US20080242658A1 - Inhibitors of Iap - Google Patents

Inhibitors of Iap Download PDF

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Publication number
US20080242658A1
US20080242658A1 US10/594,413 US59441305A US2008242658A1 US 20080242658 A1 US20080242658 A1 US 20080242658A1 US 59441305 A US59441305 A US 59441305A US 2008242658 A1 US2008242658 A1 US 2008242658A1
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Prior art keywords
alkyl
phenyl
ethyl
cycloalkyl
substituted
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Inventor
Mark G Palermo
Sushil Kumar Sharma
Christopher Straub
Run-Ming Wang
Leigh Zawel
Yanlin Zhang
Zhuoliang Chen
Yaping Wang
Fan Yang
Wojciech Wrona
Gang Liu
Mark G. Charest
Feng He
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Novartis AG
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Individual
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34962601&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20080242658(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US10/594,413 priority Critical patent/US20080242658A1/en
Publication of US20080242658A1 publication Critical patent/US20080242658A1/en
Priority to US13/178,946 priority patent/US8207183B2/en
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SHARMA, SUSHIL KUMAR, HE, FENG, CHAREST, MARK G., CHEN, ZHUOLIANG, LIU, GANG, PALERMO, MARK G., STRAUB, CHRISTOPHER, WANG, RUN-MING, WANG, YAPING, WRONA, WOJCIECH, YANG, FAN, ZAWEL, LEIGH, ZHANG, YANLIN
Priority to US13/456,274 priority patent/US8338440B2/en
Abandoned legal-status Critical Current

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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to novel compounds that inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs).
  • IAPs Apoptosis Proteins
  • the present invention includes novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action rely on the inhibition of the Smac/IAP interaction, and more particularly useful in therapies for the treatment of proliferative diseases, including cancer.
  • Programmed cell death plays a critical role in regulating cell number and in eliminating stressed or damaged cells from normal tissues. Indeed, the network of apoptotic signaling mechanisms inherent in most cell types provides a major barrier to the development and progression of human cancer. Since most commonly used radiation and chemo-therapies rely on activation of apoptotic pathways to kill cancer cells, tumor cells which are capable of evading programmed cell death often become resistant to treatment.
  • Apoptosis signaling networks are classified as either intrinsic when mediated by death receptor-ligand interactions or extrinsic when mediated by cellular stress and mitochondrial permeabilization. Both pathways ultimately converge on individual Caspases. Once activated, Caspases cleave a number of cell death-related substrates, effecting destruction of the cell.
  • Tumor cells have devised a number of strategies to circumvent apoptosis.
  • One recently reported molecular mechanism involves the overexpression of members of the IAP (Inhibitor of Apoptosis) protein family.
  • IAPs sabotage apoptosis by directly interacting with and neutralizing Caspases.
  • the prototype IAPs, XIAP and cIAP have three functional domains referred to as BIR 1, 2 & 3 domains.
  • BIR3 domain interacts directly with Caspase 9 and inhibits its ability to bind and cleave its natural substrate, Procaspase 3.
  • a proapoptotic mitochondrial protein Smac (also known as DIABLO), is capable of neutralizing XIAP and/or cIAP by binding to a peptide binding pocket (Smac binding site) on the surface of BIR3 thereby precluding interaction between XIAP and/or cIAP and Caspase 9.
  • Smac also known as DIABLO
  • the present invention relates to therapeutic molecules that bind to the Smac binding pocket thereby promoting apoptosis in rapidly dividing cells.
  • Such therapeutic molecules are useful for the treatment of proliferative diseases, including cancer.
  • Smac analogs would bind to BIR3 domain of IAPs and will remove the IAP's inhibition of activated Caspase 9 which would then go on to induce apoptosis.
  • the present invention relates generally to novel compounds that inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs).
  • IAPs Apoptosis Proteins
  • the present invention includes novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action rely on the inhibition of the Smac/IAP interaction, and more particularly useful in therapies for the treatment of proliferative diseases, including cancer.
  • the present invention relates to compounds of the formula (I)
  • R 1 is H; C 1 -C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl or C 3 -C 10 cycloalkyl which are unsubstituted or substituted;
  • R 2 is H; C 1 -C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl or C 3 -C 10 cycloalkyl which are unsubstituted or substituted;
  • R 3 is H; —CF 3 ; —C 2 F 5 ; C 1 -C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl; —CH 2 -Z or R 2 and R 3 together with the nitrogen form a het ring;
  • Z is H; —OH; F; Cl; —CH 3 ; —CF 3 ; —CH 2 Cl; —CH 2 F or —CH 2 OH;
  • R 4 is C 1 -C 16 straight or branched alkyl; C 1 -C 16 alkenyl; C 1 -C 16 alkynyl; or —C 3 -C 10 cycloalkyl; —(CH 2 ) 1-6 -Z 1 ; —(CH 2 ) 0-6 -aryl; and —(CH 2 ) 0-6 -het; wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; Z 1 is —N(R 8 )—C(O)—C 1 -C 10 alkyl; —N(R 8 )—C(O)—(CH 2 ) 1-6 —C 3 -C 7 cycloalkyl; —N(R 8 )—C(O)—(CH 2 ) 0-6 -phenyl; —N(R 8 )—C(O)—(CH 2 ) 1-6 -het; —C(O)
  • R 8 is H; —CH 3 ; —CF 3 ; —CH 2 OH or —CH 2 Cl;
  • R 9 and R 10 are each independently H; C 1 -C 4 alkyl; C 3 -C 7 cycloalkyl; —(CH 2 ) 1-6 —C 3 -C 7 cycloalkyl; —(CH 2 ) 0-6 -phenyl; wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R 9 and R 10 together with the nitrogen form het; R 5 is H; C 1 -C 10 -alkyl; aryl; phenyl; C 3 -C 7 cycloalkyl; —(CH 2 ) 1-6 —C 3 -C 7 cycloalkyl; —C 1 -C 10 alkyl-aryl; —(CH 2 ) 0-6 —C 3 -C 7 cycloalkyl-(CH 2 ) 0-6 -phenyl; —(CH 2 ) 0-4 CH—((CH 2 ) 1-4
  • n 0-5;
  • X is —CH or N
  • Ra and Rb are independently an O, S, or N atom or C 0-8 alkyl wherein one or more of the carbon atoms in the alkyl chain may be replaced by a heteroatom selected from O, S or N, and where the alkyl may be unsubstituted or substituted;
  • Rd is selected from:
  • Q is N, O, S, S(O), or S(O) 2 ;
  • Ar 1 and Ar 2 are substituted or unsubstituted aryl or het;
  • Rf and Rg are each independently H; —C 1 -C 10 alkyl; C 1 -C 10 alkylaryl; —OH; —O—C 1 -C 10 alkyl; —(CH 2 ) 0-6 —C 3 -C 7 cycloalkyl; —O—(CH 2 ) 0-6 -aryl; phenyl; aryl; phenyl-phenyl; —(CH 2 ) 1-6 -het; —O—(CH 2 ) 1-6 -het; —OR 11 ; —C(O)—R 11 ; —C(O)—N(R 11 )(R 12 ); —N(R 11 )(R 12 ); —S—R 11 ; —S(O)—R 11 ; —S(O) 2 —R 11 ; —S(O) 2
  • the present invention also related to the use of compound of formula I in the treatment of proliferative diseases, especially those dependent on the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs), or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, methods of use of compounds of formula (I) in the treatment of said diseases, pharmaceutical preparations comprising compounds of formula (I) for the treatment of said diseases, compounds of formula (I) for use in the treatment of said diseases.
  • IAPs Inhibitor of Apoptosis Proteins
  • Aryl is an aromatic radical having 6 to 14 carbon atoms, which may be fused or unfused, and which is unsubstituted or substituted by one or more, preferably one or two substituents, wherein the substituents are as described below.
  • Preferred “aryl” is phenyl, naphthyl or indanyl.
  • Het refers to heteroaryl and heterocyclic rings and fused rings containing aromatic and non-aromatic heterocyclic rings. “Het” is a 5-7 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, and S.
  • Suitable het substituents include unsubstituted and substituted pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, 1,4-oxathiapane, furyl, thienyl, pyrrole, pyrazole, triazole, 1,2,3-triazole, tetrazolyl, oxadiazole, thiophene, imidazol, pyrrolidine, pyrrolidone, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine, quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran
  • the het substituents are unsubstituted or substituted on a carbon atom by halogen, especially fluorine or chlorine, hydroxy, C 1 -C 4 alkyl, such as methyl and ethyl, C 1 -C 4 alkoxy, especially methoxy and ethoxy, nitro, —O—C(O)—C 1 -C 4 alkyl or —C(O)—O—C 1 -C 4 alkyl or on a nitrogen by C 1 -C 4 alkyl, especially methyl or ethyl, —O—C(O)—C 1 -C 4 alkyl or —C(O)—O—C 1 -C 4 alkyl, such as carbomethoxy or carboethoxy.
  • halogen especially fluorine or chlorine
  • hydroxy C 1 -C 4 alkyl, such as methyl and ethyl, C 1 -C 4 alkoxy, especially methoxy and ethoxy, nitro
  • heterocyclic ring is a nitrogen-containing ring, such as aziridine, azetidine, azole, piperidine, piperazine, morphiline, pyrrole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, and the like.
  • Halogen is fluorine, chlorine, bromine or iodine, especially fluorine and chlorine.
  • alkyl includes straight or branched chain alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and branched pentyl, n-hexyl and branched hexyl, and the like.
