WO2005121090A1 - Piperidines substituees a activite antiangiogenique - Google Patents

Piperidines substituees a activite antiangiogenique Download PDF

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Publication number
WO2005121090A1
WO2005121090A1 PCT/US2005/019128 US2005019128W WO2005121090A1 WO 2005121090 A1 WO2005121090 A1 WO 2005121090A1 US 2005019128 W US2005019128 W US 2005019128W WO 2005121090 A1 WO2005121090 A1 WO 2005121090A1
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group
alkyl
hydrogen
amino
carbonyl
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PCT/US2005/019128
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English (en)
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Fortuna Haviv
Michael F. Bradley
Andrew J. Schneider
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Abbott Laboratories
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel compounds having activity useful for treating conditions which arise from or are exacerbated by angiogenesis, pharmaceutical compositions comprising the compounds, methods of treatment using the compounds, and methods of inhibiting angiogenesis.
  • Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions these molecules appear to maintain the micro vasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods that may last for weeks, or in some cases, decades. However, when necessary, such as during wound repair, these same cells can undergo rapid proliferation and turnover within as little as five days (Folkman, J. and Shing, Y., J. Biol.
  • angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as "angiogenic diseases") are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exacerbate an existing pathological condition. For example, ocular neovascularization has been implicated as the most common cause of blindness. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness.
  • the present invention provides a compound of Formula (I) (I) or a therapeutically acceptable salt or ester thereof, wherein L is selected from the group consisting of a bond and alkylene; R ⁇ is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • R is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, cyclo alkylcarbonyl, cycloalkylalkylcarbonyl, heteroarylalkylcarbonyl, heterocyclealkylcarbonyl, and heterocyclecarbonyl
  • ⁇ is selected from the group consist
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 16 )carbonylalkyl
  • R ⁇ is selected from the group consisting of aryl, arylalkyl, cycloalkyl, cyclo alkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, hydroxy and NZ 1 Z 18
  • R 12 is selected from the group consisting of hydrogen, R 12a , and phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylthio, alkylthio alkyl, alkynyl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, hydroxy
  • the present invention provides a pharmaceutical composition comprising a compound of Formula (I), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of inhibiting tumor growth in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating fibrosarcoma in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating lung carcinoma in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (I) or a therapeutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (I), or a therapeutically acceptable salt thereof, to prepare a medicament for inhibiting angiogenesis in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a therapeutically acceptable salt thereof, to prepare a medicament for inhibiting tumor growth in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a therapeutically acceptable salt thereof, to prepare a medicament for treating cancer in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a therapeutically acceptable salt thereof, to prepare a medicament for treating fibrosarcoma in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a therapeutically acceptable salt thereof, to prepare a medicament for treating fibrosarcoma in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a therapeutically acceptable salt thereof, to prepare a medicament for treating fibrosarcoma in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a therapeutically acceptable salt thereof, to prepare a medicament for treating fibrosarcoma in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (I), or a therapeutically acceptable salt thereof, to prepare a medicament for treating fibrosarcoma in a ma
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; R 1 is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, (NZ ⁇ Z 2 )alkylcarbonyl,
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and heteroarylcarbonyl
  • R 5 is selected from the group consisting of alkyl and (NZ 8 Z )alkyl
  • R ⁇ and R 7 are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl
  • R 8 is selected from the group consisting of heterocycle
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 16 )carbonylalkyl
  • R ⁇ is selected from the group consisting of hydroxy and NZ 1 Z 18
  • R 12 is selected from the group consisting of hydrogen and phenyl
  • Zi, Z 2 , Z 3 , Z 5 , Z 6 , Z , Z 8 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl
  • Z 4 and Z 9 are independently selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl
  • Z 13 , Z 1 , Z 17 , and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; R t is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and (NZiZ 2 )alkylcarbonyl; R 8 is selected from the group consisting
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 16 )carbonylalkyl
  • Rn is selected from the group consisting of hydroxy and NZ 17 Z 18
  • R 12 is selected from the group consisting of hydrogen and phenyl
  • Zi, Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl
  • Z 13 , Z 14 , Z 17 , and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and (NZ 1 Z2)alkylcarbonyl; R 8 is aryl wherein the aryl is phenyl substituted with at least one carboxy group; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of carboxyalkyl and
  • NZ 15 Z 16 carbonylalkyl
  • Rn is selected from the group consisting of hydroxy and NZ 17 Z 18
  • R 12 is selected from the group consisting of hydrogen and phenyl
  • Zi, Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl
  • Z 13 , Z 1 , Z 17 , and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; R.
