EP0641301A1 - Stilbenderivate als antikrebsmittel - Google Patents

Stilbenderivate als antikrebsmittel

Info

Publication number
EP0641301A1
EP0641301A1 EP93914032A EP93914032A EP0641301A1 EP 0641301 A1 EP0641301 A1 EP 0641301A1 EP 93914032 A EP93914032 A EP 93914032A EP 93914032 A EP93914032 A EP 93914032A EP 0641301 A1 EP0641301 A1 EP 0641301A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
lower alkoxy
alkoxy
lower alkyl
pharmaceutical composition
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.)
Withdrawn
Application number
EP93914032A
Other languages
English (en)
French (fr)
Inventor
Mark S. Cushman
Ernest Hamel
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.)
Research Corp Technologies Inc
Original Assignee
Research Corp Technologies Inc
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 Research Corp Technologies Inc filed Critical Research Corp Technologies Inc
Publication of EP0641301A1 publication Critical patent/EP0641301A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/10—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
    • 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
    • C07C233/16—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 singly-bound oxygen atoms
    • C07C233/24—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 singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—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 singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of 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
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/10—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/16—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/37—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by etherified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
    • C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
    • C07C323/36—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal 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
    • C07C45/45—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
    • C07C45/61—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
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • 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
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • 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
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic 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
    • C07C65/21—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 ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/017—Esters of hydroxy compounds having the esterified hydroxy 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
    • C07C69/66—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
    • C07C69/67—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 saturated acids
    • C07C69/708—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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

