WO2013173283A1 - Dosage regimen for a pi-3 kinase inhibitor - Google Patents

Dosage regimen for a pi-3 kinase inhibitor Download PDF

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Publication number
WO2013173283A1
WO2013173283A1 PCT/US2013/040877 US2013040877W WO2013173283A1 WO 2013173283 A1 WO2013173283 A1 WO 2013173283A1 US 2013040877 W US2013040877 W US 2013040877W WO 2013173283 A1 WO2013173283 A1 WO 2013173283A1
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Prior art keywords
substituted
pharmaceutically acceptable
compound
formula
unsubstituted
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PCT/US2013/040877
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English (en)
French (fr)
Inventor
Samit Hirawat
Cristian MASSACESI
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Novartis Ag
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Priority to NZ700924A priority Critical patent/NZ700924A/en
Priority to RU2014150860A priority patent/RU2630975C2/ru
Priority to MX2014013904A priority patent/MX360892B/es
Priority to CN201380025377.6A priority patent/CN104349779A/zh
Priority to SG11201406550QA priority patent/SG11201406550QA/en
Priority to BR112014028420A priority patent/BR112014028420A2/pt
Priority to US14/400,444 priority patent/US10213432B2/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to KR1020147031775A priority patent/KR20150009540A/ko
Priority to AU2013263043A priority patent/AU2013263043B2/en
Priority to EP13729120.9A priority patent/EP2849756A1/en
Priority to JP2015512735A priority patent/JP6381523B2/ja
Priority to CA2872526A priority patent/CA2872526A1/en
Publication of WO2013173283A1 publication Critical patent/WO2013173283A1/en
Priority to ZA2014/07406A priority patent/ZA201407406B/en
Priority to TN2014000433A priority patent/TN2014000433A1/fr
Priority to IL235567A priority patent/IL235567B/en
Priority to PH12014502547A priority patent/PH12014502547A1/en
Priority to HK15103031.8A priority patent/HK1202435A1/xx
Priority to US16/230,737 priority patent/US20190134052A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a dosage regimen for a phosphatidylinositol 3-kinase (PI-3 kinase) inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a dosage regimen for the treatment of patients suffering from a proliferative disease, such as, for example, cancer, with a phosphatidylinositol 3-kinase (PI-3 kinase) inhibitor compound of formula (I) or a
  • Class 1A PI3Ks are heterodimers composed of a catalytic p1 10 subunit
  • the Class 1 B sub-class has one family member, a heterodimer composed of a catalytic p1 10 ⁇ subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 67:481 (1998); Sappel et al., Curr. Biol. 15:566 (2005)).
  • the modular domains of the p85/55/50 subunits include Src Homology (SH2) domains that bind phosphotyrosine residues in a specific sequence context on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and localization of Class 1 A PI3Ks.
  • Class 1 B PI3K is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 89:105 (1997)); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615-675 (2001 )).
  • PI-3 kinase inhibitors are useful therapeutic compounds for the treatment of various conditions in humans.
  • Aberrant regulation of PI3K which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels.
  • the tumor suppressor gene PTEN which dephosphorylates phosphoinositides at the 3' position of the inositol ring and in so doing antagonizes PI3K activity, is functionally deleted in a variety of tumors.
  • the genes for the p1 10a isoform, PIK3CA, and for Akt are amplified and increased protein expression of their gene products has been demonstrated in several human cancers.
  • PI-3 kinase inhibitors may produce a negative side effect, including but not limited to, mood alteration, hyperglycemia, rash, diarrhea, anorexia, nausea, fatigue, pruritus and mucositis, at therapeutic doses.
  • Daily administration of 100 mg of BKM120 to human patients in need thereof may induce such negative side effects as described in Bendell et al., J. Clin. Oncology (2012 Jan. 20), 30(3): 282-90.
  • This invention relates to a method of treating a proliferative disease in a human patient in need of such treatment, comprising administering to said patient a compound of formula (I) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount of about 60 to about 120 mg daily for five consecutive days in any seven day period.
  • the invention relates to a method of treating a proliferative disease comprising first administering to a human patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount of about 60 to about 120 mg daily, second determining said patient has a condition selected from neutropenia, thrombocytopenia, serum creatine, elevated bilirubin, asymptomatic amylase and/or lipase elevation, mood alteration, neurotoxicity, hyperglycemia, rash, diarrhea, anorexia, nausea, fatigue, pneumonitis, pruritus and mucositis, after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof after administration of about 60 mg to about 120 mg daily to said human patient, and third reducing the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof to about 60 mg to about 120 mg daily for five consecutive days in any seven day period.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in the treatment of a proliferative disease wherein the medicament comprises about 60 to about 120 mg of compound of formula (I) is administered to a human patient in need thereof for five consecutive days in any seven day period.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a proliferative disease comprising administering about 60 to about 120 mg of compound of formula (I) or a pharmaceutically acceptable salt thereof for five consecutive days in any seven day period.
  • a therapeutic regimen comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount of about 60 to about 120 mg of compound of formula (I) or a pharmaceutically acceptable salt thereof for five consecutive days in any seven day period and wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.
  • a pharmaceutical composition for use in the treatment of a proliferative disease in a human patient in need thereof comprising a therapeutically effective amount of about 60 to about 120 mg of a compound of formula (I) or pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients which is administered for five consecutive days in any seven day period.
  • a package comprising the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable pharmaceutically acceptable excipients in combination with instructions to administer said composition in an amount of about 60 mg to about 120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof for five consecutive days in any seven day period.
  • This invention relates to a method of treating a proliferative disease in a human patient in need of such treatment, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount of about 60 to about 120 mg daily for five consecutive days in any seven day period.