  • ⁇ is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and (NZ 1 Z 2 )alkylcarbonyl;
  • R 8 is arylalkyl wherein the aryl is phenyl substituted with at least one carboxy group;
  • R 9 is selected from the group consisting of hydrogen and alkyl;
  • R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 1 6)carbonylalkyl;
  • R n is selected from the group consisting of hydroxy and NZ 1 Z 18 ;
  • R 12 is selected from the group consisting of hydrogen and phenyl;
  • Zi, Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl; and
  • Z 13 , Z ⁇ 4 , Z 1 , and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; R t is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and (NZ 1 Z 2 )alkylcarbonyl; R 8 is cycloalkyl wherein the cycloalkyl is substituted with at least one carboxy group; R is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 16 )carbonylalkyl; Rn is selected from the group consisting of hydroxy and NZ 17 Z 18 ; R 12 is selected from the group consisting of hydrogen and phenyl; Zi, Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl; and Z 13 , Z 14 , Z 17 , and Z 18 are independently selected from the group consisting of hydrogen, alkylene;
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; Rt is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and (NZ 1 Z 2 )alkylcarbonyl; R 8 is cycloalkylalkyl wherein the cycloalkyl is substituted with at least one carboxy group; R is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 1 6)carbonylalkyl; Rn is selected from the group consisting of hydroxy and NZ 17 Z 18 ; R 12 is selected from the group consisting of hydrogen and phenyl; Z ⁇ , Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl; and Z 13 , Z 1 , Z 1 , and Z 18 are independently selected from the group consisting of
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; Ri is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and (NZiZ 2 )alkylcarbonyl; R 8 is heterocyclealkyl wherein the heterocycle is substituted with at least one carboxy group; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 1 6)carbonylalkyl; R is selected from the group consisting of hydroxy and NZ 17 Z 18 ; R 12 is selected from the group consisting of hydrogen and phenyl; Zi, Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl; and Z 13 , Z 14 , Z 17 , and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyal
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; Ri is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and (NZ 1 Z 2 )alkylcarbonyl; R 8 is heteroaryl wherein the heteroaryl is substituted with at least one carboxy group; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 16 )carbonylalkyl; Rn is selected from the group consisting of hydroxy and NZ 17 Z 18 ; R 12 is selected from the group consisting of hydrogen and phenyl; Z 1?
  • Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl; and Z 13 , Z 1 , Z 17 , and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene; R] is selected from the group consisting of hydrogen, alkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and (NZ 1 Z 2 )alkylcarbonyl; R 8 is heteroarylalkyl wherein the heteroaryl is substituted with at least one carboxy group; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 16 )carbonylalkyl; Rn is selected from the group consisting of hydroxy and NZ 17 Z 18 ; R 12 is selected from the group consisting of hydrogen and phenyl; Z Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl; and Z 13 , Z 14 , Z 17 , and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; Ri is selected from the group consisting of hydrogen, alkylcarbonyl, and (NZiZ 2 )alkylcarbonyl; R 8 is selected from the group consisting of hydroxy, NZ 13 Z 14 and heterocycle wherein the heterocycle is azetidinyl substituted with one carboxy group; R 12 is selected from the group consisting of hydrogen and phenyl; and Z 2 are independently selected from the group consisting of hydrogen and alkyl; and Z 13 and Z 1 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ;
  • Ri is selected from the group consisting of hydrogen, alkylcarbonyl, and (NZiZ 2 )alkylcarbonyl;
  • R 8 is selected from the
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; Ri is heteroarylcarbonyl wherein the heteroaryl is pyridinyl; R 8 is selected from the group consisting of hydroxy, NZ 13 Z 1 and heterocycle wherein the heterocycle is azetidinyl substituted with one carboxy group; R 12 is selected from the group consisting of hydrogen and phenyl; Zi and Z 2 are independently selected from the group consisting of hydrogen and alkyl; and Z 13 and Z 14 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; Ri is heterocyclealkylcarbonyl wherein the heterocycle is selected from the group consisting of piperidinyl and piperazinyl; R 8 is selected from the group consisting of hydroxy, NZ 13 Z 1 and heterocycle wherein the heterocycle is azetidinyl substituted with one carboxy group; R 12 is selected from the group consisting of hydrogen and phenyl; and Z 2 are independently selected from the group consisting of hydrogen and alkyl; and Z 13 and Z 1 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ;
  • Ri is heterocyclealkylcarbonyl wherein the heterocycle is selected from the group consisting of piperidinyl and piperazinyl;
  • R 8 is selected
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; Ri is selected from the group consisting of hydrogen, alkylcarbonyl, and
  • R 8 is R 9 is selected from the group consisting of hydrogen and alkyl;
  • R 10 is selected from the group consisting of carboxyalkyl and
  • NZi 5 Z 16 carbonylalkyl
  • R is selected from the group consisting of hydroxy and NZ ⁇ 7 Z 18
  • R 12 is selected from the group consisting of hydrogen and phenyl
  • Z l3 Z 2 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl
  • Z 17 and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; Ri is heteroarylcarbonyl wherein the heteroaryl is pyridinyl; R 8 is ; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Zi 6 )carbonylalkyl; Rn is selected from the group consisting of hydroxy and NZ 17 Z 18 ; R 12 is selected from the group consisting of hydrogen and phenyl; Z l3 Z 2 , Z 15 , and Z ⁇ 6 are independently selected from the group consisting of hydrogen and alkyl; and Z 17 and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; Ri is heteroarylcarbonyl wherein the heteroaryl
  • the present invention provides a compound of Formula (I) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; Ri is heterocyclealkylcarbonyl wherein the heterocycle is selected from the group consisting of piperidinyl, piperazinyl, and pyrrolidinyl wherein the heterocycle is optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl, hydroxy, oxo, and NR A R B ; R A and R B are independently selected from the group consisting of hydrogen
  • R 8 is ;
  • R 9 is selected from the group consisting of hydrogen and alkyl;
  • R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 16 )carbonylalkyl;
  • Rn is selected from the group consisting of hydroxy and NZ 17 Z ⁇ 8 ;
  • R 1 is selected from the group consisting of hydrogen and phenyl;
  • Zi, Z 2 , Z 15 and are independently selected from the group consisting of hydrogen and alkyl;
  • Z ⁇ ⁇ and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of
  • L is selected from the group consisting of a bond and alkylene
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • j is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, cyclo alkylcarbonyl, cyclo alky lalkylcarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heterocyclealkylcarbonyl, and heterocyclecarbonyl
  • R 8 is selected from the group consisting of aryl, arylalkyl, cycloalkyl, cyclo alkylalkyl, heterocyclecarbonyl
  • R 8 is selected from the group consist
  • heterocyclealkyl, heteroaryl, heteroarylalkyl, hydroxy, NZ 13 Z 14 , and R 9 is selected from the group consisting of hydrogen and alkyl; Rio is selected from the group consisting of carboxyalkyl and (NZ 15 Zi6)carbonylalkyl; Rn is selected from the group consisting of aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, hydroxy and NZ 17 Z 18 ; R 12 is selected from the group consisting of hydrogen, R 12a , and phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylthio, alkylthio alkyl, alkynyl, carboxy,
  • the present invention provides a compound of Formula (II) wherein L is a bond; R 2 is (NZ 3 Z 4 )alkyl; R 3 is hydrogen; R is alkylcarbonyl; R 8 is NZ ⁇ 3 Z 14 ; R 12 is phenyl; Z 3 and Z 4 are hydrogen; Z 13 and Z ⁇ 4 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (II) wherein L is a bond; R 2 is (NZ 3 Z )alkyl; R 3 is hydrogen; R 4 is alkylcarbonyl; R 8 is hydroxy; Ri 2 is phenyl; and Z 3 and Z are hydrogen.