Definitions

  • the present invention relates to the use of stilbene derivatives and stilbene-like derivatives as anti-cancer agents, pharmaceutical compositions of these compounds and to novel compounds thereof.
  • Tropical and subtropical shrubs and trees of the Combretacae family represent a potentially unexplored source of new compounds which have useful biological properties.
  • the genus Combretrum is known in the medical practices of Africa and India for treating various illness such as leprosy and cancer.
  • Combretrum micranthum and Combretrum zeyheri have received any substantial scientific work.
  • African tree Combretrum caffrum has been found to contain certain agents which were determined to be highly cytotoxic. These agents isolated from the African tree Combretrum caffrum are referred to as combretasatins.
  • R ⁇ is OH or OCH 3 ;
  • R 2 is H or 0CH 3 ; or
  • R ⁇ and R 2 taken together is -0CH 2 0-;
  • R 3 is H or OH;
  • R 4 is OH or 0CH 3 and wherein the configuration of the double bond in formula (A) is cis.
  • These compounds were tested to determine their murine 388 lymphocytic leukemia inhibitation.
  • these combretasatin derivatives are limited by their relatively low solubility in water and saline. This has led to an increased interest in the syntheses and evaluation of polymethoxylated stilbenes and dihydrostilbenes as potential anti-cancer agents.
  • the present invention is also directed to pharmaceutical compositions thereof and their use as anti-cancer agents.
  • the present invention relates to a series of cis-, trans- and dihydro- stilbenes and N-arylbenzylamines, and aryl benzoamides and the compounds thereof as anti-cancer agents to be administered to animals.
  • the present invention is directed to the use of compounds having the structural formula (I):
  • Ar and Ar ⁇ are independently aryl or heteroaryl; and Ar may be mono, di, tri, or tetrasubstituted with R' and Ar r may be mono, di, tri, or tetrasubstituted with
  • R 13 , R 14 , R 15 and R 16 are independently hydrogen or lower alkyl
  • each R* may be the same or different and consists of R 1,, R perpetratZ, R3, and R4., and each R" may be the same or different and consists of R 5 , R 6 , R 7 and R fl ; wherein each R, X, R restroom2., R3,, R4,, R e 5, R c o, R,/ and R jurisdiction o are independently hydrogen, lower alkyl, aryl, halo, amino, lower alkylamino, diloweralkylamino, lower alkoxy , lower aralkyl, arylkoxy, lower aralkoxy, cyano, aryloxy, mercapto, lower alkylthio, amino lower alkyl, carboxy, carbolower alkoxy, C0NHR 9 , NHC0(R g ), lower alkanoyl, nitro, CF 3 , lower alkyl carbonyloxy, amino lower alkoxy, lower alkyl amino lower alkoxy,
  • R g is hydrogen or lower alkyl
  • R ⁇ 1 n 0 R -, ⁇ I*f R, 1-/, R , D S an d R , n 9 are independently lower alkyl ; and R 12 is lower alkyl or lower alkoxy; and the pharmaceutical composition containing these compounds as the active ingredients thereof. Also, the invention relates to novel compounds encompassed by Formula I.
  • R 1 , R", Ar, Ar 1 and X are as defined hereinabove.
  • the Ar group is substituted by R ⁇ f R 2 , R 3 and R 4 while Ar ⁇ is substituted by R 5 , R 6 , R 7 and R ⁇ .
  • Ar and Ar ⁇ can independently be unsubstituted, monosubstituted, disubstituted, trisubstituted or tetrasubstituted; however the compound of Formula I must contain at least two alkoxy groups and preferably at least three alkoxy groups.
  • the alkoxy groups may be substituted as only Ar or Ar ⁇ or may be substituted as both Ar and Ar ⁇ In an especially preferred embodiment, at least two of the alkoxy groups are substituted on Ar; and in a most preferred embodiment, at least three of the alkoxy groups are substituted on Ar ⁇ .
  • the present invention contemplates employing the compounds in Formula I in compositions to be administered in an effective dosage amount to animals as potential new anti-cancer agents.
  • aryl when used alone or in combination, refers to an aromatic group which contains from 6 up to 18 ring carbon atoms and up to a total of 25 carbon atoms and includes the polynuclear aromatics. These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. Polynuclear aromatic compound is meant to encompass bicyclic, tricyclic fused aromatic ring systems containing from 10-18 ring carbon atoms and up to a total of 25 carbon atoms.
  • the aryl group includes phenyl, and the polynuclear aromatics e.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like.
  • the preferred aryl group is naphthyl and especially phenyl.
  • heteroaryl when used alone or in combination, is a nitrogen, sulfur or oxygen containing heteroaromatic group.
  • the ring heteroatoms are either nitrogen, sulfur or oxygen.
  • the heteroaryl groups may be monocyclic, bicyclic, or polycyclic; but if it contains more than 1 ring, the rings are fused. Furthermore, the heteroaryl groups are planar.
  • the heteroaryl groups contain 1-4 ring heteroatoms and from 5-14 ring atoms.
  • the heteroaryl group contains from 1- 13 and preferably 3-13 ring carbon atoms and up to a total of 18 carbon atoms.
  • the heteroaryl includes such groups as thienyl, benzothienyl, naphthathienyl, thianthrenyl, furyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, benzoxazolyl; benzoxathiazolyl, benzothiazolyl and benzoisothiazolyl, and the like, and the N-oxides of the nitrogen containing heteroaryl, such as the N-oxides of pyridyl, pyrazinyl, pyrimidinyl and the like.
  • the preferred heteroaryl groups contain up to 10 ring atoms and 1 or 2 ring heteroatoms and up to a total of 15 carbon atoms.
  • the heterocyclic group contains at least 1 ring nitrogen atom.
  • Preferred heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, oxazolyl, thiazolyl, benzooxazolyl, imidazolyl, indolyl, quinolyl, isoquinolyl, thiazolyl, benzothiazolyl, benzoxazolyl and pyrrolyl.
  • the especially preferred heteroaryl groups include thienyl, pyrazinyl, pyrimidinyl, pyridyl, thiazolyl, and the N-oxide of pyridyl.
  • the most preferred heteroaryl group is pyridyl.
  • alkyl groups when used alone or in combination with other groups, are lower alkyl contain from 1 to 6 carbon atoms and may be straight chained or branched. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
  • alkyl groups contain 1-4 carbon atoms; more preferred alkyl groups contain 1-3 carbon atoms.
  • the most preferred alkyl group is methyl.
  • Alkylene as used herein refers to a bridging alkyl group of the formula C n H 2n . Examples include CH 2 , -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - and the like.
  • lower alkoxy refers to -0- alkyl groups, wherein alkyl is as defined hereinabove.
  • the alkoxy group is bonded to the main chain, aryl or heteroaryl group through the oxygen bridge.
  • the alkoxy group may be straight chained or branched; although the straight-chain is preferred. Examples include methoxy, ethyloxy, propoxy, butyloxy, t-butyloxy, i-propoxy, and the like.
  • Preferred alkoxy groups contain 1-4 carbon atoms, especially preferred alkoxy groups contain 1-3 carbon atoms. The most preferred alkoxy group is methoxy.
  • C II-0-Alkyl wherein the acyl group is bonded to the main chain and alkyl is as defined hereinabove.
  • Examples include COOMe, COOEt, COOPr, and the like.
  • the preferred group is COOMe.
  • Halo includes fluoro, bromo, chloro or iodo.
  • “Lower Alkylamino” refers to a group wherein one alkyl group is bonded to an amino nitrogen, i.e., NH(alkyl) .
  • the NH is the bridge connecting the alkyl group to the aryl or heteroaryl. Examples include NHMe, NHEt, NHPr, and the like.
  • lower diloweralkylamino refers to a group wherein two alkyl groups, which may be the same or different are bonded to an amino nitrogen and the dialkylamino group is bonded to the aryl or heteroaryl through an NH bridge. It is preferred that both alkyl groups are the same. Examples include NMe 2 , N(Me)(Et), NEt 2 , and the like, the most preferred is NMe 2 .
  • lower arylalkyl when used alone or in combination, refers to an aryl-alkylene bond, i.e., the aryl alkyl group is bonded as a substituent through the alkylene moiety.
  • Examples include benzyl, phenethyl, phenpropyl, phenisopropyl, phenbutyl, and the like, diphenyl methyl, 1,2-diphenyl methyl, and the like.
  • arylalkoxy refers to an 0-aryl group wherein the arylalkoxy group is attached as a substituent through an oxygen bridge.
  • aralkoxy refers to an O-arylalkyl group wherein the aralkoxy is attached as a substituent through the oxygen atom.
  • Alkylthio refers to an S-alkyl group, wherein the alkylthio is attached as a substituent through the S atom.
  • amino lower alkyl refers to a group of the formula alkylene-NH 2 , wherein this group is attached as a substituent through the alkylene moiety. Examples include -CH,NH , CH,CH,NH, and the like.
  • lower alkenoyl refers to a lower alkyl group, as defined, wherein one of the carbon atoms is replaced by a carbonyl group. It also includes formyl. Examples include acetyl, propanoyl, butanoyl, and the like.
  • lower alkyl carbonyloxy refers to a group of the formula O-C-Alkyl, wherein the alkyl is defined herein. In other words, the lower alkyloxy- carbonyl is bonded as a substituent through the oxygen atom. Examples include O -CH , O- -CH.CH-,
  • amino lower alkoxy refers to the group -0-Alkylene-NH 2 ⁇ , wherein alkylene is defined hereinabove. This group is attached as a substituent through its oxygen atom.
  • lower alkylamino loweralkoxy refers to an amino lower alkoxy group, wherein one of the amino hydrogens is replaced by a lower alkyl group.
  • a diloweralkyl amino lower alkoxy refers to an amino lower alkoxy group wherein both amino hydrogens are replaced by an alkyl group.
  • the alkyl groups in the latter term may be the same or different but it is preferred that the alkyl groups are the same.
  • Examples of the first term include 0-(CH,•*&),•*&NH,, OCH. _NH, ⁇ , and the like;
  • examples of the second term include OCH 2 CH 2 NHMe, OCH 2 CH 2 NHEt, OCH 2 NHMe, OCH 2 NHEt, and the like, finally, examples of the latter term include OCH 2 CH 2 NMe 2 , OCH 2 CH 2 NEt 2 , and the like.
  • amino lower alkylene oxy carbonyl amino lower alkylene oxy carbonyl
  • diloweralkyl amino lower alkylene oxycarbonyl refers to an amino loweralkylene oxycarbonyl wherein both amino hydrogens are replaced by a lower Q alkyl, and the lower alkyls may be the same or different.
  • the first group include -C00-(CH 2 ) 2 NH 2 , -C00CH 2 NH 2 and the like;
  • examples of the second group include C00CH 2 NHMe, C00CH 2 NHEt, C00(CH 2 ) 2 NHMe, C00(CH 2 ) 2 NHEt and the like, while examples
  • 2c - of the latter group include C00CH 2 NMe 2 , C00CH 2 NEt 2 , COO(CH 2 ) 2 NEt 2 , C00(CH 2 ) 2 NMe 2 and the like.
  • a more especially preferred value of X is
  • Z 2 , Z 3 , Y 2 and Y 3 are independently hydrogen, cyano or carboloweralkoxy (e.g. COOMe) . It is most preferred that one of Y 2 , Z 2 , Y 3 or Z 3 is hydrogen and the other is hydrogen, cyano or carboloweralkoxy. It is most preferred that Y 2 and Z 2 are hydrogen, Y 3 is cyano or hydrogen and Z 3 is hydrogen, cyano or lower carbalkoxy (e.g., COOMe). It is most especially preferred that Z 2 , Z 3 Y 2 and Y 3 are all hydrogen.
  • a preferred value of R 13 is hydrogen; the preferred values of R 14 , R 15 and R 16 are methyl or ethyl.
  • R 1 1 C 5 and Rl, c o are the same and that both are methyl and ethyl.
  • the preferred value of Q is ethylene.
  • R 7 and R ⁇ are independently hydrogen, C 1 -C 4 lower .alkoxy, benzyloxy, acetyloxy, t-butyldimethoxy siloxy, halogen,
  • _silyl amino, 3-6 dimethylamino lower alkoxy halo (e.g., 5 chloro, bromo), nitro, NMe 2 , C ⁇ _ 4 alkylthio, C ⁇ _ 4 lower alkyl, 0(CH 2 ) 2 NMe 2 , 0(CH 2 ) 2 NEt 2 .
  • halo e.g., 5 chloro, bromo
  • R t , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R fl are independently hydrogen, methoxy, chloro, bromo, nitro, OSi(t-Bu) (CH 3 ) 2 , NMe 2 , OAc, OEt, OPr, SMe, Me, Et, iPr, t-Bu, NH 2 ,
  • R 2 , R 3 and R 4 are lower alkoxy, especially methoxy, it is more preferred that at least two of R 2 , R 3 and R 4 is lower alkoxy? especially methoxy and it is most especially preferred that R 2 , R 3 and R 4 are lower alkoxy (e.g. methoxy). Further, it is preferred that R ⁇ is hydrogen.
  • R 6 , R 7 and R 8 are other than hydrogen, and most preferably it is preferred that R 6 and R 8 are hydrogen.
  • the most preferred values of R 7 is hydrogen, halo (e.g., chloro, bromo or iodo) , lower alkoxy (e.g., OMe, OEt, OPr), diloweralkylamino (e.g., NMe 2 ) , loweralkylthio (e.g., SMe), lower alkyl, or CF 3 .
  • R 5 is hydrogen; however, if it substituted, it is preferred that R 5 may be the 2-substituent, and the preferred R 5 value at the 2-position is hydrogen or halo (e.g., Cl). It is most preferred that R 7 has the preferred embodiment described herein that R 6 and R 8 are H and that R 5 is hydrogen or 2-halo (e.g., Cl) .
  • R r R 2 , R 3 , R 4 , R 5 , R 6 , R 7 or R ⁇ are as defined hereinabove and X is defined as NHCH 2 and more preferably CH 2 NH.
  • the pharmaceutically acceptable salts are
  • T is the counterion.
  • the counterions include such groups as the halides (I, Cl, Br or F), sulfates, nitrates, benzenesulfonates, toluene sulfonates, acetates, propionates, formates, malates, tartrates, and the like.
  • the most preferred counterions are the halides, especially bromides and more especially chlorides.
  • R 5 , R g and R 8 are hydrogen and that R 7 is other than hydrogen.
  • R 2 , R 3. R4. and R7 are as defined herein. It is preferred that R 2 , R 3 and R 4 are lower alkoxy and R 7 is lower alkoxy, lower alkyl, halo, thiolower alkyl,
  • R 2 , R 3 and R 4 are lower alkoxy, and that R 7 is other than hydrogen, especially lower alkoxy, lower alkyl, halo, thio lower alkyl or CF 3 . It is most preferred that the alkyl group alone, or in combination, contains 1-2 carbons; and that it is especially most preferred that the alkyl group contains 1 carbon atom.
  • R 7 is methyl, ethyl, methoxy, ethoxy, CF 3 or thiomethyl.
  • the preferred halo is chloro, bromo and especially iodo.
  • R ? is lower alkyl, halo, thioalkyl, CF 3 and lower alkoxy as defined hereinabove.
  • the pharmaceutically acceptable salts are the most preferred embodiment, especially since the quaternary cations of Formulae lb, Ib 2 , Ib 3 and Ib 4 are soluble in aqueous solutions.
  • the most preferred quaternary salt is 4- methyl-3' ,4' ,5'-trimethoxybenzylaniline hydrochloride.
  • Preferred compounds encompassed by Formula I include:
  • a most preferred compound of Formula I is (Z)- 1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene.
  • the compounds of the present invention can be prepared by art-recognized techniques. Although the examples described hereinbelow may be specific, the syntheses are general. For example, in the Wittig reaction described hereinbelow and depicted in Scheme 1, a heteroaryl-arorylmethylene-triphenylphosphonium can in reaction with a heteroaryl or aryl aldehyde under
  • the formation of the compound of Formula Ia wherein X is CONH or CH 2 NH depicted in Scheme 6 is also general and is applicable to compounds of Formula Ia when Ar and Ar 1 are other than phenyl.
  • the reaction in Scheme 6 is general for the reaction between an aryl or heteroaryl acid chloride and an aryl or heteroaryl amino reacted under amide forming condition followed by reduction with LiAlH , as shown hereinbelow:
  • Trans-stilbene compounds 6q-6y were prepared by the Wittig-Horner reaction of phosphonate ester compounds 7a-c with the aryl aldehydes 4d and 4o-4t in DMF using sodium ⁇ methoxide as the base (Scheme II) . Under these reaction conditions, trans isomers were obtained exclusively. 4*Hydroxystilbene compounds 5o and 6o were prepared from
  • R2 Mc:
  • Compounds of the present invention exhibit tubulin polymerization inhibitory activity. They also display anti-tumor, especially anti-cancer activity, and thus, are anti-cancer agents, useful for the treatment of cancer, as shown by the assays described hereinbelow. Pharmacological Testing
  • Electrophpretically homogeneous tubulin was purified from bovine brain as described previously by
  • tubulin was preincubated at 37°C with varying compound concentrations, reaction mixtures were chilled on ice, GTP (required for the polymerization reaction) was added, and polymerization was followed at 37°C by turbidimetry at 350 nm in
  • IC 50 value > 50 ⁇ m were examined in at least two independent experiments.
  • active does not mean that a given compound has no activity.
  • the term means that it has activity, but its IC 50 value in a particular assay is > 50 ⁇ m.
