WO2004046101A2 - Cyanoguanidines and cyanoamidines as erbb2 and egfr inhibitors - Google Patents

Cyanoguanidines and cyanoamidines as erbb2 and egfr inhibitors Download PDF

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Publication number
WO2004046101A2
WO2004046101A2 PCT/US2003/035670 US0335670W WO2004046101A2 WO 2004046101 A2 WO2004046101 A2 WO 2004046101A2 US 0335670 W US0335670 W US 0335670W WO 2004046101 A2 WO2004046101 A2 WO 2004046101A2
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compound
heteroaryl
aryl
heterocyclyl
heteroarylalkyl
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PCT/US2003/035670
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English (en)
French (fr)
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WO2004046101A3 (en
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Eli Wallace
George Topalov
Qian Zhao
Joseph P. Lyssikatos
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Array Biopharma, Inc.
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Priority to NZ540092A priority Critical patent/NZ540092A/en
Priority to CA002506503A priority patent/CA2506503A1/en
Priority to JP2004553551A priority patent/JP4611745B2/ja
Priority to EP03768789A priority patent/EP1567506A4/en
Priority to MXPA05005370A priority patent/MXPA05005370A/es
Priority to AU2003291394A priority patent/AU2003291394B2/en
Publication of WO2004046101A2 publication Critical patent/WO2004046101A2/en
Publication of WO2004046101A3 publication Critical patent/WO2004046101A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/02—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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to a series of cyanoguanidine quinazoline and cyanoamidine quinazoline derivatives that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals.
  • This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
  • the type I receptor tyrosine kinase family consists of four closely related receptors: EFGR (ErbBl or HERl), ErbB2 (HER2), ErbB3 (HER) and ErbB4 (HER4). These are transmembrane glycoprotein receptors which contain an extracellular ligand binding region and, with the expection of erbB3, an intracellular catalytically active tyrosine kinase domain. These receptors transmit extracellular signals through the cytosol to the nucleus. The extracellular signal is transmitted by ligand binding to the homomeric receptor, with the exception of erbB2, of which a high affinity soluble ligand has yet to be identified.
  • EFGR ErbBl or HERl
  • HER2 ErbB2
  • HER3 ErbB3
  • HER4 ErbB4
  • the type I receptor tyrosine ' kinases either homodimerize or heterodimerize with another member of the subfamily of recept ⁇ rs.
  • ErbB2 participates in this process by heteromerization.
  • erbB2 is the preferred heterodimerization partner (Mehelsohn Oncogene 2000). Dimerization leads to activation by autophosphorylation of the intracellular domain. This autophosphorylation recruits other proteins and leads to a phosphorylation cascade that transmits the signal throughout the cell.
  • the type I receptor tyrosine kinase family signals through the ras/raf/MEK/MAPK pathway as well as the PI3K/Akt pathway. These signaling pathways lead to both cell proliferation and cell survival through inhibition of apoptosis.
  • EGFR and ErbB2 have demonstrated the role of EGFR and ErbB2 in cancer. Squamous carcinomas of the head and neck, and lung express high levels of EGFR. Also, constitutively active EGFR has been found in gliomas, breast cancer and lung cancer (Salomon et al Crit Rev Oncol Hematol 1995, 19, 183-232 - on order 6/4/02). ErbB2 overexpression occurs in ⁇ 30% of all breast cancer. It has been also implicated in other human cancers including colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate. ErbB2 overexpression has also been correlated with poor prognosis in human cancer, including metastasis, and early relapse (ref - two Slamon refs from Science and Klapper review).
  • the type I tyrosine kinase receptor family has been an active area of anti-cancer research.
  • Several inhibitors of the EGFR and the ErbB2 signaling pathway have demonstrated clinical efficacy in cancer treatment.
  • Herceptin a humanized version of anti-ErbB2 monoclonal antibody, was approved for use in breast cancer in the United States in 1998.
  • Iressa and Tarceva are small molecule inhibitors of EGFR that are expected to be launched in 2002.
  • several other antibodies and small molecules that target the interruption of the type I tyrosine kinase receptor signaling pathways are in clinical and preclinical development (Ciardiello et al).
