EP1109555A1 - Nouveaux inhibiteurs d'angiogenese - Google Patents

Nouveaux inhibiteurs d'angiogenese

Info

Publication number
EP1109555A1
EP1109555A1 EP99912408A EP99912408A EP1109555A1 EP 1109555 A1 EP1109555 A1 EP 1109555A1 EP 99912408 A EP99912408 A EP 99912408A EP 99912408 A EP99912408 A EP 99912408A EP 1109555 A1 EP1109555 A1 EP 1109555A1
Authority
EP
European Patent Office
Prior art keywords
benzoimidazol
alkyl
aryl
phenyl
heterocyclyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99912408A
Other languages
German (de)
English (en)
Other versions
EP1109555A4 (fr
Inventor
Mark T. Bilodeau
Randall W. Hungate
April M. Cunningham
Timothy J. Koester
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1109555A1 publication Critical patent/EP1109555A1/fr
Publication of EP1109555A4 publication Critical patent/EP1109555A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphospate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Accordingly, inhibitors of these tyrosine kinases are useful for the prevention and treatment chemotherapy of proliferative diseases dependent on these enzymes. For example, a method of treatment described herein relates to neoangiogenesis. Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.
  • VEGF Vascular endothelial growth factor binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1.
  • KDR mediates the mitogenic function of VEGF
  • Flt-1 appears to modulate non- mitogenic functions such as those associated with cellular adhesion.
  • Inhibiting KDR thus modulates the level of mitogenic VEGF activity.
  • Vascular growth in the retina leads to visual degeneration culminating in blindness.
  • VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy.
  • Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased p0 2 levels in mice that lead to neovascularization.
  • Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.
  • VEGF vascular endothelial growth factor
  • monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities.
  • These monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells.
  • VEGF-binding construct of Flk-1 Viral expression of a VEGF-binding construct of Flk-1, the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors.
  • Embryonic stem cells which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors.
  • KDR or Flt-1 are implicated in pathological neoangiogenesis, and these are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., diabetic retinal vascularization, as well as various forms of cancer.
  • Cancers which are treatable in accordance with the present invention demonstrate high levels of gene and protein expression.
  • cancers include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
  • Raf-activating oncogenes e.g., K-ras, erb-B
  • the present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, atherosclerosis, diabetic retinopathy or inflammatory diseases, in mammals.
  • X is N or C
  • Rj&R 3 are independently H, C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a :
  • R 2 is independently H, C,_ 6 alkyl, C 5 . 10 aryl, C3-.6 cycloalkyl,
  • R 4 &R 5 are independently H, C 0 alkyl, C3-6 cycloalkyl, C ⁇ 6 alkoxy C 2 . ⁇ o alkenyl, C 2-10 alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl,
  • C 1-6 alkoxyNR 7 R 8 halo, N0 2 , OH, -NH 2 or C 5 .
  • 10 heteroaryl said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a , or R4 and R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from R a .
  • R a is H, C 0 alkyl, halogen, N0 2 , R, NHC,. 6 alkylR ⁇ , OR, -NR
  • R is H, C j . 6 alkyl or C 1 -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C,. 10 alkyl, C3-6 cycloalkyl, COR,
  • X is N or C
  • Rj is H, C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C 6 alkyl, C 5 _ 10 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 is H, Cj., 0 alkyl, C3-6 cycloalkyl, C N6 alkoxy C 2 . 10 alkenyl, C 2 - ⁇ o alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, C ⁇ - 6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R is H, or C,. 6 alkyl, OR, halo, NH 2 or N0 2 ;
  • R is H, C J . JO alkyl, halogen, N0 2 , OR, -NR NR 7 R 8 , R 7 R 8) C 5 . 10 aryl, C 5 . 10 heteroaryl or C 3 . 10 heterocyclyl;
  • R is H, or C,_ 6 alkyl, C ⁇ -6 alkylR 9 ;
  • RQ is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl;
  • R7&R8 are independently H, C M0 alkyl, C3-6 cycloalkyl, COR, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • composition which is comprised of a compound represented by the formula I:
  • R,, R 2 , R 3 , R 4 and R 5 are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
  • Also included is a method of treating or preventing a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included is a method of treating or preventing cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.