  • a phosphatidylinositol 3-kinase inhibitor or "PI3K inhibitor” is defined herein to refer to a compound which targets, decreases or inhibits PI 3-kinase.
  • PI 3-kinase activity has been shown to increase in response to a number of hormonal and growth factor stimuli, including insulin, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, colony-stimulating factor, and hepatocyte growth factor, and has been implicated in processes related to cellular growth and transformation.
  • Alkyl refers to alkyl groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • the phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , - C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )-CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 ,
  • alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
  • Preferred alkyl groups include straight and branched chain alkyl groups having 1 to 12 carbon atoms or 1 to 6 carbon atoms.
  • Alkylene refers to the same residues as noted above for “alkyl,” but having two points of attachment.
  • exemplary alkylene groups include ethylene (-CH 2 CH 2 -), propylene (-CH2CH2CH2-), dimethylpropylene (-CH 2 C(CI-l3)2CI-l2-), and cyclohexylpropylene
  • alkenyl groups include straight chain and branched alkenyl groups and cyclic alkenyl groups having 2 to 12 carbon atoms or 2 to 6 carbon atoms.
  • Alkynyl refers to straight chain, branched, or cyclic groups from 2 to about 20 carbon atoms such as those described with respect to alkyl groups as defined above, except having one or more carbon-carbon triple bonds. Examples include, but are not limited to -C ⁇ C(H), -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -C(H 2 )C ⁇ C(H), -C(H) 2 C ⁇ C(CH 3 ), and
  • alkynyl groups include straight chain and branched alkynyl groups having 2 to 12 carbon atoms or 2 to 6 carbon atoms.
  • Alkyl, alkenyl, and alkynyl groups may be substituted.
  • Substituted alkyl refers to an alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom
  • Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • Substituted alkyl groups further include alkyl groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl, heteroaryl, heterocyclyl, or cycloalkyl group.
  • Preferred substituted alkyi groups include, among others, alkyi groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluoro, chloro, or bromo group. Another preferred substituted alkyi group is the trifluoromethyl group and other alkyi groups that contain the trifluoromethyl group. Other preferred substituted alkyi groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyi group contains a hydroxyl, alkoxy, or aryloxy group.
  • substituted alkyi groups include alkyi groups that have an amine, or a substituted or unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or
  • substituted alkyi groups include those in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl, heteroaryl, heterocyclyl, or cycloalkyl group.
  • Substituted alkenyl has the same meaning with respect to alkenyl groups that substituted alkyi groups had with respect to unsubstituted alkyi groups.
  • a substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.
  • Substituted alkynyl has the same meaning with respect to alkynyl groups that substituted alkyi groups had with respect to unsubstituted alkyi groups.
  • a substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
  • Alkoxy refers to RO- wherein R is alkyi.
  • Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy, and the like.
  • Halogen or halo refers to chloro, bromo, fluoro, and iodo groups.
  • haloalkyl refers to an alkyi radical substituted with one or more halogen atoms.
  • haloalkoxy refers to an alkoxy radical substituted with one or more halogen atoms.
  • Amino refers herein to the group -NH 2 .
  • alkylamino refers herein to the group -NRR' where R is alkyi and R' is hydrogen or alkyi.
  • arylamino refers herein to the group -NRR' where R is aryl and R' is hydrogen, alkyl, or aryl.
  • aralkylamino refers herein to the group -NRR' where R is aralkyl and R' is hydrogen, alkyl, aryl, or aralkyl.
  • Alkoxyalkyl refers to the group -alkrO-alk 2 where alki is alkyl or alkenyl, and alk 2 is alkyl or alkenyl.
  • aryloxyalkyl refers to the group -alkyl O-aryl.
  • aralkoxyalkyl refers to the group -alkylenyl-O-aralkyl.
  • Alkoxyalkylamino refers herein to the group -NR-(alkoxyalkyl), where R is typically hydrogen, aralkyl, or alkyl.
  • Aminocarbonyl refers herein to the group -C(0)-NH 2 .
  • Substituted aminocarbonyl refers herein to the group -C(0)-NRR' where R is alkyl and R' is hydrogen or alkyl.
  • arylaminocarbonyl refers herein to the group -C(0)-NRR' where R is aryl and R' is hydrogen, alkyl or aryl.
  • Aralkylaminocarbonyl refers herein to the group -C(0)-NRR' where R is aralkyl and R' is hydrogen, alkyl, aryl, or aralkyl.
  • aminosulfonyl refers herein to the group -S(0) 2 -NH 2 .
  • substituted aminosulfonyl refers herein to the group -S(0) 2 -NRR' where R is alkyl and R' is hydrogen or alkyl.
  • aralkylaminosulfonlyaryl refers herein to the group -aryl-S(0) 2 -NH-aralkyl.
  • Carbonyl refers to the divalent group -C(O)-.
  • Carbonyloxy refers generally to the group -C(0)-0. Such groups include esters, -C(0)-0-R, where R is alkyl, cycloalkyl, aryl, or aralkyl.
  • carbonyloxycycloalkyl refers generally herein to both a “carbonyloxycarbocycloalkyl” and a
  • carbonyloxyheterocycloalkyl i.e., where R is a carbocycloalkyl or heterocycloalkyl, respectively.
  • arylcarbonyloxy refers herein to the group -C(0)-0-aryl, where aryl is a mono- or polycyclic, carbocycloaryl or heterocycloaryl.
  • aralkylcarbonyloxy refers herein to the group -C(0)-0-aralkyl.
  • “Sulfonyl” refers herein to the group -S0 2 -.