  • This invention provides for cyanoguanidine and cyanoamidine substituted 4-anilino quinazolines of formula I, and pharmaceutically acceptable salts and prodrugs thereof, that are useful in the treatment of hyperproliferative diseases.
  • the present invention relates to compounds of formula I that act as EGFR and/or ErbB2 inhibitors. Also provided are formulations containing compounds of formula I and methods of using the compounds to treat a patient in need thereof. In addition, there are described processes for preparing the inhibitory compounds of formula I.
  • X is N, CH or a C-CN group
  • R 1 is independently an aryl or heteroaryl group, substituted by at least one one R 6 group, and optionally substituted by up to three R 5 groups, where
  • R 5 is cyano, chlorine, fluorine, bromine, lower alkyl, trifluoromethyl, difluoromethyl, nitro or OR 9 ;
  • R 6 is hydrogen, cyano, chlorine, fluorine, bromine, trifluoromethyl, difiuoromethyl, trifluoromethoxy, nitro, Ci-Cio alkyl, C2- 0 alkenyl, C 2 -C ⁇ o alkynyl, C3-C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, where each C1-C10 alkyl, C2-C10 alkenyl, C 2 -C ⁇ o alkynyl, C3-C10 cycloalkyl, C 3 -C 1 0 cycloalkylalkyl, aryl, arylalkyl, hetero
  • R 7 and R 10 independently represent hydrogen or C ⁇ - 6 alkyl, or R 7 and R 10 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with up to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
  • R 8 represents trifluoromethyl, C1-C 1 0 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
  • R 9 represents represents hydrogen, trifluoromethyl, C 1 - 0 alkyl, (CH 2 ) n C 3 -C ⁇ o cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or hetero
  • R 13 represents trifluoromethyl, difluoromethyl, Cj-Cio alkyl, C3-C10 alkenyl, C 3 -C 10 alkynyl, C3-C 1 0 cycloalkyl, C 3 -C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, where each of the above alkyl, alkenyl, alkynyl, cycloalkyl,
  • I ⁇ aryl, heteroaryl and heterocyclyl portion of R is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 7 SO 2 R 8 , -SO 2 NR 9 R 7 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -NR 7 C(O)OR 8 , -NR 7 C(O)R 9 , -C(O)NR 7 R 9 , -NR 7 R 9 , -NR ,0 C(O)NR 7 R 9 , -NR l0 C(NCN)NR 7 R 9 , - OR , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where R , R 8 , R 9 and R 10 are the
  • R represents hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, trifluoromethoxy, -C 10 alkyl, C 2 -C 1 0 alkenyl, C 2 -C 1 0 alkynyl, C3-C10 cycloalkyl, C 3 -C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with up to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 7 SO 2 R 8 , -SO 2 NR 9 R 7 , -C(O)R 9 ,
  • T represents Ci-Cio alkyl, C 2 -C10 alkenyl, C2-C 1 0 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with up to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 7 SO 2 R 8 , -SO 2 NR 9 R 7 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -NR 7 C(O)OR 8 , -NR 7 C
  • L is a nitrogen atom or a CR 4 group where R 4 represents hydrogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, Ci-Cio alkyl, C 2 -C ⁇ o alkenyl, C 2 -C ⁇ o alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 1 0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with up to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 7 SO 2 R 8 , -SO 2 NR 9 R 7 , -C(
  • Q is selected from CR 3 R U R 12 or NR ⁇ R 12 , where R 3 is the same as R 2 defined above and R 11 and R 12 independently represent hydrogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, C1-C 1 0 alkyl, C 2 -C 1 0 alkenyl, C 2 -C ⁇ o alkynyl, C3-C 1 0 cycloalkyl, C3-C 1 0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NR 7 SO 2 R 8 , -SO 2 NR 9 R 7 , -C(O)R 9 , -C(O)OR 9 , -OC( )R 9 , -NR 7 C(O)OR 8 , -NR 7 C(O)R 9 , -C(O)NR 7 R 9 , -NR 7
  • D represents hydrogen, trifluoromethyl, difluoromethyl, Ci-Cio alkyl, C 2 -C ⁇ o alkenyl, C 2 - Cio alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl,
  • heteroarylalkyl heterocyclyl, heterocyclylalkyl, -SO 2 NR 9 R 7 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 or -C(O)NR 7 R 9 , where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with up to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 7 SO 2 R 8 , - SO 2 NR 9 R 7 , -C(O)R 9 , -C(O)OR 9 , -OC(O)R 9 , -NR 7 C(O)OR 8 , -NR 7 C(O)R 9 , -C(O)NR 7 R 9 , -NR 7 R 9
  • R 2 examples of preferred embodiments of R 2 include, but are not limited to:
  • a method of treating hyperproliferative disease comprising administering to a mammal a therapeutically effective amount of a compound of the invention.