  • Also included in the present invention is a method of treating or preventing diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis.
  • a method of treating or preventing ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
  • a method of treating or preventing retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization.
  • Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology.
  • a method of treating or preventing age-related macular degeneration is also included.
  • alkyl refers to a monovalent alkane
  • hydrocarbon (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.
  • Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:
  • the alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
  • substituted alkyl when substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of R a , described herein.
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present.
  • Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of R a , when a substituted alkenyl group is provided.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of R a , when a substituted alkynyl group is provided.
  • Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
  • Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted with 1-3 groups of R a as defined herein.
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • heterocycle, heteroaryl, heterocyclyl or heterocyclic represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • the heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of R a .
  • Examples of such heterocyclic elements, inclusive of all possible isomers, include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, iso
  • alkoxy refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
  • halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
  • prodrug refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process.
  • exemplary prodrugs include acyl amides of the amino compounds of this inventon such as amides of alkanoic(C ⁇ _ 6 )acids, amides of aryl acids (e.g., benzoic acid) and alkane(C. perennial 6 )dioic acids.
  • Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant tyrosine kinase enzyme activity. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), etc.
  • X is N or C
  • R,&R 3 are independently H, C M0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, halo, OH, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • Ro is independently H, C,_ 6 alkyl, C 5 . 10 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 &R 5 are independently H, C,_ 10 alkyl, C3-6 cycloalkyl, C,_ 6 alkoxy C 2- ⁇ o alkenyl, C 2- ⁇ o alkynyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, C ⁇ -6 alkoxyNR 7 R 8 , halo, N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, .
  • alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a , or R4 a ⁇ j R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from R a .
  • R a is H, C 0 alkyl, halogen, N0 2 , R, NHC,. 6 alkylR 9 , OR, -NR,
  • R is H, C,. 6 alkyl or C ⁇ -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C M o alkyl, C3-6 cycloalkyl, COR, C 5 _ ⁇ 0 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • Still another aspect of this invention is described wherein . is C 0 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, C 5 . 10 heteroaryl, or C 3 . 10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is C M0 alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • R a is H, C LI O alkyl, halogen, C 1-6 alkylR 9 , CN, R, OR, NR, RNR 7 R 8 , NR 7 R 8 , R 7 R 8 and all other variables are as described above.
  • R,&R 3 are independently H, C M0 alkyl, C 5 . 10 aiyl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 is independently H, C,. 6 alkyl, C 3-6 cycloalkyl, OH, or halogen;
  • R 4 &R 5 are independently H, C,. 10 alkyl, C 3-6 cycloalkyl, C 5 . 10 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl, C ⁇ -6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ; and all other variables are as described above.
  • Another preferred subset of compounds of the present invention is realized when:
  • R 1 &R 3 are independently C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 is H or C,. 6 alkyl
  • R 4 is piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, is
  • X is N or C
  • R is H, C 0 alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C,. 6 alkyl, OH, N0 2 , -NH 2 , or halogen;
  • R 4 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, C 1-6 alkoxyNR 7 R 8 , or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 5 is H, C,. 6 alkyl, OR, halo, NH 2 or N0 2 ;
  • R a is H, C 0 alkyl, halogen, N0 2 , R, OR, -NR, NR 7 R 8j R 7 R 8 , C 5 . 10 aryl, C 5 . 10 heteroaryl or C 3 . 10 heterocyclyl,
  • R is H, or C,_ 6 alkyl, C ⁇ -6 alkylR 9 ;
  • R 9 is C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl;
  • R7&R8 are independently H, C M0 alkyl, C3-6 cycloalkyl, COR, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • R4 is C J . JO alkyl, C 3-6 cycloalkyl, C 5 .j 0 aryl, C 5 . 10 heteroaryl, or C 3 . 10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is C J . JO alkyl, C 5 .j 0 aryl, C 3 .j 0 heterocyclyl, or C 5 . 10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Rj is H, C J . J O alkyl, C 5 . 10 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H, C,_ 6 alkyl, C 3-6 cycloalkyl, OH, or halogen;
  • R 4 is H, C J . JO alkyl, C 3 . 6 cycloalkyl, C 5 ., 0 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl, Cj -6 alkoxyNR 7 R 8 , N0 2 , OH, -NH 2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ; and all other variables are as described above.