  • “Alkylsulfonyl” refers to a substituted sulfonyl of the structure -S0 2 R- in which R is alkyl.
  • Alkylsulfonyl groups employed in compounds of the present invention are typically alkylsulfonyl groups having from 1 to 6 carbon atoms in its backbone structure.
  • alkylsulfonyl groups employed in compounds of the present invention include, for example, methylsulfonyl (i.e., where R is methyl), ethylsulfonyl (i.e., where R is ethyl), propylsulfonyl (i.e., where R is propyl), and the like.
  • arylsulfonyl refers herein to the group -S0 2 -aryl.
  • aralkylsulfonyl refers herein to the group -S0 2 -aralkyl.
  • sulfonamido refers herein to -S0 2 NH 2 .
  • Carbonylamino refers to the divalent group -NH-C(O)- in which the hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced alkyl, aryl, or aralkyl group.
  • groups include moieties such as carbamate esters (-NH-C(O)-O-R) and amides -NH-C(0)-R, where R is a straight or branched chain alkyl, cycloalkyi, or aryl or aralkyl.
  • alkylcarbonylamino refers to alkylcarbonylamino where R is alkyl having from 1 to about 6 carbon atoms in its backbone structure.
  • arylcarbonylamino refers to group -NH-C(0)-R where R is an aryl.
  • aralkylcarbonylamino refers to carbonylamino where R is aralkyl.
  • Cycloalkyi refers to a mono- or polycyclic, heterocyclic or carbocyclic alkyl substituent.
  • Representative cycloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above.
  • Typical cycloalkyi substituents have from 3 to 8 backbone (i.e., ring) atoms in which each backbone atom is either carbon or a heteroatom.
  • heterocycloalkyl refers herein to cycloalkyi substituents that have from 1 to 5, and more typically from 1 to 4 heteroatoms in the ring structure. Suitable heteroatoms employed in compounds of the present invention are nitrogen, oxygen, and sulfur. Representative heterocycloalkyl moieties include, for example, morpholino, piperazinyl, piperadinyl, and the like. CarbocycloalkyI groups are cycloalkyi groups in which all ring atoms are carbon. When used in connection with cycloalkyi substituents, the term “polycyclic” refers herein to fused and non-fused alkyl cyclic structures.
  • Substituted heterocycle refers to any 3- or 4-membered ring containing a heteroatom selected from nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur; wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur atom maybe optionally oxidized; wherein the nitrogen and sulfur heteroatoms maybe optionally quarternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another 5- or 6-membered heterocyclic ring independently defined above.
  • heterocyclyl groups include, but are not limited to: unsaturated 3- to 8-membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, dihydropyridyl, pyrimidyl, pyrazinyl, tetrazolyl, (e.g., 1 H- tetrazolyl, 2H-tetrazolyl); condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, isoindolyl, indolinyl, indolizinyl, quinolyl, indazolyl; unsaturated 3- to 8-membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl); saturated 3-
  • unsaturated 3- to 8-membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiadiazolyl (e.g.
  • unsaturated 3- to 8-membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathienyl; saturated 3- to 8-membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1 ,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzodithienyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as
  • heterocycles include, for example: diazapinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methyl piperazinyl, azetidinyl,
  • Heterocyclyl groups also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones).
  • heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1 , 1 -dioxide.
  • Preferred heterocyclyl groups contain 5 or 6 ring members. More preferred heterocyclyl groups include piperazine, 1 ,2,3-triazole,
  • Unsubstituted heterocyclyl includes condensed heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members as compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups.
  • heterocyclic groups may be attached at various positions as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • R is H or a heterocyclic substituent, as described herein.
  • heterocyclics include, for example, imidazolyl, pyridyl, piperazinyl, azetidinyl, thiazolyl, furanyl, triazolyl benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, naphthpyridinyl, indazolyl, and quinolizinyl.
  • Aryl refers to optionally substituted monocyclic and polycyclic aromatic groups having from 3 to 14 backbone carbon or hetero atoms, and includes both carbocyclic aryl groups and heterocyclic aryl groups.
  • the term refers to, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example.
  • Carbocyclic aryl groups are aryl groups in which all ring atoms in the aromatic ring are carbon.
  • heteroaryl refers herein to aryl groups having from 1 to 4 heteroatoms as ring atoms in an aromatic ring with the remainder of the ring atoms being carbon atoms.
  • Unsubstituted aryl includes groups containing condensed rings such as
  • naphthalene does not include aryl groups that have other groups such as alkyl or halo groups bonded to one of the ring members, as aryl groups such as tolyl are considered herein to be substituted aryl groups as described below.
  • a preferred unsubstituted aryl group is phenyl. Unsubstituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound, however.
  • Substituted aryl group has the same meaning with respect to unsubstituted aryl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups.
  • a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein.
  • substituted aryl includes, but is not limited to tolyl, and hydroxyphenyl among others.
  • Substituted heteroaryl refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with CI, Br, F, I, -OH, -CN, C r C 3 -alkyl, C r C 6 -alkoxy, C r C 6 -alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
  • Exemplary aryl or heteroaryl moieties employed as substituents in compounds of the present invention include phenyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl, furanyl, quinolinyl, purinyl, naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, and the like.
  • Alkyl or "arylalkyl” refers to an alkyl group substituted with an aryl group.
  • heteroaryls include, for example, imidazolyl, pyridyl, thiazolyl, triazolyl benzimidazolyl, benzothiazolyl, and benzoxazolyl.
  • Biaryl refers to a group or substituent to which two aryl groups, which are not condensed to each other, are bound.