  • novel compounds encompassed by the instant invention are those described by the general formula I set forth above, including enantiomers, diastereosisomers, tautomers, pharmaceutically acceptable salts, and prodrugs thereof.
  • Ci-Cio alkyl straight or branched chain alkyl groups having 1-10 carbon atoms, 1 such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3- methylpentyl, heptyl, octyl, and the like.
  • Preferred alkyl radicals are Cj_ 6 alkyls. More preferred alkyl radicals are C 1 . 3 alkyls.
  • C 2 -C 10 alkenyl means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least one double bond and includes ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the like.
  • the preferred alkenyls are lower alkenyl having 3-5 carbon atoms.
  • C 2 -C 10 alkynyl means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and at least one triple bond and includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.
  • the preferred alkynyls are alkynyl having 3-5 carbon atoms.
  • halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
  • aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and hydroxy.
  • heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings which includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur.
  • heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
  • Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
  • the terms "carbocycle”, “carbocyclyl”, “cycloalkyl” or “C3-C 1 0 cycloalkyl” refer to saturated carbocyclic radicals having . three to ten carbon atoms.
  • the cycloalkyl can be monocyclic, or a polycyclic fused system, and can be fused to an aromatic ring. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • such cycloalkyl groups may be optionally substituted with, for example, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C ⁇ -C6)alkylamino, di(C ⁇ -.C6)alkylamino, CrC ⁇ alkenyl, CrC ⁇ alkynyl, C ⁇ -C 6 haloalkyl, Ci-C ⁇ haloalkoxy, amino(C ⁇ -C6)alkyl, mono(C ⁇ -C6)alkylamino(C ⁇ -C 6 )alkyl or di(C ⁇ - C 6 )alkylamino(C C 6 )alkyl.
  • heterocycle or “heterocyclyl” is meant one or more carbocyclic ring systems of 5-, 6-, or 7-membered rings which includes fused ring systems of 4-10 atoms containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur, and with the proviso that the ring of the group does not contain two adjacent O or S atoms.
  • a fused system can be a heterocycle fused to an aromatic group.
  • Preferred heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydro ⁇ yridinyl, 2-pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxplanyl,
  • Spiro moieties are also included within the scope of this definition.
  • the foregoing groups, as derived from the groups listed above, may be C-attached or N-attached where such is possible.
  • a group derived from pyrrole may be pyrrol- 1- yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • heterocycle groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • such heterocycle groups may be optionally substituted with, for example, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C ⁇ -C6)alkylamino, di(C ⁇ -C6)alkylamino, C 2 -C6alkenyl, C 2 -C 6 alkynyl, C 1 -C6 haloalkyl, CrC 6 haloalkoxy, amino(C ⁇ -C6)alkyl, mono(C ⁇ -C6)alkylamino(C ⁇ -C 6 )alkyl or di(C ⁇ -C 6 )alkylamino(C ⁇ -C 6 )alkyl.
  • arylalkyl means an alkyl moiety (as defined above) substituted with one or more aryl moiety (also as defined above).
  • the preferred aralkyl radicals are aryl-C ⁇ . 3 .alkyls. Examples include benzyl, phenylethyl, and the like.
  • heteroarylalkyl means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (also as defined above).
  • the preferred heteroarylalkyl radicals are 5- or 6- membered heteroaryl-C ⁇ .3.alkyl. Examples include oxazolemethyl, pyridylethyl and the like.