  • a “cycloalkyl” group means C 3 to C 10 cycloalkyl having 3 to 8 ring carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • cycloalkyl is cycloheptyl.
  • the cycloalkyl group may be unsubstituted or substituted with any of the substituents defined below, preferably halo, hydroxy or C 1 -C 4 alkyl such as methyl.
  • the amino acid residues include a residue of a standard amino acid, such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • the amino acid residues also include the side chains of uncommon and modified amino acids. Uncommon and modified amino acids are known to those of skill in the art (see for example G. B. Fields, Z.
  • the side chain of the amino acid residue contains a derivatizable group, such as COOH, —OH or amino
  • the side chain may be derivatized by a substituent that reacts with the derivatizable group.
  • a substituent that reacts with the derivatizable group.
  • acidic amino acids like aspartic and glutamic acid, or hydroxy substituted side chains, like those of serine or threonine
  • the derivative may be a substituent that facilitates transport across a cell membrane.
  • any carboxylic acid group in the amino acid residue for example, an alpha carboxylic acid group, may be derivatized as discussed above to form an ester or amide.
  • Such lipophillic substituents include a C 6 -C 30 alkyl which is saturated, monounsaturated, polyunsaturated, including methylene-interrupted polyene, phenyl, phenyl which substituted by one or two C 1 -C 8 alkyl groups, C 5 -C 9 cycloalkyl, C 5 -C 9 cycloalkyl which is substituted by one or two C 1 -C 8 alkyl groups, —X 1 -phenyl, —X 1 -phenyl which is substituted in the phenyl ring by one or two C 1 -C 8 alkyl groups, X 1 —C 5 -C 9 cycloalkyl or X 1 —C 5 -C 9 cycloalkyl which is substituted by one or two C 1 -C 8 alkyl groups; where X 1 is C 1 -C 24 alkyl which is saturated, monounsaturated or polyunsaturated and straight or branched
  • any of the above defined aryl, het, alkyl, cycloalkyl, or heterocyclic groups may be unsubstituted or independently substituted by up to four, preferably one, two or three substituents, selected from the group consisting of: halo (such as Cl or Br); hydroxy; lower alkyl (such as C 1 -C 3 lower alkyl); lower alkyl which may be substituted with any of the substituents defined herein; lower alkenyl; lower alkynyl; lower alkanoyl; alkoxy (such as methoxy); aryl (such as phenyl or benzyl); substituted aryl (such as fluoro phenyl or methoxy phenyl); amino; mono- or disubstituted amino; amino lower alkyl (such as dimethylamino); acetyl amino; amino lower alkoxy (such as ethoxyamine); nitro; cyano; cyano lower alkyl; carboxy; ester
  • R 4 and R 5 together with the N atom form a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen, oxygen or sulfur atoms (e.g. piperazinyl, pyrazinyl, lower alkyl-piperazinyl, pyridyl, indolyl, thiophenyl, thiazolyl, n-methyl piperazinyl, benzothiophenyl, pyrrolidinyl, piperidino or imidazolinyl) where the heterocyclic ring may be substituted with any of the substituents defined herein.
  • 1-4 nitrogen, oxygen or sulfur atoms e.g. piperazinyl, pyrazinyl, lower alkyl-piperazinyl, pyridyl, indolyl, thiophenyl, thiazolyl, n-methyl piperazinyl, benzothiophenyl, pyrrolidinyl, piperidino or imid
  • alkyl, cycloalkyl, aryl or het groups may be substituted by halogen, carbonyl, thiol, S(O), S(O 2 ), —OH, —SH, —OCH 3 , —SCH 3 , —CN, —SCN or nitro.
  • a compound of the invention can exist as a salt form, especially as an acid addition salt or a base addition salt.
  • a compound can exist in a salt form, such salt forms are included within the scope of the invention.
  • any salt form may be useful in chemical manipulations, such as purification procedures, only pharmaceutically acceptable salts are useful for pharmaceutically products.
  • Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable base addition salts and acid addition salts, for example, metal salts, such as alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts, and sulfonate salts.
  • Acid addition salts include inorganic acid addition salts such as hydrochloride, sulfate and phosphate, and organic acid addition salts such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate.
  • metal salts are alkali metal salts, such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt.
  • ammonium salts are ammonium salt and tetramethylammonium salt.
  • organic amine addition salts are salts with morpholine and piperidine.
  • amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine.
  • Sulfonate salts include mesylate, tosylate and benzene sulfonic acid salts.
  • any reference to the compounds hereinbefore and hereinafter especially the compounds of the formula I is to be understood as referring also to the corresponding tautomers of these compounds, especially of compounds of the formula I, tautomeric mixtures of these compounds, especially of compounds of the formula I, or salts of any of these, as appropriate and expedient and if not mentioned otherwise.
  • Any asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
  • the compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as enantiomer-pure diastereomers or pure enantiomers.
  • IAPS Apoptosis Proteins
  • An embodiment of the present invention relates to compounds of the formula (I)
  • R 1 is H; C 1 -C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl or cycloalkyl which are unsubstituted or substituted by one or more substituents selected from halogen, —OH, —SH, —OCH 3 , —SCH 3 , —CN, —SCN and nitro;
  • R 2 is H; C 1 -C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl or cycloalkyl which are unsubstituted or substituted by one or more substituents selected from halogen, —OH, —SH, —OCH 3 , —SCH 3 , —CN, —SCN and nitro;
  • R 3 is H; —CF 3 ; —C 2 F 5 ; C 1 -C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alky
  • Z is H; —OH; F; Cl; —CH 3 ; —CF 3 ; —CH 2 Cl; —CH 2 F or —CH 2 OH;
  • R 4 is C 1 -C 16 straight or branched alkyl; C 1 -C 16 alkenyl; C 1 -C 16 alkynyl; or —C 3 -C 16 cycloalkyl; —(CH 2 ) 1-6 -Z 1 ; —(CH 2 ) 0-6 -phenyl; and —(CH 2 ) 0-6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted; Z 1 is —N(R 8 )—C(O)—C 1 -C 10 alkyl; —N(R 8 )—C(O)—(CH 2 ) 1-6 —C 3 -C 7 cycloalkyl; —N(R 8 )—C(O)—(CH 2 ) 0-6 -phenyl; —N(R 8 )—C(O)—(CH 2 ) 1-6 -het; —C(O
  • R 8 is H, —CH 3 , —CF 3 , —CH 2 OH or —CH 2 Cl;
  • R 9 and R 10 are each independently H; C 1 -C 4 alkyl; C 3 -C 7 cycloalkyl; —(CH 2 ) 1-6 —C 3 -C 7 cycloalkyl; —(CH 2 ) 0-6 -phenyl; wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R 9 and R 10 together with the nitrogen form het;
  • R 5 is H; C 1 -C 10 -alkyl; C 3 -C 7 cycloalkyl; —(CH 2 ) 1-6 —C 3 -C 7 cycloalkyl; —C 1 -C 10 alkyl-aryl; —(CH 2 ) 0-6 —C 3 -C 7 cycloalkyl-(CH 2 ) 0-6 -phenyl; —(CH 2 ) 0-4 CH—((CH 2 ) 1-4 -phenyl) 2
  • n 0-5;
  • X is —CH or N
  • Ra and Rb are independently an O, S, or N atom or C 0-8 alkyl wherein one or more of the carbon atoms in the alkyl chain may be replaced by a heteroatom selected from O, S or N, and where the alkyl may be unsubstituted or substituted;
  • Rd is selected from:
  • Q is N, O, S, S(O), or S(O) 2 ;
  • Ar 1 and Ar 2 are substituted or unsubstituted aryl or het;
  • Rf and Rg are each independently H; —C 1 -C 10 alkyl; C 1 -C 10 alkylaryl; —OH; —O—C 1 -C 10 alkyl; —(CH 2 ) 0-6 —C 3 -C 7 cycloalkyl; —O—(CH 2 ) 0-6 -aryl; phenyl; aryl; phenyl-phenyl; —(CH 2 ) 1-6 -het; —O—(CH 2 ) 1-6 -het; —OR 11 ; —C(O)—R 11 ; —C(O)—N(R 11 )(R 12 ); —N(R 11 )(R 12 ); —S—R 11 ; —S(O)—R 11 ; —S(O) 2 —R 11 ; —S(O) 2
  • a further embodiment the present invention relates to the use of compound of formula I in the treatment of proliferative diseases, especially those dependent on the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs), or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases, methods of use of compounds of formula (I) in the treatment of said diseases, pharmaceutical preparations comprising compounds of formula (I) for the treatment of said diseases, compounds of formula (I) for use in the treatment of said diseases.