  • exemplary biaryl compounds include, for example, phenylbenzene, diphenyldiazene, 4-methylthio-1 -phenylbenzene, phenoxybenzene, (2-phenylethynyl)benzene, diphenyl ketone, (4-phenylbuta-1 ,3-diynyl)benzene,
  • phenylbenzylamine (phenylmethoxy)benzene, and the like.
  • Preferred optionally substituted biaryl groups include: 2-(phenylamino)-N-[4-(2-phenylethynyl)-phenyl]acetamide,
  • Heteroarylaryl refers to a biaryl group where one of the aryl groups is a heteroaryl group.
  • exemplary heteroarylaryl groups include, for example, 2-phenylpyridine,
  • phenylpyrrole 3-(2-phenylethynyl)pyridine, phenylpyrazole, 5-(2-phenyl-ethynyl)-1 ,3- dihydropyrimidine-2,4-dione, 4-phenyl-1 ,2,3-thiadiazole, 2-(2-phenylethynyl)pyrazine, 2-phenylthiophene, phenylimidazole, 3-(2-piperazinyl-phenyl)-furan, 3-(2,4-dichlorophenyl)-
  • Preferred optionally substituted heteroarylaryl groups include:
  • Heteroarylheteroaryl refers to a biaryl group where both of the aryl groups is a heteroaryl group.
  • exemplary heteroarylheteroaryl groups include, for example,
  • Preferred optionally substituted heteroarylheteroaryl groups include: 2-(4-piperazinyl-3-pyridyl)furan, diethyl-(3-pyrazin-2- yl(4-pyridyl))amine, and dimethyl ⁇ 2-[2-(5-methylpyrazin-2-yl)ethynyl](4-pyridyl) ⁇ amine.
  • Optionally substituted or “substituted” refers to the replacement of hydrogen with one or more monovalent or divalent radical.
  • Suitable substitution groups include, for example, hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyi, substituted alkyi, haloalkyi, alkyamino, haloalkylamino, alkoxy, haloalkoxy, alkoxy-alkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl,
  • heteroaralkyl-carbonyl alkylthio, aminoalkyl, cyanoalkyl, aryl, benzyl, pyridyl, pyrazolyl, pyrrole, thiophene, imidazolyl, and the like.
  • substitution group can itself be substituted.
  • the group substituted onto the substitution group can be carboxyl, halo, nitro, amino, cyano, hydroxyl, alkyi, alkoxy, aminocarbonyl, -SR, thioamido, -S0 3 H, -S0 2 R, or cycloalkyl, where R is typically hydrogen, hydroxyl or alkyi.
  • substituted substituent when the substituted substituent includes a straight chain group, the substitution can occur either within the chain (e.g. , 2-hydroxypropyl, 2-aminobutyl, and the like) or at the chain terminus (e.g. , 2-hydroxyethyl, 3-cyanopropyl, and the like).
  • Substituted substituents can be straight chain, branched or cyclic arrangements of covalently bonded carbon or heteroatoms.
  • substituted aminocarbonyl groups include, for example, those shown below. These can be further substituted by heterocyclyl groups and heteroaryl groups as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • Preferred aminocarbonyl groups include:
  • substituted alkoxycarbonyl groups include, for example, those shown below. These alkoxycarbonyl groups can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • substituted alkoxycarbonyl groups include, for example, those shown below. These alkoxycarbonyl groups can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • protected with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein.
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoroacetate.
  • a reagent such as, but not limited
  • protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others.
  • protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • Carboxy-protecting group refers to a carbonyl group which has been esterified with one of the commonly used carboxylic acid protecting ester groups employed to block or protect the carboxylic acid function while reactions involving other functional sites of the compound are carried out.
  • a carboxy protecting group can be attached to a solid support whereby the compound remains connected to the solid support as the carboxylate until cleaved by hydrolytic methods to release the corresponding free acid.
  • Representative carboxy-protecting groups include, for example, alkyl esters, secondary amides and the like.
  • composition is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a human patient, in order to prevent or treat a particular disease or condition affecting the human patient.
  • pharmaceutically acceptable is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a human patient without excessive toxicity, irritation allergic response and other problem complications
  • treating comprises a treatment relieving, reducing or alleviating at least one symptom in a human patient or effecting a delay of progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • protecting is used herein to mean prevent delay or treat, or all, as appropriate, development or continuance or aggravation of a disease in a subject.
  • prevent comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.
  • pharmaceutically effective amount or “clinically effective amount” of a combination of therapeutic agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorder treated with the combination.
  • a human patient in need of such treatment refers to a human patient diagnosed with or suffering from the identified proliferative disease.
  • WO07/084786 describes pyrimidine derivatives, which have been found to inhibit the activity of phosphatidylinositol 3-kinase (PI3K).
  • PI3K phosphatidylinositol 3-kinase
  • Specific phosphatidylinositol 3-kinase (PI3K) inhibitors suitable for the present invention, their preparation and suitable pharmaceutical formulations containing the same are described in WO07/084786 and include compounds of formula (I):
  • W is CR W or N, wherein
  • R w is selected from the group consisting of:
  • Ri a , and Ri b are independently selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • R 2a , and R 2b are independently selected from the group consisting of:
  • R3 is selected from the group consisting of:
  • R 3a , and R 3b are independently selected from the group consisting of:
  • R 4 is selected from the group consisting of
  • the phosphatidylinositol 3-kinase inhibitor compound of formula (I) may be present in the combination in the form of the free base or a pharmaceutically acceptable salt thereof.
  • Such salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively.
  • Suitable salts of the compound of formula (I) include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate,
  • the basic nitrogen-containing groups can be quaternized with such agents as alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.
  • alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl,
  • inorganic acids as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid and phosphoric acid
  • organic acids as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, methanesulfonic acid, succinic acid, malic acid
  • tetramethylammonium tetraethylammonium
  • methylamine dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, pyridine, picoline, triethanolamine and the like, and basic amino acids such as arginine, lysine and ornithine.
  • a preferred compound of formula (I) for use in the combination of the present invention is the phosphatidylinositol 3-kinase (PI3K) inhibitor 5-(2,6-di-morpholin-4-yl- pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine (hereinafter "COMPOUND A”) or its hydrochloride salt.
  • PI3K phosphatidylinositol 3-kinase
  • COMPOUND A 5-(2,6-di-morpholin-4-yl- pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine
  • the compounds of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with one additional therapeutic agent may be used for the treatment of a proliferative disease, particularly cancer.
  • cancer refers to cancer diseases that can be beneficially treated by the inhibition of PI3K, including, for example, lung and bronchus; prostate; breast; pancreas; colon and rectum; thyroid; liver and intrahepatic bile duct; hepatocellular; gastric;
  • glioma/glioblastoma endometrial; melanoma; kidney and renal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; head and neck; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; melanoma; and villous colon adenoma.
  • melanoma kidney and renal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; head and neck; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; melanoma; and villous colon adenoma.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used for the treatment of a cancer selected from lung and bronchus, prostate, breast, pancreas, colon and rectum, liver and intrahepatic bile duct, hepatocellular, gastric, glioma/ glioblastoma, and endometrial.
  • a cancer selected from lung and bronchus, prostate, breast, pancreas, colon and rectum, liver and intrahepatic bile duct, hepatocellular, gastric, glioma/ glioblastoma, and endometrial.
  • pharmaceutically acceptable salt thereof may be administered at a dosage of about 60 to about 120 mg per day to a human patient in need thereof.
  • the total daily dose may be administered to the human patient in single or divided doses.
  • Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 60 mg to about 120 mg of the compound(s) of this invention per day in single or multiple doses.
  • the compound of formula (I) is administered to a human patient in need thereof at a dosage of about 60 to about 120 mg daily for five consecutive days in any seven day period.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at dosage of about 100 mg daily for five consecutive days in any seven day period.
  • the phrase "five consecutive days in any seven day period” is intended to refer to the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered for five consecutive days in any seven day period.
  • a human patient is administered an amount of about 60 to about 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each day (daily) for five consecutive days and then not administered any compound of formula (I) or a pharmaceutically acceptable salt thereof for two consecutive days before receiving any further doses of said compound.
  • the compound of formula (I) is 5-(2,6-di-morpholin-4-yl- pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine (hereinafter "COMPOUND A”) or a pharmaceutically acceptable salt thereof which is administered orally at dosage of about 100 mg daily for five consecutive days in any seven day period. It is discovered that reduction of the weekly dosing of the compound of formula (I) or a pharmaceutically acceptable salt thereof from about 60 to about 120 mg daily (i.e., 7 days per week) to about 60 to about 120 mg daily for five consecutive days in any seven day period is effective to treat a proliferative disorder in human patient in need thereof while relieving, reducing, or alleviating negative side effects.
  • COMPONENT A 5-(2,6-di-morpholin-4-yl- pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine
  • negative side effects include neutropenia, thrombocytopenia, serum creatine (e.g., 2-3 x ULN, or > 3.0 - 6.0 x ULN or > 6.0 x ULN), elevated bilirubin, asymptomatic amylase and/or lipase elevation (e.g, CTCAE Grade 3 (>2.0-5.0 x ULN) or Grade 4 (>5.0 x ULN)), mood alteration (e.g., CTCAE Grade 2, 3, or 4), neurotoxicity (e.g, > 1 CTCAE Grade level Increase),
  • the invention relates to a method of treating a proliferative disease in a patient in need thereof comprising first administering to such human patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof in amount of about 60 to about 120 mg daily, second determining said patient has a condition selected from neutropenia, thrombocytopenia, serum creatine, elevated bilirubin, asymptomatic amylase and/or lipase elevation, mood alteration, neurotoxicity,
  • the human patient is administered 100 mg daily of the compound of formula (I) or a pharmaceutically acceptable salt thereof for five consecutive days in any seven day period.
  • the invention relates to a method of treating a proliferative disease comprising first administering to a human patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 60 to about 120 mg daily, second determining said patient has a condition selected from neutropenia, thrombocytopenia, serum creatine, elevated bilirubin, asymptomatic amylase and/or lipase elevation, mood alteration, neurotoxicity, hyperglycemia, rash, diarrhea, anorexia, nausea, fatigue, pneumonitis, pruritus and mucositis after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof after administration of about 60 to about 120 mg daily to said human patient, and third reducing the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof to about 60 to about 120 mg daily for five consecutive days in any seven day period, wherein the condition selected from neutropenia, thrombocytopenia, serum creatine, elevated bili
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in the treatment of a proliferative disease wherein the medicament comprising a therapeutically effective dose of about 60 to about 120 mg of compound of formula (I) is administered to a human patient in need thereof for five consecutive days in any seven day period.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a proliferative disease comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a therapeutically effective dosage of about 60 to about 120 mg of compound of formula (I) or a pharmaceutically acceptable salt thereof for five consecutive days in any seven day period.
  • pharmaceutically acceptable salt thereof is administered at a therapeutically effective dosage of about 60 to about 120 mg for five consecutive days in any seven day period.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in any method set forth above A therapeutic regimen comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in an therapeutically effective amount of about 60 to about 120 mg of compound of formula (I) or a pharmaceutically acceptable salt thereof for five consecutive days in any seven day period and wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent.