  • Me means methyl
  • Et means ethyl
  • Bu means butyl
  • Ac means acetyl
  • phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic and basic groups which may be present in the compounds of formula 1 or of the compounds made in accordance with the examples herein.
  • the compounds of formula 1 that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula 1 as well as the compounds prepared in the examples are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesy
  • phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic and basic groups which may be present in the compounds of formula 1.
  • the compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula 1 are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyatej estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate
  • Those compounds of the present invention that are acidic in nature are capable of forming basic salts with various pharmaceutically acceptable cations.
  • examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
  • Certain compounds of formula I may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula I, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula I, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • the subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Isotopically labeled compound of formula I of this invention and prodrugs thereof can generally be prepared by carrying out procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • This invention also encompasses pharmaceutical compositions containing and methods of treating proliferative disorders, or abnormal cell growth, by administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of formula I.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and' sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities,, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • radical arylalkyl is attached to the structure in question by the alkyl group.
  • the compounds of the invention are administered either singly or in combination to a mammal to treat hyperproliferative disease, such as various types of cancer, e.g., cancer of the colon, ovary, bladder, stomach, lung, uterus, and prostate.
  • hyperproliferative disease such as various types of cancer, e.g., cancer of the colon, ovary, bladder, stomach, lung, uterus, and prostate.
  • the compound may be administered via any acceptable route, e.g., intra venous, oral, intra muscular, via suppository, etc.
  • the compounds can be formulated as oral dosage forms, e.g., tablets, capsules, liquid suspension, etc, as suppositories, or may be. prepared as a liquid for injection, for example.
  • the skilled practitioner can select the appropriate route and dosage amount for treatment of the specific hyperproliferative disease to be treated.
  • Step A 6-iodo-4-quinazolinone.
  • Step B 4-chloro-6-iodoquinazoline.
  • reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml).
  • DCM approximately 500 ml
  • the aqueous layer is further extracted with DCM (2x50 ml).
  • the combined organic extracts are dried (Na 2 SO ) and concentrated under reduced pressure to yield 5.2 g (99%) of desired product as a tan solid.
  • Step C 2-chloro-l-(3-fluoro-benzyloxy)-4-nitro-benzene.
  • Step D 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine.
  • Step E [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride salt.
  • Step F (3- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -prop-2-ynyl)- carbamic acid tert-butyl ester.
  • Step G [6-(3-amino-pro ⁇ -l -ynyl)-quinazolin-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]- amine.
  • Step H 1 -(3- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -prop-2-ynyl)- 2-phenyl-N-cyano-isourea.
  • Step I N-(3- ⁇ 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ - ⁇ rop-2-ynyl)- N'-cyano-N",N"-dimethylguanidine.
  • Step B 3-memyl-4-(6-memyl-pyridin-3-yloxy)-phenylamine
  • Step D (3 - ⁇ 4- [3 -Methyl-4-(6-methyl-pyridin-3 -yloxy)-phenylamino] -quinazolin-6-yl ⁇ -prop-2- ynyl)-carbamic acid tert-butyl ester.
  • Step E [6-(3-Amino-prop-l-ynyl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenyl]-amine.
  • Step F N-cyano-N'-(3- ⁇ 4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl ⁇ -prop-2-ynyl)guanidine.
  • Step A furan-2-ylmethyl-carbamic acid tert-butyl ester.
  • Step B (5- ⁇ 4-[3-ChIoro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -furan-2-
  • Step C [6-(5- Aminomethyl-furan-2-yl)-quinazolin-4-yl] - [3 -chloro-4-(3 -fluoro-benzyloxy)- phenylj-amine.
  • Step D l-(5- ⁇ 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -furan-2-
  • phenyl]-amine 148 mg, 0.313 mmol
  • diphenyl cyanocarbonimidate 83 mg, 0.348 mmol
  • a 1:2 THF:i-PrOH mixture 9 ml
  • Step E N-(5- ⁇ 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -furan-2- ylmethyl)-N'-cyano-morpholine-4-carboxamidine.
  • 2,4-Dibromothiazole (4.31 g, 17.7 mmol) are dissolved in anhydrous diethyl ether (170 ml) and the solution is cooled to -78 °C (dry ice-acetone bath).