  • IAPs Inhibitor of Apoptosis Proteins
  • One embodiment of the present invention relates to compounds of the formula (I) wherein
  • R 1 and R 2 are independently H or substituted or unsubstituted C 1 -C 4 alkyl;
  • R 4 is C 1 -C 16 straight or branched alkyl, or C 3 -C 10 cycloalkyl, wherein the alkyl or cycloalkyl may be unsubstituted or substituted;
  • R 5 is H; C 1 -C 10 alkyl; C 1 -C 10 alkyl-aryl; —C(O)—(CH 2 ) 0-6 -Phenyl; —(CH 2 ) 0-6 —C(O)-Phenyl; aryl; indanyl; naphthyl or R 5 is a residue of an amino acid, wherein the alkyl or aryl substituents are unsubstituted or substituted;
  • U is as shown in structure II:
  • n 0-5;
  • X is —CH or N
  • Ra and Rb are independently an O, S, or N atom or C 0-8 alkyl wherein one or more of the carbon atoms in the alkyl chain may be replaced by a heteroatom selected from O, S or N, and where the alkyl may be unsubstituted or substituted; Rd is selected from
  • Q is N, O, S, S(O), or S(O) 2 ;
  • Ar 1 and Ar 2 are substituted or unsubstituted aryl or het;
  • Rf and Rg are each independently H or substituted or unsubstituted C 0 -C 10 alkyl; C 1 -C 10 alkylaryl; aryl-C 1 -C 10 alkyl; het-C 1 -C 10 alkyl —C(O)—C 1 -C 4 -alkyl-phenyl; —C(O)—C 1 -C 4 -alkyl; —SO 2 —C 1 -C 2 alkyl; —SO 2 —C 1 -C 2 alkylphenyl; —O—C 1 -C 4 -alkyl; D is —C(O)—; C 1-7 alkylene or arylene; —O—, or —S(O) r where r is 0-2; where alkyl, alkylene or arylene which may be unsubstituted or substituted with
  • U is a bicyclic saturated or unsaturated ring system, consisting of all carbon skeleton or with one or more heteroatoms such as O, N, S but preferably as shown in structure III:
  • any of the ring carbon atoms can be unsubstituted or substituted with any of the substituted defined above for R 6 , R 7 , R 6′ and R 7 ′;
  • X is CH or N
  • V is O, F 2 , Cl 2 , Br 2 , I 2 , S, YH, H 2 , NH, or C 1 -C 4 alkyl;
  • W is —CH, or —N
  • the ring atoms may be substituted with substituents independently selected from halo, H, OH, lower alkyl or lower alkoxy, wherein alkyl or alkoxy are unsubstituted or substituted by halogen, OH, lower alkyl or lower alkoxy.
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H; methyl; ethyl; chloromethyl; dichloromethyl or trifluoromethyl;
  • R 4 is —C 1 -C 4 alkyl; —C 3 -C 7 cycloalkyl; —(CH 2 ) 1-6 cycloalkyl; or —(CH 2 ) 0-6 aryl.
  • R 4 is particularly ethyl; propyl; isopropyl; t-butyl; cyclopentyl; or cyclohexyl; —CH 2 -cyclopentyl; —CH 2 -cyclohexyl or —CH 2 -phenyl.
  • R 5 is —C 1 -C 4 alkyl-phenyl; —C(O)—C 1 -C 4 alkyl-phenyl; —C 1 -C 4 alkyl-C(O)-pheny or aryl; R 5 is particularly phenylmethyl, phenylethyl and phenylpropyl; indanyl, naphthyl; —C(O)—CH 2 -phenyl or —CH 2 —C(O)-phenyl; R 6 and R 7 are H or methyl; U has the structure of formula III:
  • any of the ring carbon atoms can be unsubstituted or substituted with any of the substituted defined above for R 6 , R 7 , R 6′ and R 7 ′;
  • X is N
  • V is O or H 2 ;
  • W is —N
  • R 1 and R 3 are preferably methyl or ethyl
  • R 2 is H
  • R 4 is C 1 -C 4 alkyl; C 3 -C 7 cycloalkyl; C 1 -C 7 cycloalkyl-C 1 -C 7 alkyl; phenyl-C 1 -C 7 alkyl or aryl.
  • R 4 is particularly methyl; ethyl; butyl; isopropyl; t-butyl; or cyclohexyl; —CH 2 -cyclopentyl; —CH 2 -cyclohexyl; —CH 2 -cyclopropyl; phenyl or —CH 2 -phenyl;
  • R 5 is —C 1 -C 4 alkyl-phenyl; —C(O)—C 1 -C 4 alkyl-phenyl; —C 1 -C 4 alkyl-C(O)-pheny or aryl.
  • R 5 is particularly phenylethyl; indanyl, naphthyl; —C(O)—CH 2 -phenyl; —CH 2 —C(O)-phenyl or (CF 3 O)phenylethyl;
  • R 6 , R′ 6 , R 7 and R′ 7 are H;
  • U has the structure of formula III wherein wherein any of the ring carbon atoms can be unsubstituted or substituted with any of the substituted defined above for R 6 , R 7 , R 6′ and R 7 ′;
  • X is N
  • V is O or H 2 ;
  • W is —N
  • Another embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is H
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Rc is H
  • Ar 1 and Ar 2 are substituted or unsubstituted phenyl or het particularly tetrazolyl, 1, 2,3-triazole, pyrazole, oxazole, pyrrolyl, triazine, pyrimidine, imidazol, oxadiazol; and and D is C 1 alkyl which may optionally be substituted with halo, especially F.
  • Another embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl; C 3 -C 7 cycloalkyl; C 1 -C 7 cycloalkyl-C 1 -C 7 alkyl; phenyl-C 1 -C 7 alkyl or aryl.
  • R 4 is particularly methyl, ethyl, butyl, isopropyl, t-butyl, or cyclohexyl; —CH 2 -cyclopentyl, —CH 2 -cyclohexyl; —CH 2 -cyclopropyl; phenyl or —CH 2 -phenyl;
  • R 5 is H
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H; or R 6 is —C(O)—C 1 -C 4 alkyl-phenyl and R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Rc is H
  • Ar 1 and Ar 2 are substituted or unsubstituted phenyl or het, particularly triazine, pyrimidine, pyridine, oxazole, 2,4-difluorophenyl, Cl-phenyl or fluorophenyl; and D is N(Rh), where Rh is H, Me, —CHO, —SO 2 , —C(O), —CHOH, —CF 3 or —SO 2 CH 3 .
  • Another embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl; C 3 -C 7 cycloalkyl; C 1 -C 7 cycloalkyl-C 1 -C 7 alkyl; phenyl-C 1 -C 7 alkyl or aryl.
  • R 4 is particularly methyl, ethyl, butyl, isopropyl, t-butyl, or cyclohexyl; —CH 2 -cyclopentyl, —CH 2 -cyclohexyl; —CH 2 -cyclopropyl; phenyl or —CH 2 -phenyl;
  • R 5 is H
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Rc is H
  • Ar 1 and Ar 2 are substituted or unsubstituted phenyl or het particularly pyrimidine, pyridine, oxazole, 2-methyloxazole; and D is —O—.
  • Another embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is H
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Rc is H
  • Ar 1 and Ar 2 are substituted or unsubstituted phenyl or het; and D is S, S(O), or S(O) 2 .
  • Another embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is H
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Rc is H
  • Ar 1 and Ar 2 are substituted or unsubstituted phenyl or het, particularly oxazole, thaizole and ozadiazole; and D is C(O), or 1,3-dioxolane.
  • Another embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is H or phenyl C 1 -C 10 alkyl such as phenylethyl;
  • U has the structure of formula II wherein
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Rc and Rd are a heterocyclic ring, particularly pyrrolidine; pyrrolidin-2-one; or pyrrolidin-3-one.
  • Another embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is H, indanyl or phenyl;
  • U has the structure of formula II wherein
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Re is C 1 alkyl; and p and q are 0.
  • a further embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is H, indanyl or phenyl;
  • U has the structure of formula II wherein
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Re is C 1 alkyl; and R g is H C 1 -C 8 alkyl, methyl, ethyl, hexyl, heptyl, octyl; or CH 2 CF 3 ; or aryl-C 1 -C 4 alkyl particularly phenylethyl, furanylethyl; C 3 -C 7 cycloalkyl particularly cyclohexyl; ethylphenyl; —C(O)—C 1 -C 4 alkyl-phenyl; —C(O)—C 1 -C 4 alkyl; —C 1 -C 4 alkyl-aryl particularly —CH 2 -phenyl; —CH 2 -thiophene, —CH 2 -furan, —CH 2 -pyrrolidinyl, —CH 2 -imidazole, —CH 2 -triazole, —CH 2 -imidazole; and R f is C
  • a further embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is H, indanyl or phenyl;
  • U has the structure of formula II wherein
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Re is C 1 alkyl; and R g and R f form a ring selected from het or aryl particularly 2,3,4,5-tetrahydrobenzo[c]azepine; 1,2,3,4 tetrahydroquinoline; indanyl which may be substituted with C 1 -C 4 alkylphenyl
  • a further embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is phenyl;
  • U has the structure of formula II wherein
  • X is N
  • Q is O, S, S(O) or S(O) 2 ;
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Re is C 1 alkyl; q is 0;
  • Rc is H
  • R f is C 2 alkyl.
  • a further embodiment is directed to a compound of formula (I) wherein
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is especially H, methyl, ethyl, chloromethyl, dichloromethyl or trifluoromethyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is phenyl;
  • U has the structure of formula II wherein
  • X is N
  • R 6 , R′ 6 , R 7 , and R′ 7 are H;
  • n O
  • Rc is H
  • R f is OC 1 alkyl.
  • R 3 and R 4 have the stereochemistry indicated in formula IV, with the definitions of the variable substituents and preferences described herein above also applying to compounds having the stereochemistry indicated in formula IV.
  • R 1 and R 3 are preferably methyl or ethyl;
  • R 2 is H, methyl, ethyl, or substituted methyl especially chloromethyl, dichloromethyl and trifluoromethyl; preferably R 2 is H or unsubstituted methyl;
  • R 4 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl particularly isopropyl, t-butyl, cyclopentyl, or cyclohexyl;
  • R 5 is —C 1 -C 4 -alkyl-phenyl, particularly phenylmethyl, phenylethyl and phenylpropyl, indanyl, naphthyl; and
  • R 6 and R 7 are H or methyl.