  • the present invention provides a compound of Formula (II) wherein L is a bond; R 2 is (NZ 3 Z 4 )alkyl; R 3 is hydrogen; R 4 is alkylcarbonyl; R 8 is heterocycle wherein the heterocycle is azetidinyl substituted with one carboxy group; R 12 is phenyl; and Z 3 and Z 4 are hydrogen.
  • the present invention provides a compound of Formula (II) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; R 2 is heterocyclealkyl wherein the heterocycle is piperidinyl; R 3 is selected from the group consisting of hydrogen and alkyl; j is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and heteroarylcarbonyl wherein the heteroaryl is pyridinyl optionally substituted with one alkyl group; R 8 is selected from the group consisting of hydroxy, NZ ⁇ 3 Z 14 , and heterocycle wherein the heterocycle is azetidinyl substituted with one carboxy group; R 1 2 is selected from the group consisting of hydrogen and phenyl; Z 3 , Z 5 , Z 6 , and Z 7 are independently selected from the group consisting of hydrogen and alkyl; Z 4 is selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl wherein
  • the present invention provides a compound of Formula (II) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; R 2 is selected from the group consisting of alkyl, (NZ 3 Z )alkyl, and R 3 is selected from the group consisting of hydrogen and alkyl; j is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and heteroarylcarbonyl wherein the heteroaryl is pyridinyl optionally substituted with one alkyl
  • R 8 is R is selected from the group consisting of hydrogen and alkyl
  • R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Z 1 6)carbonylalkyl
  • Rn is selected from the group consisting of hydroxy and NZ 17 Z 18
  • R 12 is selected from the group consisting of hydrogen and phenyl
  • Z 3 , Z 5 , Z 6 , Z , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl
  • Z 4 is selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl wherein the heteroaryl is pyridinyl
  • Z 17 and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (II) wherein L is a bond; R 2 is (NZ 3 Z 4 )alkyl; R 3 is hydrogen; j is alkylcarbonyl; R 8 is
  • the present invention provides a compound of Formula (II) wherein L is a bond; R 2 is (NZ 3 Z )alkyl; R 3 is hydrogen; t is alkylcarbonyl; Rg is
  • the present invention provides a compound of Formula (II) wherein L is a bond; R 2 is (NZ 3 Z 4 )alkyl; R 3 is hydrogen; R 4 is alkylcarbonyl; R 8 is
  • the present invention provides a compound of Formula (II) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; R 2 is heterocyclealkyl wherein the heterocycle is piperidinyl; R 3 is selected from the group consisting of hydrogen and alkyl; R is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and heteroarylcarbonyl wherein the heteroaryl is pyridinyl optionally
  • R 8 is R is selected from the group consisting of hydrogen and alkyl; Rio is selected from the group consisting of carboxyalkyl and
  • NZ 15 Z 16 carbonylalkyl
  • Rn is selected from the group consisting of hydroxy and NZ 17 Z 18 ;
  • R 12 is selected from the group consisting of hydrogen and phenyl; Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl; and Z ⁇ and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula (II), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (II) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of inhibiting tumor growth in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (II) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (II) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating fibrosarcoma in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (II) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating lung carcinoma in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (II) or a therapeutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (II), or a therapeutically acceptable salt thereof, to prepare a medicament for inhibiting angiogenesis in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of
  • Formula (II), or a therapeutically acceptable salt thereof to prepare a medicament for inhibiting tumor growth in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (II), or a therapeutically acceptable salt thereof, to prepare a medicament for treating cancer in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (II), or a therapeutically acceptable salt thereof, to prepare a medicament for treating fibrosarcoma in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (II), or a therapeutically acceptable salt thereof, to prepare a medicament for treating lung carcinoma in a mammal in recognized need of such treatment.