  • n-Butyllithium (1.6 M in hexanes, 13 ml, 20.8 mmol) is added dropwise to the reaction mixture and the resulting solution is stirred at the same temperature for 30 minutes.
  • Anhydrous DMF (ml, mmol) is then added at - 78 °C and, after being stirred at the -78 °C for 30 minutes, the reaction mixture is warmed to room temperature over a period of 2 hours.
  • Step B 2-Azidomethyl-4-bromo-thiazole.
  • Step E (4-Trimethylstannyl- thiazol-2-ylmethyl)-carbamic acid tert-butyl ester
  • Step F (4- ⁇ 4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]quinazolin-6-yl ⁇ -thiazol-2- ylmethyl)-carbamic acid ter-butyl ester
  • Step G [6-(2-Aminomethyl-thiazol-4-yl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3- yloxy)-phenyl]-amine
  • Step H l-(4- ⁇ 4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]quinazolin-6-yl ⁇ -thiazol- 2-ylmethyl)-2-phenyl-N-cyano isourea
  • Step I N-cyano-N'-(4- ⁇ 4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl ⁇ -thiazol-2-ylmethyl)guanidine l-(4- ⁇ 4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]quinazolin-6-yl ⁇ -thiazol- 2-ylmethyl)-2-phenyl-N-cyano isourea (8.4 mg, 0.014 mmol) is dissolved in a 1:1 mixture of THF:i-PrOH (2 ml), and treated with 2.0 M ammonia solution in MeOH (0.1 ml).
  • Step E Acetic acid 4-hydroxy-7-methoxy-quinazolin-6-yl ester
  • Step F Acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester
  • reaction mixture is poured into excess ice: water mixture (100 mL) and extracted with DCM (500 mL). The aqueous layer is further extracted with DCM (2x50 mL). The combined organic extracts are dried (Na 2 SO ) and concentrated under reduced pressure to yield 5.63 g (22.34 mmol, 80%) of desired product as a tan solid.
  • Step G 4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-ol
  • Step H (3- ⁇ 4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6- yloxy ⁇ -propyl)-carbamic acid tert-butyl ester
  • Step I [6-(3-Amino-pro ⁇ oxy)-7-methoxy-quinazolin-4-yl]-[3-chloro-4-(pyridin-2-ylmethoxy)- phenyl] -amine
  • Step J N-(3- ⁇ 4-[3-ChIoro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6- yloxy ⁇ -propyl)-N'-cyano-N"-(2-dimethylamino-ethyl)-N"-methylguanidine
  • Step A l-(3-Fluoro-benzyl)-5-nitro-lH-indazole
  • Step C [l-(3-Fluoro-benzyl)-lH-indazol-5-yl]-(6-iodo-quinazolin-4-yl)-amine hydrochloride
  • step E 4-chloro-6-iodoquinazoline (1.18 g, 4.06 mmol) is mixed with l-(3-Fluoro-benzyl)-lH-indazol-5-ylamine (1.09 g, 4.52 mmol), and a mixture of DCE (10ml) and t-BuOH (10 ml) is added. The mixture is heated at 90 °C (oil bath temperature) for 8 hours. At 5 hours of heating LC/MS reveals substantial amount of product. Yield is 1.35 g (56%).
  • Step D (3- ⁇ 4-[l-(3-Fluoro-benzyl)-lH-indazol-5-ylamino]-quinazolin-6-yl ⁇ -prop-2-ynyl)- carbamic acid tert-butyl ester
  • Step E [6-(3-Amino-prop- 1 -ynyl)-quinazolin-4-yl]-[ 1 -(3-fluoro-benzyl)-l H-indazol-5-yl]-amine
  • Step F l-(3- ⁇ 4-[l-(3-Fluoro-benzyl)-lH-indazol-5-ylamino]-quinazolin-6-yl ⁇ -prop-2-ynyl)-2- phenyl-3-cyano-isourea
  • Step G N-cyano-N'-(3- ⁇ 4-[l-(3-Fluoro-benzyl)-lH-indazol-5-ylamino]-quinazolin-6-yl ⁇ -prop- 2-ynyl)-morpholine-4-carboxamidine
  • Step B [6-(3-Amino-propenyl)-quinazolin-4-yl]-[l-(3-fluoro-benzyl)-lH-indazol-5-yl]-amine
  • step E The desired product was obtained through a procedure analogous to the one outlined in Example 9, step E.