  • R 6 , R 7 , R 6′ , and R 7′ is H. If one of R 6 , R 7 , R 6′ , and R 7′ is other than H, it is especially hydroxyl or phenoxy.
  • KOTMS is defined as potassium trimethysilanoate.
  • Step A This step involves the formation of an aziridine ring via standard base mediated conditions.
  • Step B This step involves the formation of a secondary amine via the reaction of an alkyl bromide with excess amine in the presence of a base.
  • Step C This step involves the coupling of a secondary amine with an activated derivative of the aziridine methyl ester to form an amide substituted aziridine.
  • Step D This step involves the intramolecular cycloaddition of the aziridine to the tethered alkene through a thermally accessible azomethine ylide intermediate.
  • Step E This step involves the reduction of the amide to an amine via standard reduction conditions employing DIBAL-H.
  • Step F This step involves the removal of the benzylic protecting group using standard palladium conditions under a hydrogen atmosphere.
  • Step G This step involves coupling of the scaffold with a t-Boc protected natural or unnatural amino acid using standard peptide coupling conditions followed by the removal of the t-Boc group with TFA.
  • Step H This step involves the coupling of the amine generated in the preceding step with a t-Boc protected or tertiary natural or unnatural amino acid using standard peptide coupling conditions followed by the removal of the t-Boc group with TFA if applicable. The product is then purified by high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • the compounds of the present invention are useful for treating proliferative diseases.
  • the present invention further relates to a method of treating a proliferative disease which comprises administering a therapeutically effective amount of a compound of the invention to a mammal, preferably a human, in need of such treatment.
  • a proliferative disease is mainly a tumor disease (or cancer) (and/or any metastases).
  • the inventive compounds are particularly useful for treating a tumor which is a breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreas cancer, neuroblastoma, head and/or neck cancer or bladder cancer, or in a broader sense renal, brain or gastric cancer; in particular (i) a breast tumor; an epidermoid tumor, such as an epidermoid head and/or neck tumor or a mouth tumor; a lung tumor, for example a small cell or non-small cell lung tumor; a gastrointestinal tumor, for example, a colorectal tumor; or a genitourinary tumor, for example, a prostate tumor (especially a hormone-refractory prostate tumor); or (ii) a proliferative disease that is refractory to the treatment with other chemotherapeutics; or (iii)
  • a proliferative disease may furthermore be a hyperproliferative condition such as leukemias, hyperplasias, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • a hyperproliferative condition such as leukemias, hyperplasias, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis.
  • the inventive compound is selectively toxic or more toxic to rapidly proliferating cells than to normal cells, particularly in human cancer cells, e.g., cancerous tumors, the compound has significant antiproliferative effects and promotes differentiation, e.g., cell cycle arrest and apoptosis.
  • the compounds of the present invention may be administered alone or in combination with other anticancer agents, such as compounds that inhibit tumor angiogenesis, for example, the protease inhibitors, epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors and the like; cytotoxic drugs, such as antimetabolites, like purine and pyrimidine analog antimetabolites; antimitotic agents like microtubule stabilizing drugs and antimitotic alkaloids; platinum coordination complexes; anti-tumor antibiotics; alkylating agents, such as nitrogen mustards and nitrosoureas; endocrine agents, such as adrenocorticosteroids, androgens, anti-androgens, estrogens, anti-estrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists and somatostatin analogues and compounds that target an enzyme or receptor that is overexpressed and/or otherwise involved a specific metabolic pathway that is upregulated in the tumor cell
  • the present invention further relates to a method of promoting apoptosis in rapidly proliferating cells, which comprises contacting the rapidly proliferating cells with an effective apoptosis promoting amount of a non-naturally-occurring compound that binds to the Smac binding site of XIAP and/or cIAP proteins.
  • the non-naturally-occurring compound a compound of present formula I or IV.
  • the present invention further relates to a method of treating or inhibiting myeloma, especially multiple myeloma.
  • myeloma as used herein relates to a tumor composed of cells of the type normally found in the bone marrow.
  • multiple myeloma as used herein means a disseminated malignant neoplasm of plasma cells which is characterized by multiple bone marrow tumor foci and secretion of an M component (a monoclonal immunoglobulin fragment), associated with widespread osteolytic lesions resulting in bone pain, pathologic fractures, hypercalcaemia and normochromic normocytic anaemia. Multiple myeloma is incurable by the use of conventional and high dose chemotherapies.
  • the invention relates to a method of treating myeloma, especially myeloma which is resistant to conventional chemotherapy.
  • the invention relates also to pharmaceutical compositions comprising a compound of formula I, to their use in the therapeutic (in a broader aspect of the invention also prophylactic) treatment or a method of treatment of a kinase dependent disease, especially the preferred diseases mentioned above, to the compounds for said use and to pharmaceutical preparations and their manufacture, especially for said uses.
  • the present invention also relates to pro-drugs of a compound of formula I that convert in vivo to the compound of formula I as such. Any reference to a compound of formula I is therefore to be understood as referring also to the corresponding pro-drugs of the compound of formula I, as appropriate and expedient.
  • pharmacologically acceptable compounds of the present invention may be present in or employed, for example, for the preparation of pharmaceutical compositions that comprise an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as active ingredient together or in admixture with one or more inorganic or organic, solid or liquid, pharmaceutically acceptable carriers (carrier materials).
  • compositions according to the invention are those for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (especially a human), that comprise an effective dose of the pharmacologically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier.
  • the dose of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • the invention relates also to a method of treatment for a disease that responds to inhibition of a protein kinase and/or a proliferative disease, which comprises administering a (against the mentioned diseases) prophylactically or especially therapeutically effective amount of a compound of formula I according to the invention, or a tautomer thereof or a pharmaceutically acceptable salt thereof, especially to a warm-blooded animal, for example a human, that, on account of one of the mentioned diseases, requires such treatment.
  • the dose of a compound of the formula I or a pharmaceutically acceptable salt thereof to be administered to warm-blooded animals preferably is from approximately 3 mg to approximately 10 g, more preferably from approximately 10 mg to approximately 1.5 g, most preferably from about 100 mg to about 1000 mg/person/day, divided preferably into 1-3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.
  • compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragées, tablets or capsules.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes.
  • a compound of the formula I may also be used to advantage in combination with other antiproliferative agents.
  • antiproliferative agents include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; tel
  • aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g.
  • AROMASIN Formestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON. Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMA. Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR. Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g. under the trademark ORIMETEN.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g. breast tumors.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX.
  • Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA.
  • Fulvestrant can be formulated as disclosed in U.S. Pat. No.
  • 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.
  • CASODEX bicalutamide
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is disclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX. Abarelix can be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO99/17804).
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CAMPTOSAR.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTIN.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS.
  • Teniposide can be administered, e.g. in the form as it is marketed, e.g.
  • Doxorubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN.
  • Epirubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS.
  • Mitoxantrone can be administered, e.g. in the form as it is marketed, e.g. under the trademark NOVANTRON.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing agents and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof.
  • Paclitaxel may be administered e.g. in the form as it is marketed, e.g. TAXOL.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE.
  • Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN R.P.
  • Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN.
  • Discodermolide can be obtained, e.g., as disclosed in U.S. Pat. No. 5,010,099.
  • Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat. No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247.
  • Epothilone A and/or B are also included.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN.
  • Ifosfamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark HOLOXAN.
  • histone deacetylase inhibitors or “HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes compounds disclosed in WO 02/22577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide and pharmaceutically acceptable salts thereof. It further especially includes Suberoylanilide hydroxamic acid (SAHA).
  • SAHA Suberoylanilide hydroxamic acid
  • anti-plastic antimetabolite includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating agents, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark XELODA.
  • Gemcitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR.
  • the monoclonal antibody trastuzumab which can be administered, e.g., in the form as it is marketed, e.g. under the trademark HERCEPTIN.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN.
  • compound “compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds” as used herein includes, but is not limited to: protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.:
  • FGF-Rs fibroblast growth factor-receptors
  • IGF-IR insulin-like growth factor receptor I
  • Trk receptor tyrosine kinase family compounds which target, decrease or inhibit the activity of the Trk receptor tyrosine kinase family
  • c-Met receptor compounds targeting, decreasing or inhibiting the activity of the c-Met receptor
  • PKC protein kinase C
  • Raf Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK and Ras/MAPK family members, or PI(3) kina
  • examples of further compounds include e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds such as those disclosed in WO 00/09495; FTIs; PD184352 or QAN697 (a P13K inhibitor); g) compounds targeting, decreasing or inhibiting the activity of a protein-tyrosine kinase, such as imatinib mesylate (GLIVEC/GLEEVEC) or tyrphostin.
  • GLIVEC/GLEEVEC imatinib mesylate
  • a tyrphostin is preferably a low molecular weight (Mr ⁇ 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4- ⁇ [(2,5-dihydroxyphenyl)methyl]amino ⁇ -benzoic acid adamantyl ester; NSC 680410, adaphostin); and h) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor
  • EGF receptor ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g.
  • WO 96/33980 e.g. compound ZD 1839
  • WO 95/03283 e.g. compound ZM105180
  • trastuzumab HERCEPTIN
  • cetuximab Iressa
  • Tarceva Tarceva
  • CI-1033 EKB-569
  • GW-2016 E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO 03/013541.
  • anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (THALOMID) and TNP-470.