  • the present invention provides a compound of Formula (III)
  • L is selected from the group consisting of a bond and alkylene
  • R 3 is selected from the group consisting of hydrogen and alkyl
  • R5 is selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl
  • R 7 is selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, cyclo
  • heteroarylalkyl, hydroxy, NZ 13 Z 1 , and R 9 is selected from the group consisting of hydrogen and alkyl; w is selected from the group consisting of carboxyalkyl and (NZ 15 Z 16 )carbonylalkyl; Rn is selected from the group consisting of aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, hydroxy and NZ ⁇ 7 Z 18 ; R 12 is selected from the group consisting of hydrogen, R ⁇ 2a , and phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylthio, alkylthio alkyl, alkynyl, carboxy, cyano, hal
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is selected from the group consisting of carboxyalkyl and (NZ 15 Zi 6 )carbonylalkyl
  • Rn is selected from the group consisting of hydroxy and NZ 17 Z 18
  • R 12 is selected from the group consisting of hydrogen and phenyl
  • Z 3 , Z 5 , Z 6 , Z , Z 8 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl
  • Z 4 and Z are independently selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl
  • Z 13 , Z 14 , Z 17 , and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • R ⁇ and R 7 are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl;
  • R 8 is selected from the group consisting of hydroxy, NZ 13 Z 14 , and heterocycle wherein the heterocycle is azetidinyl substituted with one carboxy group;
  • R 12 is selected from the group consisting of hydrogen and phenyl;
  • Z 3 , Z 5 , Z 6 , Z 7 , and Z 8 are independently selected from the group consisting of hydrogen and alkyl;
  • Z 4 and Z 9 are independently selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl wherein the heteroaryl is pyridinyl;
  • Z 13 and Z 14 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (III) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; R 2 is alkyl; R 3 is selected from the group consisting of hydrogen and alkyl; R 5 is (NZ 8 Z 9 )alkyl; R5 and R are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; R 8 is selected from the group consisting of hydroxy, NZ 13 Z 14 , and heterocycle wherein the heterocycle is azetidinyl substituted with one carboxy group; R 12 is selected from the group consisting of hydrogen and phenyl; Z 8 is selected from the group consisting of hydro gen and alkyl; Z 9 is selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl wherein the heteroaryl is pyridinyl; and Z 13 and Z 14 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • L
  • NZ 1 5Z 1 6)carbonylalkyl (NZ 1 5Z 1 6)carbonylalkyl; Rn is selected from the group consisting of hydroxy and NZ ⁇ 7 Z 18 ;
  • Ri 2 is selected from the group consisting of hydrogen and phenyl;
  • Z 3 , Z5, Z 6 , Z 7 , Z 8 , Z15, and Zi 6 are independently selected from the group consisting of hydrogen and alkyl;
  • Z 4 and Z 9 are independently selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl;
  • Z ⁇ 7 and Z 18 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a compound of Formula (III) wherein L is selected from the group consisting of a bond and alkylene wherein the alkylene is CH 2 ; R 2 is alkyl; R 3 is selected from the group consisting of hydrogen and alkyl; R 5 is (NZ 8 Z 9 )alkyl; R 5 and R 7 are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl; Rg is R 9 is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of carboxyalkyl and
  • NZ 15 Z 16 carbonylalkyl
  • R is selected from the group consisting of hydroxy and NZ 1 Z 18 ;
  • R 12 is selected from the group consisting of hydrogen and phenyl;
  • Z 8 , Z 15 , and Z 16 are independently selected from the group consisting of hydrogen and alkyl;
  • Z 4 and Z 9 are independently selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl;
  • Z 1 and Z ⁇ 8 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula (III), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
  • the present invention provides a method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (III) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of inhibiting tumor growth in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (III) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (III) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating fibrosarcoma in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (III) or a therapeutically acceptable salt thereof.
  • the present invention provides a method of treating lung carcinoma in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of Formula (III) or a therapeutically acceptable salt thereof.