  • Anticancer agents for use with the invention include, but are not limited to, one or more of the following set forth below:
  • Kinase inhibitors for use as anticancer agents in conjunction with the compositions of the present invention include inhibitors of Epidermal Growth Factor Receptor (EGFR) kinases such as small molecule quinazolines, for example gefitinib (US 5457105, US 5616582, and US 5770599), ZD-6474 (WO 01/32651 ), erlotinib (Tarceva®, US 5,747,498 and WO 96/30347), and lapatinib (US 6,727,256 and WO
  • EGFR Epidermal Growth Factor Receptor
  • Vascular Endothelial Growth Factor Receptor (VEGFR) kinase inhibitors including SU-1 1248 (WO 01/60814), SU 5416 (US 5,883, 1 13 and WO 99/61422), SU 6668 (US 5,883, 1 13 and WO 99/61422), CHIR-258 (US 6,605,617 and US 6,774,237), vatalanib or PTK-787 (US 6,258,812), VEGF-Trap (WO 02/57423), B43-Genistein (WO-096061 16), fenretinide (retinoic acid p-hydroxyphenylamine) (US 4,323,581 ), IM-862 (WO 02/62826), bevacizumab or Avastin® (WO 94/10202), KRN-951 , 3-[5-(methylsulfonylpiperadine methyl)- indolylj-quinolone, AG-13736 and AG-13925, pyrrolo
  • Estrogen-targeting agents for use in anticancer therapy in conjunction with the compositions of the present invention include Selective Estrogen Receptor Modulators (SERMs) including tamoxifen, toremifene, raloxifene; aromatase inhibitors including Arimidex® or anastrozole; letrozole; Estrogen Receptor Downregulators (ERDs) including Faslodex® or fulvestrant.
  • SERMs Selective Estrogen Receptor Modulators
  • ESDs Estrogen Receptor Downregulators
  • Anti-Androgens for use in anticancer therapy in conjunction with the compositions of the present invention include flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and corticosteroids.
  • inhibitors for use as anticancer agents in conjunction with the compositions of the present invention include protein farnesyl transferase inhibitors including tipifarnib or R-1 15777 (US 2003134846 and WO 97/21701 ), BMS-214662, AZD- 3409, and FTI-277; topoisomerase inhibitors including merbarone and diflomotecan (BN- 80915); mitotic kinesin spindle protein (KSP) inhibitors including SB-743921 and MKI-833; protease modulators such as bortezomib or Velcade® (US 5,780,454), XL-784; and cyclooxygenase 2 (COX-2) inhibitors including non-steroidal antiinflammatory drugs I (NSAIDs).
  • protein farnesyl transferase inhibitors including tipifarnib or R-1 15777 (US 2003134846 and WO 97/21701 ), BMS-214662, AZD- 3409, and FTI-2
  • cancer Chemotherapeutic Drugs Particular cancer chemotherapeutic agents for use as anticancer agents in conjunction with the compositions of the present invention include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCy
  • Daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®, US 2004073044), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-
  • Nolvadex® teniposide
  • Vumon® 6-thioguanine
  • thiotepa thiotepa
  • tirapazamine Tirazone®
  • topotecan hydrochloride for injection Hycamptin®
  • vinblastine Velban®
  • Vincristine Oncovin®
  • vinorelbine® vinorelbine
  • Alkylating agents for use in conjunction with the compositions of the present invention for anticancer therapeutics include VNP-40101 M or cloretizine, oxaliplatin (US 4, 169,846, WO 03/24978 and WO 03/04505), glufosfamide, mafosfamide, etopophos (US 5,041 ,424), prednimustine; treosulfan; busulfan; irofluven (acylfulvene); penclomedine; pyrazoloacridine (PD-1 15934); 06-benzylguanine; decitabine (5-aza-2- deoxycytidine); brostallicin; mitomycin C (MitoExtra); TLK-286 (Telcyta®); temozolomide; trabectedin (US 5,478,932); AP-5280 (Platinate formulation of Cisplatin); porfiromycin; and clearazide (meclore
  • Chelating agents for use in conjunction with the compositions of the present invention for anticancer therapeutics include tetrathiomolybdate (WO
  • Biological response modifiers such as immune modulators, for use in conjunction with the compositions of the present invention for anticancer therapeutics include staurosprine and macrocyclic analogs thereof, including UCN-01 , CEP-701 and midostaurin (see WO 02/30941 , WO 97/07081 , WO 89/07105, US 5,621 , 100, WO 93/07153, WO 01/04125, WO 02/30941 , WO 93/08809, WO 94/06799, WO 00/27422, WO 96/13506 and WO 88/07045); squalamine (WO 01/79255); DA-9601 (WO 98/04541 and US 6,025,387); alemtuzumab; interferons (e.g.
  • interleukins specifically IL-2 or aldesleukin as well as IL-1 , IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL- 1 1 , IL-12, and active biological variants thereof having amino acid sequences greater than 70% of the native human sequence; altretamine (Hexalen®); SU 101 or leflunomide (WO 04/06834 and US 6,331 ,555); imidazoquinolines such as resiquimod and imiquimod (US 4,689,338, 5,389,640, 5,268,376, 4,929,624, 5,266,575, 5,352,784, 5,494,916, 5,482,936, 5,346,905, 5,395,937, 5,238,944, and 5,525,612); and SMIPs, including benzazoles, anthraquinones, thiosemicarbazones, and tryptanthrins
  • Anticancer vaccines for use in conjunction with the compositions of the present invention include Avicine® (Tetrahedron Letters 26, 1974 2269-70);
  • oregovomab (OvaRex®); Theratope® (STn-KLH); Melanoma Vaccines; GI-4000 series (Gl- 4014, GI-4015, and GI-4016), which are directed to five mutations in the Ras protein;
  • GlioVax-1 MelaVax; Advexin® or INGN-201 (WO 95/12660); Sig/E7/LAMP-1 , encoding HPV-16 E7; MAGE-3 Vaccine or M3TK (WO 94/05304); HER-2VAX; ACTIVE, which stimulates T-cells specific for tumors; GM-CSF cancer vaccine; and Listeria monocytogenes- based vaccines.