  • Rj is C 5 _i 0 aryl, C 3 . 10 heterocyclyl, or C 5 . 10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 2 &R 3 are independently H or Cj. 6 alkyl
  • R 4 is C J . JO alkyl, C 5 ., 0 aryl, C 5 . 10 heteroaryl, C 3 . 10 heterocyclyl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from
  • X & W are independently N or C
  • R j &R 3 are independently H, C J . J0 alkyl, C 3-6 cycloalkyl, C 5 .j 0 aryl, halo, OH, C 3 _i 0 heterocyclyl, or C 5 .j 0 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R 9 is independently H, Cj. 6 alkyl, C 5 ., 0 aryl, C3-6 cycloalkyl, OH, N0 2 , -NH 2 , or halogen;
  • R is independently H, Cj. 10 alkyl, C3-6 cycloalkyl, Cj. 6 alkoxy C 2 _ ⁇ o alkenyl, C 2- ⁇ o alkynyl, C 5 .j 0 aryl, C 3 .j 0 heterocyclyl, Cj. 6 alkoxyNR 7 R 8 , halo, N0 2 , OH, -NH 2 or C 5 . 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • Rio is H, or Cj. 6 alkyl, Cj. 6 alkylR 9 , C 5 . 10 aryl, C 3 . 10 heterocyclyl, NHC j . 6 alkylR 9; said alkyl (where R is C j . 6 alkyl), aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R is H, C J . JO alkyl, halogen, N0 2 , OR, -NR RNR 7 R 8 , NR 7 R 8 ,
  • R 7 R 8 CN, C 5 ., 0 aryl, C 5 . 10 heteroaryl or C 3 .j 0 heterocyclyl;
  • R is H, Cj. 6 alkyl or Cj. 6 alkylR 9 ;
  • R 9 is C 5 .jo aryl, C 3 .j 0 heterocyclyl, or C 5 .] 0 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R7&R8 are independently H, C 0 alkyl, C3-6 cycloalkyl, COR,
  • C 5 _jo aryl, C 3 .j 0 heterocyclyl, or C 5 .j 0 heteroaryl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • R 10 is H, C,., 0 alkyl, Cj -6 alkylR 9 , C 5 .j 0 aryl, C 5 . 10 heteroaryl, or C 3 .j 0 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a and all other variables are as described above.
  • Examples of the compounds of this invention are:
  • the invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with a carrier.
  • pharmaceutically acceptable salts and “hydrates” refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, abso ⁇ tion, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which are also important in the selection are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • a counterion e.g., an alkali metal cation such as sodium or potassium.
  • suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality.
  • the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
  • salts also include acid addition salts.
  • the compound can be used in the form of salts derived from inorganic or organic acids or bases. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate,
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • any variable e.g., aryl, heterocyle, Rl, etc
  • the compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.
  • the compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
  • the carrier employed may be, for example, either a solid or liquid.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders.
  • Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
  • oral solid dosage forms examples include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500mg.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
  • the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
  • dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors.
  • An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses.
  • An example of a suitable parenteral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection.
  • An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day.
  • An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.
  • the compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds.
  • the non-limiting examples that follow are illustrations of the compounds of the instant invention and are not meant to limit the invention in any way.
  • Nitroaniline 5 (0.213 g, 0.665 mmol) and palladium on carbon (10%, 100 mg) were stirred in 8 mL 3: 1 EtOH/AcOH. The reaction was put under a balloon of H 2 . After 2 h the reaction was filtered through a plug of celite and the filtrate was concentrated to dryness. The resulting residue was dissolved in 1.5 mL trimethylorthoformate and heated to 120 ° C for 30 min. The solution was cooled concentrated to dryness and purified by flash column chromatography (2 x 15 cm silica gel, 1 : 1 hexane/ethyl acetate) which provided 6.
