMPOSITIONS BASED ON 2-MERCAPTO-IMIDAZOLE DERIVATIVES AND PREPARATION OF THESE DERIVATIVES
JPH01199940A (en) Phenoxyacetic acid derivative
JPH06312973A (en) New pheynlsulfamide derivative
JPH01125372A (en) Imidazolylalkyloxybenzene derivative
JPH0656759A (en) 5-amino-2-phenoxysulfonanilide compound

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed