Cancer Research Technology Limited

The Institute of Cancer Research

Vernalis &r&d) Ltd.

Vernalis (cambridge) Limited

Cti Biopharma Corp.

Other

Novartis Ag

National University of Singapore

The Institute of Cancer

Institute of Cancer Research of Royal Cancer Hospital

Vernalis Limited

Brian William Dymock

Martin James Drysdale

Edward McDonald

Kwai Ming Cheung

Paul Webb

Thomas Peter Matthews

Harry Finch

Karen Elizabeth James

Anthony Deodaunia William

Xavier Barril-Alonso

Cheng H Lee

Michael Mutz

Allan Michael Jordan

Christoph Max Krell

Mandy Christine Beswick

Holger Petersen

Christofe Fromont

Weijia Zheng

Paul Workman

Cheng Hsia Angeline Lee

Laurence Pearl

Chrisostomos Prodromou

Cheng Shang See

Paul Andrew Brough

Xavier Barrilalonso

Sang Hyun Lee

Mayumi Kitagawa

Edward Mcdonald

Thomas Peter Mathews

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R, is a group of formula (IA): &#x2014;Ar-(Alk)-(Z)-(Alk)-Q, wherein in any compatible combination Aris an optionally substituted aryl or heteroaryl radical, Alkand Alkare optionally substituted divalent C-Calkylene or C-Calkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO.sub.2-, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S) NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;NRSO&#x2014; or &#x2014;NR&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk)p-(Z)-(Alk)-Q wherein Q, Alk, Alk, Z, p, r and s are as defined above in relation to group (IA); and Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

Isoxazole compounds as inhibitors of heat shock proteins

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R, is a group of formula (IA): &#x2014;Ar-(Alk)-(Z)-(Alk)-Q, wherein in any compatible combination Aris an optionally substituted aryl or heteroaryl radical, Alkand Alkare optionally substituted divalent C-Calkylene or C-Calkenylene radicals, p, r and s are independently 0 or 1, Z is &#x2014;O&#x2014;, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO.sub.2-, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S)NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;NRSO&#x2014; or &#x2014;NR&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk)p-(Z)-(Alk)-Q wherein Q, Alk, Alk, Z, p, r and s are as defined above in relation to group (IA); and Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

A compound of formula I, wherein the compound of formula I has the structure: wherein Rto R, Y, L, Z and Xto Xhave meanings given in the description, said compounds having utility in the treatment of hyperproliferative disease. 

Selective anti-cancer compounds

The present invention relates to certain salts of a 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (Compound I) which have been found to have improved properties. In particular the present invention relates to the citrate salt of this compound. The invention also relates to pharmaceutical compositions containing the citrate salt and methods of use of the citrate salt in the treatment of certain medical conditions. 

11-2(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt

The present invention relates to certain salts of a 9E-15-(2-pyrrolidin-1-yl-ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14,16,18(26),20,22-nonaene (Compound I) which have been found to have improved properties. In particular the present invention relates to the citrate salt of this compound. The invention also relates to pharmaceutical compositions containing the citrate salt and methods of use of the citrate salt in the treatment of certain medical conditions. 

(9E)-15-(2-pyrrolidin-1-yl-ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2.5).1(14,18)]hexacosa-1(24),2,4,9,14,16,18(26),20,22-nonaene citrate salt

The present invention relates to certain salts of a 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26triaza-tetra-cyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (Compound I) which have been found to have improved properties. In particular the present invention relates to the maleate salt of this compound. The invention also relates to pharmaceutical compositions containing this salt and methods of use of the salt in the treatment of certain medical conditions. 