  • compositions of the present invention also include antisense compositions, such as AEG- 35156 (GEM-640); AP-12009 and AP-1 1014 (TGF-beta2-specific antisense oligonucleotides); AVI-4126; AVI-4557; AVI-4472; oblimersen (Genasense®); JFS2;
  • antisense compositions such as AEG- 35156 (GEM-640); AP-12009 and AP-1 1014 (TGF-beta2-specific antisense oligonucleotides); AVI-4126; AVI-4557; AVI-4472; oblimersen (Genasense®); JFS2;
  • aprinocarsen (WO 97/29780); GTI-2040 (R2 ribonucleotide reductase mRNA antisense oligo) (WO 98/05769); GTI-2501 (WO 98/05769); liposome-encapsulated c-Raf antisense oligodeoxynucleotides (LErafAON) (WO 98/43095); and Sirna-027 (RNAi-based therapeutic targeting VEGFR-1 mRNA).
  • proliferative diseases that may be treated with a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent include, but not limited to, those set forth above.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dosage of about 60 mg to about 120 mg, preferably 100 mg, daily for five consecutive days in any seven day period.
  • the administration of said combination may result not only in a beneficial effect, e.g. therapeutic effect as compared to either mnonotherapy, e.g, a synergistic therapeutic effect, e.g. with regard to alleviating, delaying progression of or inhibiting the symptoms, but also in further surprising beneficial effects, e.g. fewer side-effects, an improved quality of life or a decreased morbidity, compared with a monotherapy applying only one of the
  • a further benefit is that lower doses of the active ingredients of said combination can be used, for example, that the dosages need not only often be smaller, but are also applied less frequently, or can be used in order to diminish the incidence of side-effects observed with one of the combination partners alone. This is in accordance with the desires and requirements of the patients to be treated.
  • pharmacological activity of a combination of the invention may, for example, be
  • Suitable clinical studies are in particular, for example, open label, dose escalation studies in patients with a proliferative disease, including for example a tumor disease, e.g., breast cancer. Such studies prove in particular the synergism of the therapeutic agents of the combination of the invention.
  • the beneficial effects on a proliferative disease may be determined directly through the results of these studies which are known as such to a person skilled in the art. Such studies may be, in particular, be suitable to compare the effects of a monotherapy using the therapeutic agents and a combination of the invention.
  • the dose of the phosphatidylinositol 3-kinase inhibitor compound of formula (I), e.g., COMPOUND A is escalated until the Maximum Tolerated Dosage is reached, and the combination partner is administered with a fixed dose.
  • phosphatidylinositol 3- kinase inhibitor compound of formula (I), e.g., COMPOUND A may be administered in a fixed dose and the dose of the combination partner may be escalated.
  • Each patient may receive doses of the phosphatidylinositol 3-kinase inhibitor either daily or intermittently.
  • the efficacy of the treatment may be determined in such studies, e.g., after 12, 18 or 24 weeks by evaluation of symptom scores every 6 weeks.
  • a pharmaceutical composition for use in the treatment of a proliferative disease in a human patient in need thereof comprising a therapeutically effective amount of about 60 to about 120 mg of a compound of formula (I) or pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients which is administered for five consecutive days in any seven day period.
  • a pharmaceutical composition comprising a compound of formula (I) or a
  • pharmaceutically acceptable salt thereof alone or in combination with at least one additional therapeutic agent (i.e., combination partner), for enteral or parenteral administration
  • additional therapeutic agent i.e., combination partner
  • enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art.
  • a unit dosage form containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with at least one additional therapeutic agent, may be in the form of micro-tablets enclosed inside a capsule, e.g. a gelatin capsule.
  • a gelatin capsule as is employed in pharmaceutical formulations can be used, such as the hard gelatin capsule known as CAPSUGEL, available from Pfizer.
  • Pharmaceutical compositions of the present invention may optionally further comprise additional conventional carriers or excipients used for pharmaceuticals. Examples of such carriers include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, and fillers, diluents, colorants, flavours and preservatives.
  • Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL from International Specialty Products (Wayne, NJ); cross-linked sodium carboxymethylcellulose or
  • croscarmellose sodium e.g., AC-DI-SOL from FMC; and cross-linked calcium
  • the disintegrant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1 % to about 5% by weight of composition.
  • binders examples include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, Ml); sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
  • the binder may be present in an amount from about 0% to about 50%, e.g., 2-20% by weight of the composition.
  • Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the lubricant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the lubricant may be present in an amount from about 0.1 % to about 1.5% by weight of composition.
  • the glidant may be present in an amount from about 0.1 % to about 10% by weight.
  • Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • the filler and/or diluent e.g., may be present in an amount from about 0% to about 80% by weight of the composition.
  • a package comprising the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable pharmaceutically acceptable excipients in combination with instructions to administer said composition in a therapeutically effective amount of about 60 mg to about 120 mg for five consecutive days in any seven day period.