  • the effect of agents on the binding of [ 3 H]colchicine (obtained from Amersham) to tubulin was measured by the DEAE-filter technique.
  • compound 5a was found to be approximately 140 times more cytotoxic against HT-29 cells and about 10 times more cytotoxic against MCF-7 cells than co bretastatin A-4 (la). However, 5a was found to be about 20 times less cytotoxic against A-549 cells, 30 times less cytotoxic against SKMEL-5, and 7 times less cytotoxic against MLM cells than combretastatin A-4 (la).
  • trans-stilbenes had lower activity. This includes tetramethylated piceatannol (6y), and its methoxylated derivatives 6s, 6t, 6u and 6v. Only two dihydrostilbenes (compounds 8a and 8n) were found to be highly active, with 8a being the second most cytotoxic agent prepared (ED 50 values about 2 X 10 " ⁇ M) . Compound 8a was more cytotoxic than dihydrocombretastatin A-4 (lc) in all five cancer cell lines studied here.
  • combretastatins The mechanism of action of the combretastatins has been shown to be at the microtubule level, since they cause cells to accumulate in apparent metaphase arrest and inhibit in vitro microtubule assembly. They bind specifically to tubulin, the major component of microtubules, at the colchicine binding site, since combretastatin A-4 (la) has been shown to competitively inhibit the binding of radiolabeled colchicine to tubulin.
  • combretastatin A-4 la
  • Compound 5a is a most potent new agent as an inhibitor of tubulin polymerization, with an IC 50 value (2.2 ⁇ M) essentially indistinguishable from those of combretastatin A-4 and podophyllotoxin and somewhat higher than that of thiocolchicine. This is in agreement both with compound 5a possessing one of the highest cytotoxicity of the new compounds and with its close similarity to combretastatin A-4 (la) in its overall effects on the cell lines evaluated. The difference in IC 50 values between the two dihydrostilbene compounds lc and 8a was more noticeable.
  • the combretastatin A-4 analog lc had an IC 50 value of 3.3 ⁇ M, only modestly lower than the IC 50 value of combretastatin A-4, but the corresponding hydrogenation of compound 5a to yield compound 8a resulted in an almost 4-fold increase in the IC5 E hinder0 value, from 2.2 to 7.9 ⁇ r M.
  • dihydrocombretastatin A-4 compound lc
  • compound 8a as an inhibitor of tubulin polymerization
  • the latter agent was more cytotoxic with the cell lines studied here.
  • the halogenated cis stilbenes 5e, 5g and 5h were not much less active than la and 5a as inhibitors of tubulin polymerization, they were about 1000-fold less cytotoxic.
  • the cytotoxic compounds gave reproducible results in the tubulin polymerization assay with the exception of the trans stilbenes lb and 6n.
  • Initial evaluation of these compounds in the tubulin polymerization assay yielded results concordant with the cytotoxicity data, although the apparent IC 50 value obtained in the polymerization assay for 6n was difficult to reproduce and that for lb initially obtained in the current experiments was lower than that obtained previously.
  • both'lb and 6n solutions increased in activity with storage, and that, when care was taken to evaluate the solutions immediately after their preparation, neither trans stilbene was able to significantly inhibit tubulin polymerization. This suggested that both compounds were unstable in solution, and that more active agents might be formed during their storage.
  • cytotoxic properties of these two agents may similarly result from chemical changes in solution.
  • 500 MHz MR analysis of 6n in solution demonstrated significant formation of the cis isomer 5n.
  • the ratio of 6n:5n was 1:1 after 24 hours of the dissolution of pure 6n in DMSO at room temperature.
  • H NMR analysis over a period of one month at frequent intervals confirmed the formation of about 3% and 10% of the cis isomer (compound la) after two and four weeks, respectively.
  • Compounds 5a and 8a can be taken as standards for structure activity comparisons of cis stilbenes and dihydrostilbenes, respectively, in the tubulin polymerization assay. Without exception, when the same modified analog was available in both series, a greater loss of activity occurred in the dihydrostilbene than in the analogous cis stilbene (cf. 5b and 6b; 5f and 6f; 5n and 6n; 5p and 6p) .
  • An enhancement of antitubulin activity in the 5a/8a structure was obtained by modification of the substituents on the B-phenyl ring by the addition of a single hydroxy group at position 3' (as occurs in combretastatin A-4 (la) and dihydrocombretastatin A-4 (lc)) or addition of two hydroxy groups in a vicinal diol arrangement at positions 2' and 3' (as occurs in combretastatin A-l and B-l).
  • Combretastatin A-4 (la) and compound lc inhibit the binding of radiolabeled colchicine to tubulin. Therefore Formula I compounds were evaluated in this assay too.
  • the Formula I compounds relative activity as inhibitors of colchicine binding correlated well with their activity as inhibitors of tubulin polymerization.
  • the mechanism of action of the new compounds like that of the combretastatins, thus appears to involve an interaction of the drug with the colchicine binding site of tubulin. Only compound 5a, however, approached the nearly total inhibition of colchicine binding observed with equimolar combretastatin A-4 (la).
  • the compounds 15a-f were highly cytotoxic in all five cancer cell cultures, with potencies from 100 times less than to equal to that of combretastatin A-4.