  • TAALOMID thalidomide
  • TNP-470 TNP-470.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25, e.g. okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes are e.g. retinoic acid, ⁇ - ⁇ - or ⁇ -tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • Cox-2 inhibitors such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • bisphosphonates as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL.
  • Clodronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS.
  • titaniumudronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID.
  • “Pamidronic acid” can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIATM.
  • “Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX.
  • “Ibandronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT.
  • “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL.
  • “Zoledronic acid” can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulphate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons, e.g. interferon ⁇ .
  • inhibitor of Ras oncogenic isoforms e.g. H-Ras, K-Ras, or N-Ras
  • H-Ras, K-Ras, or N-Ras refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a “farnesyl transferase inhibitor”, e.g. L-744832, DK8G557 or R115777 (Zarnestra).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g. telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include e.g. PS-341 and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP inhibitor”) as used herein includes, but is not limited to collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
  • MMP inhibitor matrix metalloproteinase inhibitor
  • agents used in the treatment of hematologic malignancies includes, but is not limited to FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of Flt-3; interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of Flt-3
  • interferon 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan
  • ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • kits which target, decrease or inhibit the activity of Flt-3 are especially compounds, proteins or antibodies which inhibit Flt-3, e.g. PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteasome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to trastuzumab (HerceptinTM), Trastuzumab-DM1, erlotinib (TarcevaTM), bevacizumab (AvastinTM), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant e.g. intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • compounds of formula I can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of formula I can be administered in combination with e.g. farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • a compound of the formula I may also be used to advantage in combination with known therapeutic processes, e.g., the administration of hormones or especially radiation.
  • a compound of formula I may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • ком ⁇ онент there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula I and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g. synergistic, effect, or any combination thereof.
  • the organic layer is dried and concentrated under vacuum.
  • the residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:9) to provide a yellow oil.
  • the yellow oil is dissolved in dichloromethane (20 mL), TFA (10 mL) is added and the mixture is stirred at room temperature for 3 h.
  • the mixture is concentrated and the residue is dissolved in dichloromethane (100 mL) and neutralized with saturated sodium bicarbonate.
  • the solution is extracted with dichloromethane (3 ⁇ 50 mL).
  • the organic extracts are combined, dried and concentrated under vacuum to provide 1.75 g (79% two steps) of the title compound which is used in next step without further purification or characterization.
  • But-3-enyl-((S)-1-phenyl-ethyl)-amine (A): To a solution of S-( ⁇ )-1-phenyl ethylamine (15.75 g, 130 mmol) in 150 mL of DMF at 0° C. is added K 2 CO 3 (53.9 g, 390 mmol) in small portions. After stirring at 0° C. for 10 min, 4-bromobutene (13.5 g, 100 mmol) is added dropwise and followed by NaI (58.5 g, 390 mmol) in small portions. The reaction mixture, a white suspension, is heated to 95° C. and stirred overnight/16 hrs.
  • D (2S,3R)-3-But-3-enyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid ethyl ester (1.0 g, 3.32 mmol) is dissolved in EtOH (10 mL) with HCl (0.5 mL, 37%), and cooled to ⁇ 70° C. Ozone gas is bubbled though the solution for about 10 min or until the solution is turned very light blue color.
  • the residue is purified by flash chromatography (silica gel; Hexane/EtOAc 4:1) to provide a yellow oil.
  • the yellow oil is dissolved in dichloromethane (20 mL), TFA (10 mL) is added and the mixture is stirred at room temperature for 3 h.
  • the mixture is concentrated and the residue is dissolved in dichloromethane (100 mL) and neutralized with saturated sodium bicarbonate.
  • the solution is extracted with dichloromethane (3 ⁇ 50 mL).
  • the organic extracts are combined, dried and concentrated under vacuum to provide 1.04 g (68% two steps) of the title compound E which is used in the next step without further purification or characterization.
  • Compound 32 is prepared as follows:
  • an ELISA and a cell based assays are utilized.
  • the remaining GST-BIR3 fusion protein is monitored by ELISA assay involving first, incubation with goat anti-GST antibodies followed by washing and incubation with alkaline phosphatase conjugated anti-goat antibodies. Signal is amplified using Attophos (Promega) and read with Cytoflour Ex 450 nm/40 and Em 580 nm.
  • IC 50 s correspond to concentration of compound which displaces half of GST-BIR3 signal.
  • the IC 50 for non-biotinylated Smac is 400 nM.
  • the IC 50 values of compounds listed in Table 1 in the described ELISA assays ranged from 0.005-10 ⁇ M.
  • the ability of compounds to inhibit tumor cell growth in vitro is monitored using the CellTiter 96® AQ ueous Non-Radioactive Cell Proliferation Assay (Promega).
  • This assay is composed of solutions of a novel tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling reagent (phenazine methosulfate) PMS.
  • MTS is bioreduced by cells into a formazan product, the absorbance of which is measured at 490 nm.
  • the conversion of MTS into the aqueous soluble formazan product is accomplished by dehydrogenase enzymes found in metabolically active cells.
  • the quantity of formazan product as measured by the amount of 490 nm absorbance is directly proportional to the number of living cells in culture.
  • the IC 50 values of compounds listed in Table 1 in the described cell assays ranged from 0.005-50 ⁇ M.
  • Tablets 1 Comprising Compounds of the Formula (I)
  • Tablets comprising, as active ingredient, 50 mg of any one of the compounds of formula (I) mentioned in the preceding Examples 9-194 of the following composition are prepared using routine methods:
  • composition Active Ingredient 50 mg Wheat starch 60 mg Lactose 50 mg Colloidal silica 5 mg Talcum 9 mg Magnesium stearate 1 mg Total 175 mg
  • Manufacture The active ingredient is combined with part of the wheat starch, the lactose and the colloidal silica and the mixture pressed through a sieve. A further part of the wheat starch is mixed with the 5-fold amount of water on a water bath to form a paste and the mixture made first is kneaded with this paste until a weakly plastic mass is formed.
  • the dry granules are pressed through a sieve having a mesh size of 3 mm, mixed with a pre-sieved mixture (1 mm sieve) of the remaining corn starch, magnesium stearate and talcum and compressed to form slightly biconvex tablets.
  • Tablets comprising, as active ingredient, 100 mg of any one of the compounds of formula (I) of Examples 9-194 are prepared with the following composition, following standard procedures:
  • composition Active Ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL 20 mg Aerosil 2 mg Magnesium stearate 5 mg Total 447 mg
  • Manufacture The active ingredient is mixed with the carrier materials and compressed by means of a tabletting machine (Korsch EKO, Stempel sacrificer 10 mm).
  • Capsules comprising, as active ingredient, 100 mg of any one of the compounds of formula (I) given in Examples 9-194, of the following composition are prepared according to standard procedures:
  • Active Ingredient 100 mg Avicel 200 mg PVPPXL 15 mg Aerosil 2 mg Magnesium stearate 1.5 mg Total 318.5 mg
  • Manufacturing is done by mixing the components and filling them into hard gelatine capsules, size 1.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110034469A1 (en) * 2009-08-04 2011-02-10 Takeda Pharmaceutical Company Limited Heterocyclic Compound

Families Citing this family (147)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7345081B2 (en) 2004-03-23 2008-03-18 Genentech, Inc. Azabicyclo-octane inhibitors of IAP
PL2253614T3 (pl) 2004-04-07 2013-03-29 Novartis Ag Inhibitory IAP
KR100926203B1 (ko) 2004-07-02 2009-11-09 제넨테크, 인크. Ｉａｐ의 억제제
JP5230865B2 (ja) * 2004-07-15 2013-07-10 テトラロジック ファーマシューティカルズ コーポレーション Ｉａｐ結合性化合物
MX2007007195A (es) 2004-12-20 2007-10-08 Genentech Inc Inhibidores de pirrolidina de iap.
CA2598838A1 (en) * 2005-02-23 2006-08-31 Prexa Pharmaceuticals, Inc. Multimediator 5-ht6 receptor antagonists, and uses related thereto
EA012810B1 (ru) 2005-02-25 2009-12-30 Тетралоджик Фармасеутикалс Димерные ингибиторы ингибиторов белков апоптоза (iap)
WO2006107964A2 (en) * 2005-04-06 2006-10-12 Novartis Ag Processes to prepare 6-phenethyl-octahydro-pyrrolo [2 , 3-c] pyridine and related compounds
WO2006122408A1 (en) * 2005-05-18 2006-11-23 Aegera Therapeutics Inc. Bir domain binding compounds
US20100256046A1 (en) * 2009-04-03 2010-10-07 Tetralogic Pharmaceuticals Corporation Treatment of proliferative disorders
CA2617642A1 (en) * 2005-08-09 2007-02-22 Tetralogic Pharmaceuticals Corporation Treatment of proliferative disorders
AU2006308453B9 (en) 2005-10-25 2011-12-01 Pharmascience Inc. IAP BIR domain binding compounds
WO2007106192A2 (en) * 2005-12-19 2007-09-20 Genentech, Inc. Inhibitors of iap
US20090005411A1 (en) * 2005-12-20 2009-01-01 Novartic Ag Combinations of Organic Compounds
TWI504597B (zh) * 2006-03-16 2015-10-21 Pharmascience Inc 結合於細胞凋亡抑制蛋白（ｉａｐ）之桿狀病毒ｉａｐ重複序列（ｂｉｒ）區域之化合物
CN101415411A (zh) * 2006-04-05 2009-04-22 诺瓦提斯公司 用于治疗癌症的治疗剂组合
RU2452492C2 (ru) * 2006-04-05 2012-06-10 Новартис Аг КОМБИНАЦИИ, ВКЛЮЧАЮЩИЕ ИНГИБИТОРЫ Bcr-Abl/c-Kit/PDGF-R TK, ДЛЯ ЛЕЧЕНИЯ РАКА
US8168383B2 (en) 2006-04-14 2012-05-01 Cell Signaling Technology, Inc. Gene defects and mutant ALK kinase in human solid tumors
PL2450437T3 (pl) 2006-04-14 2017-12-29 Cell Signaling Technology Inc Defekty genu i zmutowana kinaza ALK w ludzkich guzach litych
BRPI0711591A2 (pt) 2006-05-16 2011-11-16 Aegera Therapeutics, Inc. composto de ligação de domìnio bir da iap
MX2008014502A (es) * 2006-05-16 2008-11-27 Aegera Therapeutics Inc Compuestos de union a dominio de repeticion de proteinas inhibidoras de apoptosis baculovirales de las proteinas inhibidoras de apoptosis.