  • Utility of the dosing regimen of the compounds of formula (I) of the present invention may be demonstrated in vitro, in animal test methods as well as in clinic studies.
  • Utility of the compounds of formula (I) in accordance with the present invention may be demonstrated in accordance with the methods hereinafter described:
  • Patients are initially screened for presence of advanced solid tumors. After screening, patients are administered 100 mg of Compound A or the hydrochloride salt thereof once time each day throughout the clinical study period in an oral dosage form. Patients are administered Compound A or the hydrochloride salt thereof and evaluated by a physician until progression of disease, death, withdrawal of consent or progression free survival for a predetermined time period. During the study period, patients are evaluated for the prevalence of negative side effects selected from neutropenia, thrombocytopenia, serum creatine, elevated bilirubin, asymptomatic amylase and/or lipase elevation, mood alteration, neurotoxicity, hyperglycemia, rash, diarrhea, anorexia, nausea, fatigue, pneumonitis, pruritus and mucositis.
  • negative side effects selected from neutropenia, thrombocytopenia, serum creatine, elevated bilirubin, asymptomatic amylase and/or lipase elevation, mood alteration, neurotoxicity, hyperglycemia, rash, diarrhea,
  • patients are administered with a modified dosing regimen of Compound A or the hydrochloride salt comprising an amount of about 100 mg of Compound A or the hydrochloride salt daily for five consecutive days in any seven day period until end of the study period.
  • the primary endpoint is progression free survival and response rate.
  • Patients are included in the study if they meet the following criteria: at least 18 years of age, ECOG performance status 0-1 , suffering from clinical stage IV invasive mammary carcinoma (ER-positive, or PR-positive) by immunohistochemistry, life expectancy equal to or greater than 6 months, adequate hematologic, hepatic and renal function (ANC > 1500/ mm 3 , platelet count > 100,000 mm 3 , HgB > 9 g/dL, creatine ⁇ 1.5 x upper limits of normal, bilirubin ⁇ 1.5 x upper limits of normal, SGOT, SGPT ⁇ 2.5 x upper limits of normal if no liver metasis present or SGOT, SGPT alkaline phosphatase ⁇ 5 x upper limits of normal if liver metasis present, capable of swallowing and retaining oral medication, disease free of prior invasive cancers for > 5 years (exception of basal or squamous cancer of skin or cervical carcinoma in situ).
  • Post-menopausal female subjects are defined prior to protocol enrollment by any of the following: Subjects at least 55 years of age; Subjects under 55 years of age and amenorrheic for at least 12 months or follicle-stimulating hormone (FSH) values > IU/L and estradiol levels ⁇ 20 IU/L; prior bilateral oophorectomy; prior radiation castration with amenorrhea for at least 6 months; current use of an LHRH agonist for more than 12 months.
  • FSH follicle-stimulating hormone
  • Patients are excluded from the study if they have any of the following: locally recurrent resectable breast cancer; pre-menopausal women not on LHRH agonists for more than 12 months prior to study screening, pregnant or lactating women; any malabsorption syndrome significantly affecting gastrointestinal function; history of other malignancy within 5 years prior to enrollment (except subjects with history of completely resectable non- melanoma skin cancer or successfully treated in situ carcinomas); patient with glucose > 160 mg/kL or HgBAI c > 7.5; concurrent anticancer therapy other than the ones specified in the protocol (discontinuing at least 1 week prior to the first dose of study as well as recovered from toxicity to ⁇ grade 1 (except for alopecia) and at least 2 weeks prior to the study for investigational drugs); prior therapy with a PI3K inhibitor; use of any prohibited concomitant medications; uncontrolled intercurrent illness including but not limited to ongoing or active infection requiring parental antibiotics, impairment of lung function (COPD > grade 2, lung conditions requiring oxygen therapy), symptom
  • Patients are administered a daily dosage of the hydrochloride salt of Compound A in the amount of 60, 80 or 100 mg per oral on Monday through Fridays only each week in combination with 2.5 mg/day per oral letrozole.
  • All patients are evaluated for negative side effects including but not limited to neutropenia, thrombocytopenia, serum creatine, elevated bilirubin, asymptomatic amylase and/or lipase elevation, mood alteration, neurotoxicity, hyperglycemia, rash, diarrhea, anorexia, nausea, fatigue, pneumonitis, pruritus and mucositis.
  • Secondary outcome for the second stage is progression free survival and response.

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KR1020147031775A KR20150009540A (ko) 2012-05-16 2013-05-14 Pi-3 키나제 억제제에 대한 투여 요법
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MX2014013904A MX360892B (es) 2012-05-16 2013-05-14 Régimen de dosificación para un inhibidor de cinasa pi-3.
CN201380025377.6A CN104349779A (zh) 2012-05-16 2013-05-14 Pi-3激酶抑制剂的剂量方案
SG11201406550QA SG11201406550QA (en) 2012-05-16 2013-05-14 Dosage regimen for a pi-3 kinase inhibitor
BR112014028420A BR112014028420A2 (pt) 2012-05-16 2013-05-14 regime de dosagem para um inibidor de quinase pi-3
US14/400,444 US10213432B2 (en) 2012-05-16 2013-05-14 Dosage regimen for a PI-3 kinase inhibitor
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RU2014150860A RU2630975C2 (ru) 2012-05-16 2013-05-14 Режим дозирования pi-3 киназы
JP2015512735A JP6381523B2 (ja) 2012-05-16 2013-05-14 Ｐｉ−３キナーゼ阻害剤の投与レジメン
ZA2014/07406A ZA201407406B (en) 2012-05-16 2014-10-13 Dosage regimen for a pi-3 kinase inhibitor
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