  • Replacement of the OMe of the B-ring with an SMe group (compound 15c) resulted in a compound which was as cytotoxic as the parent compound 15a in the A-549 and MLM cell cultures.
  • the thiomethyl compound was about one order of magnitude less cytotoxic than 5a in the MCF cell culture, while being about one order of magnitude more potent that 5a in HT-29 cells and two orders of magnitude more potent in SKMEL-5 cells.
  • the thiomethyl compound 15c is an analogue of thiocolchicine, which is more potent as a tubulin polymerization inhibitor and is more cytotoxic in certain cell cultures than colchicine.
  • Substitution with i-propyl decreased the cytotoxicity somewhat (ED 50 7.0 x 10 ⁇ 2 to 4.7 x 10 "4 ⁇ M range), as did substitution with an O-n-propyl group (compound 15b).
  • compounds 15a-f retained significant tubulin polymerization inhibitory activity relative to 5a.
  • the decreased anti-tubulin activity of the 4-isopropyl compound 15f and the lack of activity of the 4-tert-but ⁇ l compound 15g demonstrates that an increase in steric bulk at this position results in a decrease in activity.
  • the enhancement of antitubulin activity which occurred with a reduction in size of the 4-substituent in the B-ring.
  • the only new compound more effective than the parent compound 5a as an inhibitor of tubulin polymerization was 15d, in which a methyl group replaced the 4-methoxy group of 5a.
  • the potency of this agent as a tubulin polymerization inhibitor was equivalent to combretastatin A-4 (lb), the natural product, even though it lacks the adjacent hydroxyl group in the fi ⁇ ring.
  • Compounds 24a and 24c had ED 50 values of 5.0 x 10 "2 to 6.4 x 10 "3 ⁇ M in A-549, MCF-7, HT-29, and SKMEL-5 cell cultures.
  • the dimethylaminoethyl or diethylaminoethyl esters (compounds 24e and 24f) or the N-ethylamide (compound 24d) of compound 23a did not show considerable cytotoxicity.
  • Transfer of the B-ring methoxy group in compound 23a to the 3-position resulted in about 10 to 100-fold increase in the cytotoxicity in three cell lines and similar movement in compound 24a (compound 24b) reduced the cytotoxicity by 100 to 1000-fold.
  • this compound was about 10 to 100- fold less cytotoxic than l-(4-methoxyphenyl)-2-(3,4,5- trimethoxyphenyl)ethane (8a), although its activity as a tubulin polymerization inhibitor (IC 50 11 ⁇ M) was not decreased much relative to that of 8a (IC 50 7.9 ⁇ M) .
  • IC 50 11 ⁇ M tubulin polymerization inhibitor
  • 8a IC 50 7.9 ⁇ M
  • the two- carbon bridge in l-(4-methoxyphen ⁇ l)-2-(3,4,5- trimethoxyphenyl)ethane (8a) was reduced to a one carbon bridge (compounds 27, 28 and 29, Table VI). All of these compounds were less potent than 8a.
  • 3,4,4* ,5- Tetra-methoxybenzophenone (27) was about 100 times less cytotoxic than 8a, although its tubulin polymerization inhibitory activity (IC 50 7.4 ⁇ M) was essentially identical to that of 8a (IC 50 7.9 ⁇ M) .
  • Conversion of 27 to the alcohol 28 reduced cytotoxicity by another 100 times and also resulted in lower tubulin polymerization inhibitory activity (IC 50 > 40 ⁇ M) .
  • the antitubulin activities of the conformationally restricted analogues of the stilbene 5a and the dihydrostilbene 8a are included in Table VII.
  • the data indicate that the active conformation of the stilbene 5a does not approach being planar, and involves a conformation in which at least one of the phenyl rings is twisted out of the plane of the other phenyl ring.
  • the planar conformation of 5a is a high energy species due to a nonbonded interaction between the protons of the two aromatic rings that are ortho to the bridge. Consequently, a totally planar conformation of 5a is not expected to exist to any appreciable extent.
  • combretastatin A-l The X-ray structure of combretastatin A-l reveals that the normals to the least squares planes of the two phenyl rings are inclined 66° to each other. This likely represents a low energy conformation which may be involved in binding at the receptor site. Consistent with this hypothesis is the well documented and recognized fact that, the planes of the trimethoxy-benzene ring and the other oxygen-substituted ring in podophyllotoxin, colchicine, steganacin, and combretastatin A-4 exist in similar dihedral relationships, so that these natural products resemble each other structurally to some extent when bound at the receptor site.
  • Modifications can be made in the structure of combretastatin A-4 (lb) and its tetramethoxy analogue (5a) without substantially comprising cytotoxic and antitubulin activity.
  • the cis-stilbene and benzylaniline configuration is most preferred, and all bridge substituents that have been tried to date r * educe activity.
  • the methoxy groups at positions 3, 4 and 5 in the A ring is preferred and substitution at positions 4 in the B ring is also highly preferred.
  • reaction mixtures in triplicate
  • iM tubulin contained 1
  • the 4-ethyl (110b, IC 50 7.2 ⁇ m), 4-methoxy (110c, 8.9 ⁇ m) , 4-ethoxy (110d, ll.O ⁇ m), and 4-thiometh ⁇ l (llOe, 16.0 ⁇ m) analogues had less activity.
  • This trend between the potencies of the compounds as tubulin polymerization inhibitors and the size of the aniline substituent R was reflected remarkably well by the cytotoxicities in all of the cancer cell cultures studied. The smaller the substituent, the higher the cytotoxicity.
  • the compounds encompassed in Formula I have been determined to be effective inhibitors of tubulin polymerization.