  • the present invention provides a use of a compound of Formula (III), or a therapeutically acceptable salt thereof, to prepare a medicament for inhibiting angiogenesis in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (III), or a therapeutically acceptable salt thereof, to prepare a medicament for inhibiting tumor growth in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (III), or a therapeutically acceptable salt thereof, to prepare a medicament for treating cancer in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of
  • Formula (III), or a therapeutically acceptable salt thereof to prepare a medicament for treating fibrosarcoma in a mammal in recognized need of such treatment.
  • the present invention provides a use of a compound of Formula (III), or a therapeutically acceptable salt thereof, to prepare a medicament for treating lung carcinoma in a mammal in recognized need of such treatment.
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxycarbonyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkoxycarbonyl examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • alkoxysulfonyl means an alkoxy group, as defined herein, appended appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylcarbonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,
  • alkylene means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms. Representative examples of alkylene include, but are not hmited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 -,
  • alkylthio means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of alkylthio include, but are not Hmited, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • alkylthioalkyl as used herein, means an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkylthioalkyl include, but are not limited, methylthiomethyl and
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • carboxy as used herein, means a -CO 2 H group.
  • carboxyalkyl as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl, and 3-carboxypropyl.
  • cyano as used herein, means a -CN group.
  • cycloalkyl as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 8 carbons, examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkylalkyl as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
  • the cycoalkyl groups of the present invention are optionally substituted with 1, 2, 3, or 4 substituents selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylthio, alkynyl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR A R B and (NRAR ⁇ )carbonyl.
  • substituents selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylthio, alkynyl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR A R B and (NRAR ⁇ )carbonyl.
  • halo or halogen as used herein,
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifiuoromethoxy, and pentafluoroethoxy.
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heteroaryl as used herein, means a monocyclic heteroaryl ring or a bicyclic heteroaryl ring.
  • the monocyclic heteroaryl ring is a 5 or 6 membered ring.
  • the 5 membered ring has two double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S.
  • the 6 membered ring has three double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S.
  • the bicyclic heteroaryl ring consists of the 5 or 6 membered heteroaryl ring fused to a phenyl group or the 5 or 6 membered heteroaryl ring fused to a cycloalkyl group or the 5 or 6 membered heteroaryl ring fused to a cycloalkenyl group or the 5 or 6 membered heteroaryl ring fused to another 5 or 6 membered heteroaryl ring.
  • Nitrogen heteroatoms contained within the heteroaryl may be optionally oxidized to the N-oxide.
  • heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl.
  • Representative examples of heteroaryl include, but are not hmited to, benzothienyl, benzoxadiazolyl, cinnolinyl, 5,6-dihydroisoquinolinyl, 7,8-dihydroisoquinolinyl, 5,6-dihydroquinolinyl, 7,8-dihydroquinolinyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyridinium N-oxid
  • heteroaryl groups of the present invention are substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylthio, alkynyl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B and (NRARB)carbonyl.
  • Heteroaryl groups of the present invention that are substituted can exist as tautomers.
  • the present invention encompasses all tautomers of substituted heteroaryl groups.
  • heteroarylalkyl means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heteroarylalkylcarbonyl means a heteroarylalkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • heteroarylcarbonyl means a heteroaryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • heteroarylcarbonyl include, but are not limited to, pyridinylcarbonyl and 6-methylpyridinylcarbonyl.
  • heterocycle or “heterocyclic” as used herein, means a monocyclic heterocyclic ring that consists of a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S.
  • the 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • Representative examples of the monocyclic heterocyclic ring include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazohdinyl, morpholinyl, oxadiazohnyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyr
  • heterocycles of this invention are substituted with 0, 1, 2,or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylthio, alkynyl, carboxy, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR A R B and (NRAR B )carbonyl.
  • Representative examples include, but are not limited to, 3-amino-2-oxopyrrolidinyl, 2-carboxyazetidinyl, and 3-carboxyazetidinyl.
  • heterocyclealkyl means a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkyl include, but are not Hmited to, piperidin-4- ylmethyl, piperazin-1-ylmethyl, 3-methyl-l-pyrrolidin-l-ylbutyl, ( lR)-3 -methyl- 1-pyrroHdin- 1-ylbutyl, and (lS)-3 -methyl- 1-pyrroHdin-l-ylbutyl.