MX2009000824A (es) * 2006-07-24 2009-02-04 Tetralogic Pharmaceuticals Cor Antagonistas dimericos de las proteinas inhibidoras de la apoptosis.
WO2008014229A2 (en) * 2006-07-24 2008-01-31 Tetralogic Pharmaceuticals Corporation Dimeric iap inhibitors
JP5452223B2 (ja) 2006-07-24 2014-03-26 テトラロジック ファーマシューティカルズ コーポレーション Ｉａｐ阻害剤
WO2008014240A2 (en) * 2006-07-24 2008-01-31 Tetralogic Pharmaceuticals Corporation Dimeric iap inhibitors
US20100056495A1 (en) * 2006-07-24 2010-03-04 Tetralogic Pharmaceuticals Corporation Dimeric iap inhibitors
PE20110217A1 (es) 2006-08-02 2011-04-01 Novartis Ag DERIVADOS DE 2-OXO-ETIL-AMINO-PROPIONAMIDA-PIRROLIDIN-2-IL-SUSTITUIDOS COMO INHIBIDORES DEL ENLACE DE LA PROTEINA Smac AL INHIBIDOR DE LA PROTEINA DE APOPTOSIS
AU2007307763A1 (en) * 2006-10-12 2008-04-17 Novartis Ag Pyrrolydine derivatives as IAP inhibitors
RU2009118487A (ru) * 2006-10-19 2010-11-27 Новартис АГ (CH) Органические соединения
KR20090087094A (ko) * 2006-11-28 2009-08-14 노파르티스 아게 Ｉａｐ 억제제 및 ｆｌｔ3 억제제의 조합물
WO2008085610A1 (en) * 2006-11-28 2008-07-17 Novartis Ag Use of iap inhibitors for the treatment of acute myeloid leukemia
CN101605786A (zh) * 2006-12-19 2009-12-16 健泰科生物技术公司 细胞凋亡抑制剂的咪唑并吡啶抑制剂
WO2008109057A1 (en) * 2007-03-02 2008-09-12 Dana-Farber Cancer Institute, Inc. Organic compounds and their uses
CA2684169C (en) 2007-04-12 2012-06-19 Joyant Pharmaceuticals, Inc. Smac mimetic dimers and trimers useful as anti-cancer agents
NZ598890A (en) * 2007-04-30 2013-10-25 Genentech Inc Inhibitors of iap
JP2010528587A (ja) * 2007-05-07 2010-08-26 テトラロジック ファーマシューティカルズ コーポレーション アポトーシス阻害タンパク質のアンタゴニストに対する感受性のバイオマーカーとしてＴＮＦα遺伝子の発現を用いる方法
WO2008144925A1 (en) * 2007-05-30 2008-12-04 Aegera Therapeutics Inc. Iap bir domain binding compounds
DK2240506T3 (da) * 2008-01-11 2013-04-08 Genentech Inc IAP inhibitorer
MX2010007948A (es) * 2008-01-24 2010-10-04 Tetralogic Pharm Corp Inhibidores de proteinas de apoptosis.
US20110117081A1 (en) * 2008-05-05 2011-05-19 Aegera Therapeutics, Inc. Functionalized pyrrolidines and use thereof as iap inhibitors
EP2296650B1 (en) 2008-05-16 2020-05-06 Novartis AG Immunomodulation by iap inhibitors
US20110171171A1 (en) * 2008-06-27 2011-07-14 Aegera Therapeutics, Inc. Bridged secondary amines and use thereof as iap bir domain binding compounds
US8835393B2 (en) 2008-08-02 2014-09-16 Genentech, Inc. Inhibitors of IAP
JP2012500272A (ja) * 2008-08-16 2012-01-05 ジェネンテック， インコーポレイテッド Ｉａｐのアザインドールインヒビター
AU2009293403A1 (en) * 2008-09-17 2010-03-25 Tetralogic Pharmaceuticals Corp. IAP inhibitors
US8841067B2 (en) 2009-01-09 2014-09-23 Dana-Farber Cancer Institute, Inc. NOL3 is a predictor of patient outcome
CN102458116B (zh) * 2009-05-28 2014-12-31 泰特拉洛吉克药业公司 Iap抑制剂
JP5631387B2 (ja) * 2009-05-28 2014-11-26 テトラロジック ファーマシューティカルズ コーポレーション Ｉａｐ阻害剤
CN101928326B (zh) * 2009-06-24 2015-07-08 中国人民解放军军事医学科学院毒物药物研究所 取代的氨酰基五元杂环烷类化合物及其用途
US8283372B2 (en) 2009-07-02 2012-10-09 Tetralogic Pharmaceuticals Corp. 2-(1H-indol-3-ylmethyl)-pyrrolidine dimer as a SMAC mimetic
MX351274B (es) 2009-08-12 2017-10-06 Novartis Ag Formulaciones orales sólidas y formas cristalinas de un inhibidor de la proteína de apoptosis.
JP2013505446A (ja) 2009-09-18 2013-02-14 ノバルティス アーゲー Ｉａｐ阻害剤化合物のためのバイオマーカー
EP2493879B1 (en) 2009-10-28 2014-05-14 Joyant Pharmaceuticals, Inc. Dimeric smac mimetics
NZ602368A (en) 2010-02-12 2014-10-31 Pharmascience Inc Iap bir domain binding compounds
UY33227A (es) 2010-02-19 2011-09-30 Novartis Ag Compuestos de pirrolopirimidina como inhibidores de la cdk4/6
JP5469779B2 (ja) * 2010-04-19 2014-04-16 エスアールアイ インターナショナル 多発性骨髄腫の治療のための組成物および方法
WO2012052758A1 (en) 2010-10-22 2012-04-26 Astrazeneca Ab Response biomarkers for iap antagonists in human cancers
GB201106817D0 (en) 2011-04-21 2011-06-01 Astex Therapeutics Ltd New compound
JP2014528409A (ja) 2011-09-30 2014-10-27 テトラロジック ファーマシューティカルズ コーポレーション 増殖性疾患（がん）の治療において使用するためのＳＭＡＣ模倣体（ビリナパント（ｂｉｒｉｎａｐａｎｔ））
GB201121132D0 (en) * 2011-12-08 2012-01-18 Dow Corning Modifying polymeric materials by amines
GB201121128D0 (en) 2011-12-08 2012-01-18 Dow Corning Treatment of filler with silane
GB201121133D0 (en) * 2011-12-08 2012-01-18 Dow Corning Hydrolysable silanes
GB201121122D0 (en) 2011-12-08 2012-01-18 Dow Corning Hydrolysable silanes and elastomer compositions containing them
GB201121124D0 (en) 2011-12-08 2012-01-18 Dow Corning Hydrolysable silanes
US20130196927A1 (en) * 2012-01-27 2013-08-01 Christopher BENETATOS Smac Mimetic Therapy
KR20150011822A (ko) 2012-05-04 2015-02-02 노파르티스 아게 Iap 억제제 요법을 위한 바이오마커
KR20140011773A (ko) * 2012-07-19 2014-01-29 한미약품 주식회사 이중 저해 활성을 갖는 헤테로고리 유도체
US9498532B2 (en) 2013-03-13 2016-11-22 Novartis Ag Antibody drug conjugates
MX366978B (es) 2013-03-15 2019-08-01 Novartis Ag Conjugados de anticuerpo - farmaco.
US20140303090A1 (en) * 2013-04-08 2014-10-09 Tetralogic Pharmaceuticals Corporation Smac Mimetic Therapy
KR20160030099A (ko) 2013-06-25 2016-03-16 더 월터 앤드 엘리자 홀 인스티튜트 오브 메디컬 리서치 세포내 감염의 치료 방법
GB201311891D0 (en) 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compound
GB201311888D0 (en) 2013-07-03 2013-08-14 Glaxosmithkline Ip Dev Ltd Novel compounds
US9249151B2 (en) * 2013-08-23 2016-02-02 Boehringer Ingelheim International Gmbh Bis-amido pyridines
US9278978B2 (en) * 2013-08-23 2016-03-08 Boehringer Ingelheim International Gmbh 6-Alkynyl Pyridine
CN115368356B (zh) 2013-12-20 2025-05-09 阿斯特克斯治疗有限公司 双环杂环化合物及其治疗用途
WO2015109391A1 (en) 2014-01-24 2015-07-30 Children's Hospital Of Eastern Ontario Research Institute Inc. Smc combination therapy for the treatment of cancer
US20180228907A1 (en) 2014-04-14 2018-08-16 Arvinas, Inc. Cereblon ligands and bifunctional compounds comprising the same
JP6768522B2 (ja) 2014-06-04 2020-10-14 サンフォード−バーンハム メディカル リサーチ インスティテュート Ｈｉｖ治療におけるアポトーシスタンパク質阻害剤（ｉａｐ）のアンタゴニストの使用
WO2016020791A1 (en) 2014-08-05 2016-02-11 Novartis Ag Ckit antibody drug conjugates
MX2017001946A (es) 2014-08-12 2017-06-19 Novartis Ag Conjugados de farmacos con anticuerpos anti-cdh6.