  • the compounds of the present invention interact effectively with the colchicine binding site of tubulin thus they represent potential antimitotic agents which may inhibit cancer cell proliferation.
  • the present new compounds form salts with acids when a basic amino function is present and salts with bases when an acid function, i.e., carboxyl, is present. All such salts are useful in the isolation and/or purification of the new products.
  • Suitable acids include, for example, hydrochloric, sulfuric, nitric, benzenesulfonic, toluene-sulfonic, acetic, maleic, tartaric and the like which are pharmaceutically acceptable.
  • Basic salts for pharmaceutical use are the Na, K, Ca and Mg salts, and the like.
  • compositions of the present invention comprise the compounds encompassed by Formula I and an acceptable pharmaceutical carrier.
  • the carrier can be any of those conventionally used and is limited only by chemico-physical considerations such as solubility and lack of reactivity with the compound and by the route of administration.
  • the carrier will be agueous and may contain solubilizing agents, buffers, preservatives, antioxidants, chelating agents, and agents to control the tonicity, such as dextrose or sodium chloride.
  • solubilizing agents such as sodium chloride.
  • the active ingredients of the therapeutic compositions and the compounds of the present invention exhibit excellent anti-cancer activity when administered in amounts ranging from about 0.001 mg to about 10.0 mg per kilogram of body weight per day.
  • a preferred dosage regimen for optimum results would be from about 0.01 mg to about 10 mg per kilogram of body weight per day, and such dosage units are employed that a total of from about 0.1 mg to about 1.0 mg per kilogram of the active compound for a subject of about 70 kg of body weight are administered in a 24-hour period in single or divided doses.
  • This dosage regimen may be adjusted to provide the optimum therapeutic response and is preferably administered one to three times a day. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a decided practical advantage is that the active compound may be administered in a convenient manner such as by the oral, intravenous (where water soluble) , intramuscular or subcutaneous routes.
  • the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 1 % of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80 % of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between 5 and 1000 mg of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint,
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • sustained release dosage forms are contemplated wherein the active ingredient is bound to an ion exchange resin which, optionally, can be coated with a diffusion barrier coating to modify the release properties of the resin.
  • the active compound may also be administered parenterally or intraperitoneally.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, but the use of a coating such as lecithin; by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and anti ungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as. required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
  • the principal active ingredient is compounded for convenient and effect administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed.
  • a unit dosage form can, for example, contain the principal active compound in amounts ranging from about 5 to about 1000 mg, with from about 5 to about 250 mg being preferred.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • Diethyl benzylphosphonate 7a, aryl aldehydes 4a-t and 1 M solution of tetra-n- butylammonium fluoride in THF were obtained from commercial sources.
  • Compounds 7b-c were prepared by the reaction of the corresponding benzyl bromides and triethyl phosphite.
  • Phosphonium bromides 3a-b were prepared by stirring a mixture of triphenyl phosphine and the corresponding benzyl bromides in toluene.
  • Combretastatin A-4 and its trans isomer were obtained from Prof. G. R. Pettit, Arizona State University.
  • Compound lc was prepared as described previously.
  • Podophyllotoxin was obtained from Aldrich Chemical Co.
  • thiocolchicine was from Roussel-Uclaf.
  • Preparative silica gel tic plates (200 micron) were purchased from Analtech.
  • reaction solution was poured into ice-cold water (500 mL) and acidified with 20% sulfuric acid (200 mL) , extracted with ether (100, 100, 50 mL) , washed with water (50 mL) and saturated sodium chloride solution (50 mL) , and dried over anhydrous sodium sulfate.
  • Evaporation of the filtrate and flash chromatography (ether: hexane, 70:30 by volume, silica gel 230-400 mesh) gave 33 as a yellow oil (1.97 g, 79.1%): IR (film) 3231 (br), 3005, 2933, 1733, 1703, 1590, 1513,
  • N-(2,3,4-trimethoxyphenethyl)acetamide (43).
  • Acetyl chloride (1.3 mL, 1.45 g, 18.2 mmol) was added dropwise to a stirred suspension of compound 42 (3g, 12.1 mmol) in 2.0 N NaOH solution (27 mL, 54.0 mmol) cooled in an ice bath. The resulting solution was stirred at 0°C for 1 h.
  • the reaction solution was extracted with CHC1 3 (50, 30, and 20 mL) and the combined CHC1 3 layer was washed with saturated NaCl solution and dried over anhydrous Na 2 S0 4 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP93914032A 1992-05-21 1993-05-20 Stilbenderivate als antikrebsmittel Withdrawn EP0641301A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US88772592A 1992-05-21 1992-05-21
US887725 1992-05-21
PCT/US1993/004807 WO1993023357A1 (en) 1992-05-21 1993-05-20 Stilbene derivatives as anticancer agents