  • Benzimidazole 7 (0.025g, 0.087 mmol) and N-(2- chloroethyl)piperidine hydrochloride (11 mg, 0.059 mmol) were dissolved in anhydrous N,N-dimethylformamide (0.5 mL). Cesuim carbonate (0.085g, 0.26 mmol) was added and the resulting mixture was heated to 50 °C. After 2 h additional and N-(2-chloroethyl)pi ⁇ eridine hydrochloride (11 mg, 0.059 mmol) was added. After 1 h the reaction was allowed to cool, quenched with water and extracted with ethyl acetate (3x).
  • the bromochloronitropyridine was dissolved in 15mL of anhydrous l-methyl-2-pyrrolidinone.
  • Aniline (3.580 mL, 0.0393 mol) was added followed by the addition of N,N-diisopropylethylamine (13.69 mL, 0.0786 mol) and the solution was heated to 120 °C. After 1.5 hr., the solution was cooled to ambient temperature and diluted with water. The product was extracted using ethyl acetate and washed with brine. The organic layer was then dried over sodium sulfate, filtered, concentrated, and dried in vacuo.
  • Bromoaromatic 10 (30 mg, 0.102 mmol), 4- methoxyphenylboronic acid (17 mg, 0.112 mmol) was dissolved in 0.75 mL dioxane followed by the addition of 204 ⁇ L of 2M sodium carbonate.
  • the vessel was flushed with argon followed by the addition of tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol) and 0.56 mL water.
  • the vessel was flushed again with argon and heated to 80 °C for 2.5 hr.
  • the solution was cooled to room temperature and diluted with water.
  • the product was extracted with ethyl acetate and washed with brine, followed by drying over sodium sulfate.
  • the organic layer was concentrated, and the product dried in vacuo.
  • the crude mixture was purified by flash column chromatography (2.5 x 8 cm silica gel, 8:2 hexane:ethyl
  • Nitroaniline 11 (1.333 g, 4.15 mmol), Zn dust(6.239 g, 95.40 mmol), and 10 mL acetic acid were mixed under argon. The solution was heated to 60 °C for 1 hr until the solution turned light green. The zinc was removed using vacuum filtration with celite and washed with acetic acid. The filtrate was concentrated and 20 mL of trimethylorthoformate was added. The solution was heated to 100 °C for 2 hr followed by cooling to ambient temperature. The solution was concentrated and the crude mixture was purified by flash column chromatography(5 x 16 cm silica gel, 6:4 ethylacetate:hexane) affording 12.
  • the aqueous layer was extracted a second time with dichloromethane w/ 3% 1-butanol.
  • the organic layers were washed with saturated sodium bicarbonate, and dried over sodium sulfate.
  • the organic layers were conentrated at aspirator pressure to remove ethyl acetate and methylene chloride; the 1-butanol and residual DMF were removed under high pressure.
  • the product was purified using flash column chromatography(silica gel 2.5 x 32.5 cm, 10:1 methylene chloride :methanol). Excess trifluoroacetic acid was added to the product to create the resulting salt, and the mixture was triturated using ether.
  • Bromoaromatic 4 (7.10 g, 24.1 mmol) and powdered zinc (36.2 g, 554 mmol, 23 equiv) were stirred in 80 mL glacial acetic acid. The mixture was heated to 60 °C. After lh the reaction was cooled and filtered through a plug of celite and concentrated to dryness. The resulting residue was dissolved in 60 mL of formic acid and heated to 100 °C overnight. The reaction was cooled and concentrated to dryness. Purification by flash column chromatography (6x25 cm silica, 55:45 hexanes/EtOAc) afforded 5.88 g benzimidazole 15 (89% yield). !
  • Benzimidazole 15 (2.91 g, 10.7 mmol), diboron pinacol ester (2.97 g, 11.7 mmol) and potassium acetate (3.14 g, 32.0 mmol) were stirred in 20 mL anhydrous DMF under Ar.
  • PdCl 2 (dppf) (0.26 g, 0.32 mmol) was added, solution was degassed and heated to 80 °C. After 20h the reaction was quenched with 125 mL of water and 50 mL of saturated aqueous NaCl and was extracted 3 x with EtOAc. The combined extracts were dried over Na 2 S0 4 , filtered and concentrated to afford 2.77 g of unpurified boronate.
  • l-Phenyl-5-pyridin-4-yl-lH-benzoimidazole (12) (8.82 g, 32.5 mmol) was dissolved in 120 mL of CH 2 C1 2 .