  • heterocyclealkylcarbonyl means a heterocyclealkyl, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of heterocyclealkylcarbonyl include, but are not limited to, piperidin-4-ylmethylcarbonyl, piperazin- 1 -ylmethylcarbonyl, 3 -methyl- 1 -pyrrolidin- 1 - ylbutylcarbonyl, (lR)-3 -methyl- 1 -pyrrolidin- 1 -ylbutylcarbonyl, (1 S)-3 -methyl- 1 -pyrrolidin- 1 -ylbutylcarbonyl.
  • heterocyclecarbonyl means a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • hydroxy means an -OH group.
  • hydroxyalkyl means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not Hmited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
  • mercapto means a -SH group.
  • NRARB as used herein, means two groups, R A and R B , which are appended to the parent molecular moiety through a nitrogen atom.
  • R A and R B are independently selected from the group consisting of hydrogen and alkyl.
  • Representative examples of NRARB include, but are not Hmited to, amino, methylamino, dimethylamino, ethylmethylamino and isopropylamino.
  • (NRARB)carbonyl as used herein, means a NR A R B group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • NARB nitrogenyl
  • (NRARB)carbonyl include, but are not Hmited to, amino carbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl.
  • Representative examples of NZ ⁇ Z 2 include, but are not Hmited to, amino, methylamino, dimethylamino, ethylmethylamino and isopropylamino .
  • (NZiZ 2 )alkyl as used herein, means a NZiZ 2 group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NZiZ 2 )alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 7-aminoheptyl and 4-isopropylaminobutyl.
  • (NZiZ 2 )alkylcarbonyl means a (NZiZ 2 )alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NZ ⁇ Z 2 )alkylcarbonyl include, but are not Hmited to, aminoacetyl, 3-aminopropanoyl, 4-aminobutanoyl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl and 4-(isopropylamino)butanoyl.
  • NZ 3 Z 4 as used herein, means two groups, Z 3 and Z 4 , which are appended to the parent molecular moiety through a nitrogen atom.
  • Z 3 is selected from the group consisting of hydrogen and alkyl.
  • Z is selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl.
  • Representative examples of NZ 3 Z 4 include, but are not Hmited to, amino, methylamino, dimethylamino, ethylmethylamino, isopropylamino, and (pyridinylcarbonyl)amino .
  • (NZ 3 Z 4 )alkyl as used herein, means a NZ 3 Z 4 group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NZ 3 Z 4 )alkyl include, but are not Hmited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 4-isopropylaminobutyl, and 4-[(pyridin-3-ylcarbonyl)amino]butyl.
  • Z 5 , Z 6 and Z 7 are independently selected from the group consisting of hydrogen and alkyl, as defined herein. Representative include, but are not limited to, [amino (imino)methyl] amino, [(dimethylamino)(imino)methyl]amino, [(dimethylamino)(imino)methyl](methyl)amino and [amino(imino)methyl](methyl)amino.
  • NZ 8 Z 9 as used herein, means two groups, Z 8 and Z 9 , which are appended to the parent molecular moiety through a nitrogen atom.
  • Z 8 is selected from the group consisting of hydrogen and alkyl.
  • NZ 8 Z 9 is selected from the group consisting of hydrogen, alkyl, and heteroarylcarbonyl.
  • Representative examples of NZ 8 Z 9 include, but are not limited to, amino, methylamino, dimethylamino, ethylmethylamino, isopropylamino, and (pyridinylcarbonyl) amino .
  • (NZ 8 Z 9 )alkyl as used herein, means a NZ 8 Z 9 group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • (NZ 8 Z 9 )alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 4-isopropylaminobutyl, and 4-[(pyridin-3-ylcarbonyl)amino]butyl.