Publications (1)

Publication Number Publication Date
EP0641301A1 true EP0641301A1 (de) 1995-03-08

Family

ID=25391732

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93914032A Withdrawn EP0641301A1 (de) 1992-05-21 1993-05-20 Stilbenderivate als antikrebsmittel

Country Status (4)

Country Link
EP (1) EP0641301A1 (de)
AU (1) AU4385293A (de)
CA (1) CA2136220A1 (de)
WO (1) WO1993023357A1 (de)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW325458B (en) * 1993-09-08 1998-01-21 Ajinomoto Kk Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer
TW334418B (en) * 1995-03-07 1998-06-21 Ajinomoto Kk Stilbene derivatives and pharmaceutical compositions
US5703130A (en) * 1995-06-07 1997-12-30 Institute Of Materia Medica, An Institute Of The Chinese Academy Of Medical Sciences Chalcone retinoids and methods of use of same
AU702423B2 (en) * 1995-06-07 1999-02-18 Institute Of Materia Medica Chalcone retinoids and methods of use of same
GB0028702D0 (en) 2000-11-24 2001-01-10 Novartis Ag Organic compounds
TW200529812A (en) 2003-12-26 2005-09-16 Chugai Pharmaceutical Co Ltd Benzamide derivatives
EP1748767B1 (de) 2004-05-28 2011-12-28 Unigen, Inc. 1-(3-methyl-2,4-dimethoxyphenyl)-3-(2',4'-dihydroxyphenyl)-propan als hochwirksamer tyrosinase-inhibitor
FR2882357B1 (fr) * 2005-02-23 2007-05-11 Fabre Pierre Dermo Cosmetique Utilisation de derives de phenanthrenes en tant qu'agents anti-inflammatoires, procede de synthese et produits intermediaires
WO2006108864A2 (en) 2005-04-15 2006-10-19 Dominion Pharmakine S.L. New nitrogenated trans-stilbene analogs, method for the obtention and medical applications thereof
CN101139358B (zh) * 2006-09-07 2011-10-12 浙江大德药业集团有限公司 乙氧基康普立停及其前药的制备和用途
US20100298402A1 (en) * 2007-11-06 2010-11-25 Orchid Research Laboratories Limited Stilbene derivatives as pstat3/il-6 inhibitors
JP2011528719A (ja) 2008-07-21 2011-11-24 ユニジェン・インコーポレーテッド スキンホワイトニング（色を薄くする）化合物系列
CN109896935A (zh) 2011-03-24 2019-06-18 尤尼根公司 用于制备二芳基丙烷的化合物和方法
WO2016179108A1 (en) 2015-05-01 2016-11-10 Georgia State University Research Foundation Benzhydrol derivatives for the management of conditions related to hypoxia inducible factors
LT3464336T (lt) 2016-06-01 2022-05-10 Athira Pharma, Inc. Junginiai
CN111875513B (zh) * 2020-08-20 2022-12-30 湖南省人民医院 一种白藜芦醇a环n(ch3)2基衍生物及其制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5946205B2 (ja) * 1976-01-01 1984-11-10 科研製薬株式会社 ベンゾイル誘導体を有効成分とする消炎鎮痛剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9323357A1 *

Also Published As

Publication number Publication date
WO1993023357A1 (en) 1993-11-25
AU4385293A (en) 1993-12-13
CA2136220A1 (en) 1993-11-25

Similar Documents

Publication Publication Date Title
US5430062A (en) Stilbene derivatives as anticancer agents
EP0641301A1 (de) Stilbenderivate als antikrebsmittel
Cushman et al. Synthesis and evaluation of analogs of (Z)-1-(4-methoxyphenyl)-2-(3, 4, 5-trimethoxyphenyl) ethene as potential cytotoxic and antimitotic agents
Cushman et al. Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization
Thakkar et al. Synthesis and protein-tyrosine kinase inhibitory activity of polyhydroxylated stilbene analogs of piceatannol
KR100220538B1 (ko) 아크리딘 유도체
US5656654A (en) Arylidene and heteroarylidene oxindole derivatives and process for their preparation
WO2004058682A1 (ja) 選択的エストロゲン受容体モジュレーター
US20080300271A1 (en) Novel compounds and a novel process for their preparation
CS208158B2 (en) Method of making the new stilbenes derivatives
Cushman et al. Synthesis and evaluation of a series of benzylaniline hydrochlorides as potential cytotoxic and antimitotic agents acting by inhibition of tubulin polymerization
US5824698A (en) Antibacterial dibenzimidazole derivatives
US5652250A (en) N-substituted β-aryl- and β-heteroaryl-α-cyanoacrylamide derivatives and process for their preparation
RU2277531C9 (ru) Новые соединения для модулирования клеточной пролиферации
CA2196370A1 (en) Isoprene derivatives
FI66835B (fi) Foerfarande foer framstaellning av nya terapeutiskt anvaendbara polyenfoereningar samt salter daerav
US5948807A (en) Spiroindanamines and Spiroindanimides
Kanao et al. Spasmolytic agents. 2. 1, 2, 3, 4-Tetrahydro-2-naphthylamine derivatives
JP2013507327A (ja) 癌治療用のジ（フェニルプロパノイド）・グリセロール誘導体
US5646150A (en) Methods of using lavendamycin analogs
JP2007530428A (ja) フルオロコンブレタスタチンおよびその誘導体
WO1996003364A1 (fr) Derive du benzoylethylene
US5929087A (en) Decahydroquinoline-based anti-cholinergic agents
EP0549348A1 (de) Arylidene-heterocyclische Derivate, Verfahren zu ihrer Herstellung und ihre Anwendung als Tyrisine-Kinase Inhibitoren
US5587385A (en) Arylidene-heterocyclic derivatives and process for their preparation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19941121

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE ES FR GB IE IT LI

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19961203