11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-maleate salt

11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt

Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, cancer: wherein Ris a group of formula &#x2014;(Ar)-(Alk)-(Z)-(Alk2)-Q wherein Aris an optionally substituted aryl or heteroaryl radical, Alk' and Alk 2 are optionally substituted divalent C-Calkylene or C-Calkenylene radicals, m, p, r and s are independently 0 or 1, Z is &#x2014;O&#x2014;, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO&#x2014;, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S)NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;NRSO&#x2014; or &#x2014;NR&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris hydrogen, an optional substituent, or an optionally substituted (C-C)alkyl, aryl or heteroaryl radical; and Ris a carboxylic ester, carboxamide or sulfonamide group. 

Substituted thieno[2,3-d]pyrimidines as HSP90 inhibitors

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R, is a group of formula (IA): &#x2014;Ar-(Alk)-(Z)-(Alk)-Q, wherein in any compatible combination Aris an optionally substituted aryl or heteroaryl radical, Alkand Alkare optionally substituted divalent C-Calkylene or C-Calkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO.sub.2-, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S)NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;NRSO&#x2014;or &#x2014;NR&#x2014; wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk)-(Z)-(Alk)-Q wherein Q, Alk, Alk, Z, p, r and s are as defined above in relation to group (IA); and Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

The present invention relates to new salt forms of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide, in particular the mesylate, hydrochloride, tartrate, phosphate and hemi fumarate salt thereof; to crystalline forms of such salts; to polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide; to hydrates and polymorphs of the new salt forms mentioned above; to the use of the new salt forms mentioned above for the manufacture of a medicament for the treatment of a disorder mediated by Hsp90; to a method for treating a disorder mediated by Hsp90 using the new salt forms; to formulations comprising such salt forms, in particular aqueous solutions suitable for intravenous administration; and to amber glass containers being filled with such formulations.

Acid addition salts, hydrates and polymorphs of 5-(2,4-dihydroxy-5-iso-propyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide and formulations comprising these forms

Isoxazoles of formula (A) or (B) wherein Ris a group of formula (IB)  The isoxazoles are inhibitors of HSP90 activity, and useful for the treatment of, for example, cancers.

Acid addition salts, hydrates and polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide and formulations comprising these forms

Compounds of formula (1) are inhibitors of HSP90 activity in vitro or in vivo, and of use in the treatment of inter alia, Cancer: wherein Ris a group of formula &#x2014;(Ar)-(Alk)-(Z)-(Alk 2)-Q wherein Aris an optionally substituted aryl or heteroaryl radical, Alk' and Alk 2 are optionally substituted divalent C-Calkylene or C-Calkenylene radicals, m, p, r and s are independently 0 or 1, Z is &#x2014;O&#x2014;, &#x2014;S&#x2014;, &#x2014;(C&#x2550;O)&#x2014;, &#x2014;(C&#x2550;S)&#x2014;, &#x2014;SO&#x2014;, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;C(&#x2550;S)NR&#x2014;, &#x2014;SONR&#x2014;, &#x2014;NRC(&#x2550;O)_, &#x2014;NRSO- or &#x2014;NR&#x2014;wherein Ris hydrogen or C-Calkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; Ris hydrogen, an optional substituent, or an optionally substituted (C-C)alkyl, aryl or heteroaryl radical; and Ris a carboxylic ester, carboxamide or sulfonamide group. 

Compounds of formula (IA) or (IB) or salts, N-oxides, hydrates or solvates thereof are Inhibitors of HSP90, and useful in the treatment of, for example, cancer: formula (IA), formula (IB) wherein Ar is an aryl or heteroaryl radical which is linked via a ring carbon, and which is substituted by a hydroxy group on a carbon in the 2-position, and which is otherwise either unsubstituted or optionally substituted; Ris hydrogen or optionally substituted C-Calkyl; Ris hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C-Calkyl, C-Calkenyl, or C-Calkynyl; or a carboxyl, carboxamide or carboxyl ester group; and Ris a carboxamide group. 

3-(2-hydroxy-phenyl)-1H-pyrazole-4-carboxylic acid amide derivatives as HSP90 inhibitors for the treatment of cancer

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Abingdon, United Kingdom

Brian William Dymock