  • the resulting solution was cooled to 0°C and to it was added mCPBA (11.2 g, 65.0 mmol). After stirring for 2.5 days an additional portion of mCPBA (3.0 g, 17 mmol) was added. After an additional 24 h the reaction solution was loaded directly onto a column (8 x 20 cm) pre-wetted with CH 2 C1 2 .
  • N-3-chloropiperidine HC1 54 mg, .275 mmol
  • cesium carbonate 164 mg, .504 mmol
  • 4 mL anhydrous N,N- dimethylformamide 4 mL
  • the vessel was placed in 60 °C oil bath with stirring under argon.
  • the reaction was heated to 80 °C after 1 day, and was stopped after 4 days after no further progression.
  • the solvent was removed via high vacuum rotary evaporation, the residue was diluted with MeOH, and filtered through a 0.7 ⁇ M syringe filter.
  • VEGF RECEPTOR KINASE ASSAY VEGF receptor kinase activity is measured by incorporation of radio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY) substrate.
  • the phosphorylated pEY product is trapped onto a filter membrane and the incoporation of radio-labeled phosphate quantified by scintillation counting.
  • the intracellular tyrosine kinase domains of human KDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519-524) were cloned as glutathione S-transferase (GST) gene fusion proteins. This was accomplished by cloning the cytoplasmic domain of the KDR kinase as an in frame fusion at the carboxy terminus of the GST gene.
  • GST glutathione S-transferase
  • Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf 1) insect cells (Invitrogen) using a baculo virus expression vector (pAcG2T, Pharmingen).
  • EDTA 0.05% triton X-100, 10 % glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride.
  • Millipore #MAFC NOB GF/C glass fiber 96 well plate.
  • reaction mix containing 5 ⁇ l of 10 X reaction buffer, 5 ⁇ l 25 mM ATP/10 ⁇ Ci [ 33 P]ATP (Amersham), and 5 ⁇ l 10 X substrate.
  • VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells.
  • Human umbilical vein endothelial cells (HUVECs) in culture proliferate in response to VEGF treatment and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation.
  • quiescent HUVEC monolayers are treated with vehicle or test compound 2 hours prior to addition of VEGF or basic fibroblast growth factor (bFGF).
  • the mitogenic response to VEGF or bFGF is determined by measuring the incorporation of [ 3 H]thymidine into cellular DNA.
  • HUVECs frozen as primary culture isolates are obtained from Clonetics Corp. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and are used for mitogenic assays at passages
  • IPX Growth factors Solutions of human VEGF 165 (500 ng/ml; R&D Systems) and bFGF (10 ng/ml; R&D Systems) are prepared in Assay Medium.
  • HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4000 cells per 100 ul Assay Medium per well in 96-well plates. Cells are growth-arrested for 24 hours at 37°C in a humidified atmosphere containing 5% C0 2 .
  • Growth-arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% [v/v] DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37°C/5% C0 2 for 2 hours to allow test compounds to enter cells.
  • I are inhibitors of VEGF and thus are useful for the inhibition of neoangiogenesis, such as in the treatment of occular disease, e.g., diabetic retinopathy and in the treatment of cancers, e.g., solid tumors.
  • the instant compounds inhibit VEGF-stimulated mitogenesis of human vascular endothelial cells in culture with IC 50 values between 150-650 nM. These compounds also show selectivity over related tyrosine kinases (e.g. FGFR1 and the Src family).

Abstract

La présente invention se rapporte à des composés qui inhibent les tyrosine-kinases, à des compositions qui contiennent des composés inhibiteurs de tyrosine-kinases et à des procédés d'utilisation d'inhibiteurs de tyrosine-kinases pour traiter, chez les mammifères, les affections/maladies dépendant des tyrosine-kinases telles que l'angiogenèse, le cancer, l'athérosclérose, la rétinopathie diabétique ou les maladies auto-immunes.
EP99912408A 1998-08-31 1999-03-11 Nouveaux inhibiteurs d'angiogenese Withdrawn EP1109555A4 (fr)

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AU3078999A (en) 2000-03-21
JP2002523459A (ja) 2002-07-30
EP1109555A4 (fr) 2001-11-21

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