WO2016079527A1 (en) 2014-11-19 2016-05-26 Tetralogic Birinapant Uk Ltd Combination therapy
WO2016097773A1 (en) 2014-12-19 2016-06-23 Children's Cancer Institute Therapeutic iap antagonists for treating proliferative disorders
US12312316B2 (en) 2015-01-20 2025-05-27 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor
JP6817962B2 (ja) 2015-01-20 2021-01-20 アルビナス・オペレーションズ・インコーポレイテッドＡｒｖｉｎａｓ Ｏｐｅｒａｔｉｏｎｓ， Ｉｎｃ． ターゲティングされたアンドロゲン受容体分解のための化合物および方法
CN104592214A (zh) * 2015-02-13 2015-05-06 佛山市赛维斯医药科技有限公司 含葡萄糖酰胺吡啶和烷氧吡嗪结构的化合物及用途
WO2016197114A1 (en) 2015-06-05 2016-12-08 Arvinas, Inc. Tank-binding kinase-1 protacs and associated methods of use
US20190194315A1 (en) 2015-06-17 2019-06-27 Novartis Ag Antibody drug conjugates
CA2988436A1 (en) * 2015-07-13 2017-01-19 Arvinas, Inc. Alanine-based modulators of proteolysis and associated methods of use
EP3337476A4 (en) 2015-08-19 2019-09-04 Arvinas, Inc. Compounds and methods for the targeted degradation of bromodomain-containing proteins
CR20180229A (es) 2015-10-29 2018-08-24 Novartis Ag Conjugados de anticuerpos que comprenden un agonista del receptor tipo toll
CN105585583B (zh) * 2016-01-20 2018-04-13 广东工业大学 一种非肽类凋亡抑制蛋白拮抗剂及其合成方法与应用
CN105566447B (zh) * 2016-01-20 2019-09-20 广东工业大学 一种凋亡抑制蛋白的类肽拮抗剂及其合成方法与应用
CN106188098B (zh) * 2016-07-06 2017-11-03 广东工业大学 一种杂化抗癌药物及其制备方法与应用
SG11201901251SA (en) * 2016-08-29 2019-03-28 Univ Michigan Regents Aminopyrimidines as alk inhibitors
JP6899993B2 (ja) * 2016-10-04 2021-07-07 国立医薬品食品衛生研究所長 複素環化合物
MX2019005007A (es) 2016-11-01 2019-07-18 Arvinas Inc Protac dirigidos a la proteína tau y métodos asociados de uso.
IL266842B (en) 2016-12-01 2022-09-01 Arvinas Operations Inc History of tetrahydronaphthalene and tetrahydroisoquinoline as estrogen receptor antagonists
US10806737B2 (en) 2016-12-23 2020-10-20 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of fetal liver kinase polypeptides
CN110753693A (zh) 2016-12-23 2020-02-04 阿尔维纳斯运营股份有限公司 Egfr蛋白水解靶向嵌合分子和相关使用方法
IL325835A (en) 2016-12-23 2026-03-01 Univ Yale Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
US11173211B2 (en) 2016-12-23 2021-11-16 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of rapidly accelerated Fibrosarcoma polypeptides
US11191741B2 (en) 2016-12-24 2021-12-07 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide
IL300417A (en) 2017-01-26 2023-04-01 Arvinas Operations Inc Bifunctional benzothiophene compounds, preparations containing them and their use in therapy
JOP20190187A1 (ar) 2017-02-03 2019-08-01 Novartis Ag مترافقات عقار جسم مضاد لـ ccr7
WO2018163051A1 (en) 2017-03-06 2018-09-13 Novartis Ag Methods of treatment of cancer with reduced ubb expression
WO2018185618A1 (en) 2017-04-03 2018-10-11 Novartis Ag Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment
AR111651A1 (es) 2017-04-28 2019-08-07 Novartis Ag Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación
US20200362058A1 (en) 2017-05-24 2020-11-19 Novartis Ag Antibody-cytokine engrafted proteins and methods of use
KR102920712B1 (ko) 2017-05-24 2026-01-30 노파르티스 아게 항체-사이토카인 생착된 단백질 및 암 치료에 있어서의 사용 방법
WO2018215937A1 (en) 2017-05-24 2018-11-29 Novartis Ag Interleukin-7 antibody cytokine engrafted proteins and methods of use in the treatment of cancer
CN111247161B (zh) * 2017-11-13 2021-12-31 正大天晴药业集团股份有限公司 用作iap抑制剂的smac模拟物及其用途
US11065231B2 (en) 2017-11-17 2021-07-20 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides
WO2019177902A1 (en) 2018-03-10 2019-09-19 Yale University Modulators of btk proteolysis and methods of use
BR112020020307A2 (pt) 2018-04-04 2021-01-12 Arvinas Operations, Inc. Moduladores de proteólise e métodos de uso associados
AR116109A1 (es) 2018-07-10 2021-03-31 Novartis Ag Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos
BR122022012697B1 (pt) 2018-07-10 2023-04-04 Novartis Ag Usos de derivados de 3-(5-hidróxi-1-oxoisoindolin-2-il)piperidina-2,6- diona, e kit
US20200038513A1 (en) 2018-07-26 2020-02-06 Arvinas Operations, Inc. Modulators of fak proteolysis and associated methods of use
US11707452B2 (en) 2018-08-20 2023-07-25 Arvinas Operations, Inc. Modulators of alpha-synuclein proteolysis and associated methods of use
CN119219628A (zh) 2018-09-07 2024-12-31 阿尔维纳斯运营股份有限公司 用于迅速加速性纤维肉瘤多肽的靶向降解的多环化合物和方法
EP3873532A1 (en) 2018-10-31 2021-09-08 Novartis AG Dc-sign antibody drug conjugates
AU2019402189B2 (en) 2018-12-20 2023-04-13 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
AU2019409132B2 (en) 2018-12-21 2026-08-06 Novartis Ag Antibodies to PMEL17 and conjugates thereof
EP3924054B1 (en) 2019-02-15 2025-04-02 Novartis AG 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
CA3123519A1 (en) 2019-02-15 2020-08-20 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020228642A1 (zh) * 2019-05-10 2020-11-19 正大天晴药业集团股份有限公司 一种用作iap抑制剂的smac模拟物的结晶及其制备方法
EP3999182A1 (en) 2019-07-17 2022-05-25 Arvinas Operations, Inc. Tau-protein targeting compounds and associated methods of use
JP2022542437A (ja) 2019-08-02 2022-10-03 ランティオペプ ベスローテン ヴェンノーツハップ 癌の処置に用いるアンジオテンシン２型（ａｔ２）受容体アゴニスト
WO2021041348A1 (en) 2019-08-26 2021-03-04 Arvinas Operations, Inc. Methods of treating breast cancer with tetrahydronaphthalene derivatives as estrogen receptor degraders
US12678509B2 (en) 2019-11-08 2026-07-14 Sanford Burnham Prebys Medical Discovery Institute Inhibitor of apoptosis (IAP) protein antagonists
US20230057071A1 (en) 2019-12-20 2023-02-23 Novartis Ag Combination of anti tim-3 antibody mbg453 and anti tgf-beta antibody nis793, with or without decitabine or the anti pd-1 antibody spartalizumab, for treating myelofibrosis and myelodysplastic syndrome
US20230056604A1 (en) 2020-01-20 2023-02-23 Astrazeneca Ab Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer
HUP2200468A1 (hu) 2020-04-29 2023-03-28 X Chem Zrt IAP antagonisták és gyógyászati alkalmazásuk
US20230181756A1 (en) 2020-04-30 2023-06-15 Novartis Ag Ccr7 antibody drug conjugates for treating cancer
US20230332104A1 (en) 2020-06-11 2023-10-19 Novartis Ag Zbtb32 inhibitors and uses thereof
EP4168007A1 (en) 2020-06-23 2023-04-26 Novartis AG Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
EP4188549A1 (en) 2020-08-03 2023-06-07 Novartis AG Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2022047145A1 (en) 2020-08-28 2022-03-03 Arvinas Operations, Inc. Rapidly accelerating fibrosarcoma protein degrading compounds and associated methods of use
AU2021342287A1 (en) 2020-09-14 2023-04-13 Arvinas Operations, Inc. Crystalline forms of a compound for the targeted degradation of estrogen receptor
TW202304979A (zh) 2021-04-07 2023-02-01 瑞士商諾華公司 抗ＴＧＦβ抗體及其他治療劑用於治療增殖性疾病之用途
AU2022258829A1 (en) 2021-04-16 2023-10-26 Novartis Ag Antibody drug conjugates and methods for making thereof
AR125874A1 (es) 2021-05-18 2023-08-23 Novartis Ag Terapias de combinación
WO2023214325A1 (en) 2022-05-05 2023-11-09 Novartis Ag Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors
JP2025524064A (ja) 2022-07-26 2025-07-25 ノバルティス アーゲー Ａｋｒ１ｃ３依存性ｋａｒｓ阻害剤の結晶形態
EP4584258A1 (en) 2022-09-07 2025-07-16 Arvinas Operations, Inc. Rapidly accelerated fibrosarcoma (raf) degrading compounds and associated methods of use
PE20260006A1 (es) 2023-01-26 2026-01-06 Arvinas Operations Inc Protacs degradadores de kras basados en cereblon y usos relacionados con los mismos
EP4729523A1 (en) * 2024-10-16 2026-04-22 Prosion GmbH Bicyclic dipeptide mimetics and their use