  • Step C l-(3- ⁇ 4-[l-(3-Fluoro-benzyl)-lH-indazol-5-ylamino]-quinazolin-6-yl ⁇ -allyl)-2-phenyl-3- cyano-isourea
  • Step D N-cyano-N'-(3- ⁇ 4-[l-(3-Fluoro-benzyl)-lH-indazol-5-ylamino]-quinazolin-6-yl ⁇ -allyl)- N"-(2-methoxy-ethyl)-N"-methylguanidine
  • the extent to which the compounds of the present invention modulate ErbB kinase activity can be determined using the following enzyme-linked immunosorbent assay (ELISA), which employs a microtiter plate coated with a protein tyrosine kinase specific polymer substrate. The phosphorylation reaction is performed on poly-Glu-Tyr 4:1 (PGT) coated
  • microtiter plates in the presence on Mg* "1" , ATP and EGFR.
  • the phosphorylated polymer substrate is detected with a phosphotyrosine specific monoclonal antibody conjugated to horseradish peroxidase (HRP).
  • HRP horseradish peroxidase
  • TMB Chromogenic substrate
  • the assay is performed in a 96-well microtiter plate (Immunlon 4, available from
  • microtiter plates may be stored at 2-8 °C with 150 ⁇ L of 0.1% Tween 20 in PBS in each well.
  • the compound to be tested is dissolved in DMSO at an initial concentration of 1.0 mM. This initial concentration is diluted 1 :25 in DMSO, and the resulting solution is further serially
  • Reaction Buffer 50 mM HEPES, 125 mM NaCl, 24 mM MgCl 2 , 0.1 mM Na 3 VO 4 (boiled at pH 10 until colorless - approximately 10 minutes - and cooled prior to use), pH 7.3,
  • Buffer for control is placed in a separate microtiter plate well, along with 50 ⁇ L Reaction Buffer
  • the optical density at 450 nm of each well is determined using a microtiter plate reader.
  • a dose response curve is generated by plotting optical density versus compound concentration. IC 50 is calculated from this curve using methods known in the art.

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NZ540092A NZ540092A (en) 2002-11-20 2003-11-10 Cyanoguanidines and cyanoamidines as ErbB2 and EGFR inhibitors
CA002506503A CA2506503A1 (en) 2002-11-20 2003-11-10 Cyanoguanidines and cyanoamidines as erbb2 and egfr inhibitors
JP2004553551A JP4611745B2 (ja) 2002-11-20 2003-11-10 ＥｒｂＢ２及びＥＧＦＲ阻害剤としてのシアノグアニジン及びシアノアミジン
EP03768789A EP1567506A4 (en) 2002-11-20 2003-11-10 CYANOGUANIDINES AND CYANOAMIDINES AS INHIBITORS OF ERBB2 AND EGFR
MXPA05005370A MXPA05005370A (es) 2002-11-20 2003-11-10 Cianoguanidinas y cianoamidinas como inhibidores de erbb2 y egfr.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016347A1 (en) * 2003-08-18 2005-02-24 Pfizer Products Inc. Dosing schedule for erbb2 anticancer agents
WO2005023315A3 (en) * 2003-09-11 2005-11-17 Yissum Res Dev Co Radiolabeled anilinoquinazolines and their use in radioimaging and radiotherapy
US7172749B2 (en) 2001-03-12 2007-02-06 Yissum Research Development Company Of The Hebrew University Of Jerusalem Radiolabeled irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and their use in radioimaging and radiotherapy
WO2007104560A1 (de) * 2006-03-15 2007-09-20 Grünenthal GmbH Substituierte 4-amino-chinazolin-derivate als regulatoren von metab0tr0pischen glutamatrezeptoren und ihre verwendung zur herstellung von arzneimitteln
US7579356B2 (en) 2005-05-04 2009-08-25 Janssen Pharmaceutica Nv Thia-tetraazaacenaphthylene kinase inhibitors
US7659284B2 (en) 2004-09-15 2010-02-09 Janssen Pharmaceutica Nv Thiazolopyridine kinase inhibitors
