Vernalis &r&d) Ltd.

Cancer Research Technology Limited

The Institute of Cancer Research

Ipsen Biopharm Limited

Ipsen Pharma S.a.s.

Vernalis (cambridge) Limited

Les Laboratoires Servier

Ipsen Limited

Vernalis Limited

Paul Webb

James Brooke Murray

James Edward Paul Davidson

Martin James Drysdale

Edward McDonald

Brian William Dymock

András Kotschy

Thomas Peter Matthews

Kwai Ming Cheung

Karen Elizabeth James

Harry Finch

Mary White

Julie Partington

Simon Bedford

Maïa Chanrion

Attila Paczal

Stephen Stokes

Frédéric Colland

Nicolas Foloppe

Andrea Fiumana

Ana Leticia Maragno

Jérôme-Benoit Starck

Emma Sanders

Tibor Novák

Andy Pickett

András Herner

Edward Mcdonald

Thomas Peter Mathews

Mátyás Pál TIMÁRI

Andrew Pickett

Naveed Panjwani

Method for treating a disease, condition, or syndrome in a subject comprising administering, to a subject in need thereof, a solid or liquid pharmaceutical composition comprising:

Pharmaceutical composition containing botulinum neurotoxin

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

A method of treating a mammal suffering from a cancer responsive to inhibition of protein kinase activity, by administering to the mammal an amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, effective to inhibit protein kinase activity, wherein the compound of formula (I) is: 

Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity

Solid and liquid pharmaceutical compositions comprising botulinum neurotoxin complex or high purity botulinum neurotoxin and a surfactant. The composition may comprise a crystalline agent.

Pharmaceutical composition comprising botulinum, a non ionic surfactant, sodium chloride and sucrose

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.

The invention relates to a solid or liquid pharmaceutical composition comprising botulinum neurotoxin complex (type A, B, C, D, E, F or G) or high purity botulinum neurotoxin (type A, B, C, D, E, F or G), and a surfactant. In particular the invention relates to a solid or liquid pharmaceutical composition comprising a crystalline agent.

Compounds of formula (I) have checkpoint kinase 1 (CHK1) inhibitory activity: wherein R, R, Rand Rare independently selected from hydrogen, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, methylamino and dimethylamino; R, and Rare independently selected from hydrogen, hydroxy, C-Calkyl, fluoro-(C-C)-alkyl, hydroxy-(C-C)-alkyl, C-Calkoxy, fluoro-(C-C)-alkoxy, hydroxy-(C-C)-alkoxy, &#x2014;N(R)&#x2014;R, -Alk-N(R)&#x2014;R, &#x2014;O-Alk-N(R)&#x2014;R, &#x2014;C(&#x2550;O)OH, carboxy-(C-C)-alkyl, or &#x2014;C(&#x2550;O)&#x2014;NH&#x2014;R; Alk is a straight or branched chain divalent C-Calkylene radical; Rand Rare independently selected from hydrogen, hydroxy, or C-Calkoxy; X is a straight chain divalent C-Calkylene radical, optionally substituted on one or more carbons by Rand/or R; W is selected from &#x2014;C(&#x2550;O)&#x2014;N(&#x2014;R)&#x2014; or &#x2014;N(&#x2014;R)&#x2014;C(&#x2550;O)&#x2014;; Y is hydrogen, C-Calkyl, C-Calkoxy, or halo; and Q is selected from optionally substituted phenyl, optionally substituted cyclohexyl, or an optionally substituted 6-membered monocyclic heteroaryl ring.

Compounds of formula (I) have checkpoint kinase 1 (CHK1) inhibitory activity: wherein R, R, Rand Rare independently selected from hydrogen, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, methylamino and dimethylamino; R, and Rare independently selected from hydrogen, hydroxy, C-Calkyl, fluoro-(C-C)-alkyl, hydroxy-(CC)-alkyl, C-Calkoxy, fluoro-(C-C)-alkoxy, hydroxy-(C-C)-alkoxy, -AIk-N(R)&#x2014;R, -0-AIk-N(R)&#x2014;R, &#x2014;C(&#x2550;O)OH, carboxy-(C-C)-alkyl, or &#x2014;C(&#x2550;O)&#x2014;NH&#x2014;R; AIk is a straight or branched chain divalent C-Calkylene radical; Rand Rare independently selected from hydrogen, hydroxy, or C-Calkoxy; X is a straight chain divalent C-Calkylene radical, optionally substituted on one or more carbons by Rand/or R; W is selected from &#x2014;C(&#x2550;O)&#x2014;N(&#x2014;R)&#x2014; or &#x2014;N(&#x2014;R)&#x2014;C(&#x2550;O)&#x2014;; Y is hydrogen, C-Calkyl, C-Calkoxy, or halo; and Q is selected from optionally substituted phenyl, optionally substituted cyclohexyl, or an optionally substituted 6-membered monocyclic heteroaryl ring. 

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.

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.

The invention relates to a stable solid pharmaceutical composition comprising factor VIII. Such a composition is devoid of amino acids and comprises: (a) factor VIII; (b) a surfactant; (c) calcium chloride; (d) sucrose; (e) sodium chloride; (f) trisodium citrate; and (g) a buffer devoid of amino acids; and has a pH from 6 to 8 prior to lyophilization and after reconstitution in water for injection. The invention also relates to the liquid pharmaceutical composition obtainable after dilution of said stable solid pharmaceutical composition with sterile water optionally containing sodium chloride.

Stable pharmaceutical composition containing factor VIII

Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: (A), (B) wherein R, is a group of formula (IA): &#x2014;Ar-(Alk)p-(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&#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 (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. 

Growing community of inventors

Abington, United Kingdom

Paul Webb