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278793A (en) * 1977-04-02 1981-07-14 Hoechst Aktiengesellschaft Cephem derivative
US4720484A (en) * 1985-01-07 1988-01-19 Adir S.A.R.L. Peptide compounds having a nitrogenous polycyclic structure
US5411942A (en) * 1989-12-07 1995-05-02 Carlbiotech Ltd. A/S Peptide derivative, pharmaceutical preparation containing it and method for treatment of glaucoma
US5559209A (en) * 1993-02-18 1996-09-24 The General Hospital Corporation Regulator regions of G proteins
US6472172B1 (en) * 1998-07-31 2002-10-29 Schering Aktiengesellschaft DNA encoding a novel human inhibitor-of-apoptosis protein
US20020160975A1 (en) * 2001-02-08 2002-10-31 Thomas Jefferson University Conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO for mediating apoptosis
US6608026B1 (en) * 2000-08-23 2003-08-19 Board Of Regents, The University Of Texas System Apoptotic compounds
US20030157522A1 (en) * 2001-11-09 2003-08-21 Alain Boudreault Methods and reagents for peptide-BIR interaction screens
US20040171554A1 (en) * 2003-02-07 2004-09-02 Genentech, Inc. Compositions and methods for enhancing apoptosis
US20050197403A1 (en) * 2004-03-01 2005-09-08 Board Of Regents, The University Of Texas System Dimeric small molecule potentiators of apoptosis
US20050214802A1 (en) * 2003-11-13 2005-09-29 Genentech, Inc. Compositions and methods for the screening pro-apoptotic compounds
US20060167066A1 (en) * 2004-12-20 2006-07-27 Genentech, Inc. Pyrrolidine inhibitors of IAP
US7419975B2 (en) * 2004-04-07 2008-09-02 Novartis Ag Organic compounds

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1524747A (en) 1976-05-11 1978-09-13 Ici Ltd Polypeptide
DE3372965D1 (en) 1982-07-23 1987-09-17 Ici Plc Amide derivatives
JPS59141547A (ja) 1983-02-01 1984-08-14 Eisai Co Ltd 鎮痛作用を有する新規ペプタイドおよび製法
GB8327256D0 (en) 1983-10-12 1983-11-16 Ici Plc Steroid derivatives
US5093330A (en) 1987-06-15 1992-03-03 Ciba-Geigy Corporation Staurosporine derivatives substituted at methylamino nitrogen
US5010099A (en) 1989-08-11 1991-04-23 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds, compositions containing same and method of preparation and use
NZ243082A (en) 1991-06-28 1995-02-24 Ici Plc 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof
AU661533B2 (en) 1992-01-20 1995-07-27 Astrazeneca Ab Quinazoline derivatives
TW225528B (sr) 1992-04-03 1994-06-21 Ciba Geigy Ag
GB9314893D0 (en) 1993-07-19 1993-09-01 Zeneca Ltd Quinazoline derivatives
ATE446955T1 (de) 1995-03-30 2009-11-15 Pfizer Prod Inc Chinazolinone derivate
GB9508538D0 (en) 1995-04-27 1995-06-14 Zeneca Ltd Quinazoline derivatives
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
US5843901A (en) 1995-06-07 1998-12-01 Advanced Research & Technology Institute LHRH antagonist peptides
PL188959B1 (pl) 1995-07-06 2005-05-31 Novartis Ag Pirolopirymidyny i sposoby ich wytwarzania
US5760041A (en) 1996-02-05 1998-06-02 American Cyanamid Company 4-aminoquinazoline EGFR Inhibitors
GB9603095D0 (en) 1996-02-14 1996-04-10 Zeneca Ltd Quinazoline derivatives
CN100503580C (zh) 1996-04-12 2009-06-24 沃尼尔·朗伯公司 酪氨酸激酶的不可逆抑制剂
BR9709959A (pt) 1996-06-24 2000-05-09 Pfizer Derivados tricìclicos de fenilamino substituìdo para o tratamento de doenças hiperproliferativas
AU716610B2 (en) 1996-08-30 2000-03-02 Novartis Ag Method for producing epothilones, and intermediate products obtained during the production process
DE938597T1 (de) 1996-09-06 2000-03-09 Obducat Ab Verfahren für das anisotrope ätzen von strukturen in leitende materialien
WO1998010767A2 (en) 1996-09-13 1998-03-19 Sugen, Inc. Use of quinazoline derivatives for the manufacture of a medicament in the treatment of hyperproliferative skin disorders
EP0837063A1 (en) 1996-10-17 1998-04-22 Pfizer Inc. 4-Aminoquinazoline derivatives
ATE267197T1 (de) 1996-11-18 2004-06-15 Biotechnolog Forschung Gmbh Epothilon d, dessen herstellung und dessen verwendung als cytostatisches mittel bzw. als pflanzenschutzmittel
US6441186B1 (en) 1996-12-13 2002-08-27 The Scripps Research Institute Epothilone analogs
CO4940418A1 (es) 1997-07-18 2000-07-24 Novartis Ag Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso
GB9721069D0 (en) 1997-10-03 1997-12-03 Pharmacia & Upjohn Spa Polymeric derivatives of camptothecin
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
CA2322157C (en) 1998-02-25 2012-05-29 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
ES2342240T3 (es) 1998-08-11 2010-07-02 Novartis Ag Derivados de isoquinolina con actividad que inhibe la angiogenia.
CN100381566C (zh) 1998-11-20 2008-04-16 科森生物科学公司 产生环氧噻酮及其衍生物的重组方法和材料
NZ516918A (en) 2000-05-23 2004-06-25 Vertex Pharma Caspase inhibitors and uses thereof
PE20020354A1 (es) 2000-09-01 2002-06-12 Novartis Ag Compuestos de hidroxamato como inhibidores de histona-desacetilasa (hda)
WO2004007529A2 (en) * 2002-07-15 2004-01-22 The Trustees Of Princeton University Iap binding compounds
TWI238824B (en) 2001-05-14 2005-09-01 Novartis Ag 4-amino-5-phenyl-7-cyclobutyl-pyrrolo[2,3-d]pyrimidine derivatives
GB0119249D0 (en) 2001-08-07 2001-10-03 Novartis Ag Organic compounds
CA2491041A1 (en) * 2002-07-02 2004-01-15 Novartis Ag Peptide inhibitors of smac protein binding to inhibitor of apoptosis proteins (iap)
CN1933847A (zh) 2004-01-16 2007-03-21 密歇根大学董事会 Smac肽模拟物及其应用
KR100926203B1 (ko) 2004-07-02 2009-11-09 제넨테크, 인크. Ｉａｐ의 억제제
PE20110217A1 (es) 2006-08-02 2011-04-01 Novartis Ag DERIVADOS DE 2-OXO-ETIL-AMINO-PROPIONAMIDA-PIRROLIDIN-2-IL-SUSTITUIDOS COMO INHIBIDORES DEL ENLACE DE LA PROTEINA Smac AL INHIBIDOR DE LA PROTEINA DE APOPTOSIS

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278793A (en) * 1977-04-02 1981-07-14 Hoechst Aktiengesellschaft Cephem derivative
US4720484A (en) * 1985-01-07 1988-01-19 Adir S.A.R.L. Peptide compounds having a nitrogenous polycyclic structure
US5411942A (en) * 1989-12-07 1995-05-02 Carlbiotech Ltd. A/S Peptide derivative, pharmaceutical preparation containing it and method for treatment of glaucoma
US5559209A (en) * 1993-02-18 1996-09-24 The General Hospital Corporation Regulator regions of G proteins
US6472172B1 (en) * 1998-07-31 2002-10-29 Schering Aktiengesellschaft DNA encoding a novel human inhibitor-of-apoptosis protein
US6608026B1 (en) * 2000-08-23 2003-08-19 Board Of Regents, The University Of Texas System Apoptotic compounds
US20020160975A1 (en) * 2001-02-08 2002-10-31 Thomas Jefferson University Conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO for mediating apoptosis
US20030157522A1 (en) * 2001-11-09 2003-08-21 Alain Boudreault Methods and reagents for peptide-BIR interaction screens
US20040171554A1 (en) * 2003-02-07 2004-09-02 Genentech, Inc. Compositions and methods for enhancing apoptosis
US20050214802A1 (en) * 2003-11-13 2005-09-29 Genentech, Inc. Compositions and methods for the screening pro-apoptotic compounds
US20050197403A1 (en) * 2004-03-01 2005-09-08 Board Of Regents, The University Of Texas System Dimeric small molecule potentiators of apoptosis
US7419975B2 (en) * 2004-04-07 2008-09-02 Novartis Ag Organic compounds
US20060167066A1 (en) * 2004-12-20 2006-07-27 Genentech, Inc. Pyrrolidine inhibitors of IAP

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110034469A1 (en) * 2009-08-04 2011-02-10 Takeda Pharmaceutical Company Limited Heterocyclic Compound

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