US8080558B2 (en) 2007-10-29 2011-12-20 Natco Pharma Limited 4-(tetrazol-5-yl)-quinazoline derivatives as anti-cancer agent
EP2540705A3 (en) * 2006-11-02 2013-10-30 AstraZeneca AB (Publ) Process for preparing indol-5-oxy-quinazoline derivatives and intermediates
US8987284B2 (en) 2009-07-02 2015-03-24 Newgen Therapeutics, Inc. Phosphorus containing quinazoline compounds and methods of use
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US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0326459D0 (en) 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033980A1 (en) 1995-04-27 1996-10-31 Zeneca Limited Quinazoline derivatives
WO1998002438A1 (en) 1996-07-13 1998-01-22 Glaxo Group Limited Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
GB2345486A (en) 1999-01-11 2000-07-12 Glaxo Group Ltd Heteroaromatic protein tyrosine kinase inhibitors
WO2000044728A1 (en) 1999-01-27 2000-08-03 Pfizer Products Inc. Substituted bicyclic derivatives useful as anticancer agents
EP1067123A1 (en) 1998-03-31 2001-01-10 Kyowa Hakko Kogyo Co., Ltd. Nitrogenous heterocyclic compounds
EP1110953A1 (en) 1995-03-30 2001-06-27 Pfizer Inc. Quinazoline derivatives
WO2001098277A2 (en) 2000-06-22 2001-12-27 Pfizer Products Inc. Substituted bicyclic derivatives for the treatment of abnormal cell growth

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0880508T3 (da) * 1996-02-13 2003-06-30 Astrazeneca Ab Quinazolinderivater som VEGF-inhibitorer

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1110953A1 (en) 1995-03-30 2001-06-27 Pfizer Inc. Quinazoline derivatives
WO1996033980A1 (en) 1995-04-27 1996-10-31 Zeneca Limited Quinazoline derivatives
WO1998002438A1 (en) 1996-07-13 1998-01-22 Glaxo Group Limited Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
EP1067123A1 (en) 1998-03-31 2001-01-10 Kyowa Hakko Kogyo Co., Ltd. Nitrogenous heterocyclic compounds
GB2345486A (en) 1999-01-11 2000-07-12 Glaxo Group Ltd Heteroaromatic protein tyrosine kinase inhibitors
WO2000044728A1 (en) 1999-01-27 2000-08-03 Pfizer Products Inc. Substituted bicyclic derivatives useful as anticancer agents
WO2001098277A2 (en) 2000-06-22 2001-12-27 Pfizer Products Inc. Substituted bicyclic derivatives for the treatment of abnormal cell growth

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SALOMON ET AL., CRIT REV ONCOL HEMATOL, vol. 19, 1995, pages 183 - 232
See also references of EP1567506A4

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US7172749B2 (en) 2001-03-12 2007-02-06 Yissum Research Development Company Of The Hebrew University Of Jerusalem Radiolabeled irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and their use in radioimaging and radiotherapy
WO2005016347A1 (en) * 2003-08-18 2005-02-24 Pfizer Products Inc. Dosing schedule for erbb2 anticancer agents
WO2005023315A3 (en) * 2003-09-11 2005-11-17 Yissum Res Dev Co Radiolabeled anilinoquinazolines and their use in radioimaging and radiotherapy
US7659284B2 (en) 2004-09-15 2010-02-09 Janssen Pharmaceutica Nv Thiazolopyridine kinase inhibitors
US7579356B2 (en) 2005-05-04 2009-08-25 Janssen Pharmaceutica Nv Thia-tetraazaacenaphthylene kinase inhibitors
WO2007104560A1 (de) * 2006-03-15 2007-09-20 Grünenthal GmbH Substituierte 4-amino-chinazolin-derivate als regulatoren von metab0tr0pischen glutamatrezeptoren und ihre verwendung zur herstellung von arzneimitteln
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