  • the term as used herein, means Z ⁇ 0 , Z ⁇ and Z ⁇ 2 are independently selected from the group consisting of hydrogen and alkyl, as defined herein. include, but are not limited to, [amino(imino)methyl]amino, [(dimethylamino)(imino)methyl]amino,
  • NZ 13 Z 14 as used herein, means two groups, Z 13 and Z 14 , which are appended to the parent molecular moiety through a nitrogen atom.
  • Z ⁇ 3 and Z 14 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • NZ 13 Z 14 include, but are not limited to, amino, methylamino, dimethylamino, ethylmethylamino, isopropylamino, 2-(carboxyethyl)amino, 3-(carboxypropyl)amino, and 4-(carboxybutyl)amino.
  • the term "NZ ⁇ 5 Zi6" as used herein, means two groups, Z 15 and Z 16 , which are appended to the parent molecular moiety through a nitrogen atom.
  • Z 15 and Z 16 are independently selected from the group consisting of hydrogen and alkyl.
  • NZ 15 Z ⁇ 6 include, but are not limited to, amino, methylamino, dimethylamino, ethylmethylamino, and isopropylamino.
  • (NZ 15 Z 16 )carbonyl as used herein, means a NZ15Z 1 6 group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • (NZ 15 Z 1 6)carbonyl include, but are not Hmited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and (ethylmethylamino)carbonyl
  • (NZ 15 Z 16 )carbonylalkyl include, but are not limited to, amino carbonylmethyl, 2-(aminocarbonyl)ethyl, 3-(aminocarbonyl)propyl, 4- (amino carbonyl)butyl, 5-(aminocarbonyl)pentyl, and 6-(aminocarbonyl)hexyl.
  • Z 17 and Z ⁇ 8 are independently selected from the group consisting of hydrogen, alkyl, and carboxyalkyl.
  • NZ 17 Z 18 include, but are not limited to, amino, methylamino, dimethylamino, ethylmethylamino, isopropylamino, 2-(carboxyethyl)amino, 3-(carboxypropyl)amino, and 4-(carboxybutyl)amino.
  • Z 19 and Z 20 are independently selected from the group consisting of hydrogen and alkyl.
  • NZ 19 Z 20 include, but are not limited to, amino, methylamino, dimethylamino, ethylmethylamino and isopropylamino.
  • (NZ 19 Z 20 )alkyl as used herein, means a NZ 19 Z 20 group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • (NZ 19 Z 2 o)alkyl include, but are not limited to, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 7-aminoheptyl and 4-isopropylaminobutyl.
  • nitro as used herein, means a -NO 2 group.
  • Compounds of the present invention can exist as stereoisomers, wherein asymmetric or chiral centers are present. Stereoisomers are designated (R) or (S) depending on the configuration of substituents around the chiral carbon atom.
  • Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures foUowed by resolution well-known to those of ordinary skill in the art.
  • HMVEC human microvascular endotheHal cell
  • the HMVEC cells were starved overnight in DME containing 0.01% bovine serum albuminutes (BSA). CeUs were then harvested with trypsin and resuspended in DME with 0.01% BSA at a concentration of 1.5 X 106 cells per mL. CeUs were added to the bottom of a 48 well modified Boyden chamber (Nucleopore Corporation, Cabin John, MD).
  • the chamber was assembled and inverted, and cells were allowed to attach for 2 hours at 37 °C to polycarbonate chemotaxis membranes (5 ⁇ m pore size) that had been soaked in 0.01% gelatin overnight and dried.
  • the chamber was then reinverted, and test substances (total volume of 50 ⁇ L), including activators, 15 ng/mL bFGF/VEGF, were added to the wells of the upper chamber.
  • the apparatus was incubated for 4 hours at 37 °C. Membranes were recovered, fixed and stained (Diff Quick, Fisher Scientific) and the number of cells that had migrated to the upper chamber per 3 high power fields counted.
  • the compounds of the present invention including, but not limited to, those specified in the examples possess anti-angiogenic activity.
  • angiogenesis inhibitors such compounds are useful in the treatment of both primary and metastatic solid tumors, including carcinomas of breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, urinary tract (including kidney, bladder and urotheHum), female genital tract (including cervix, uterus, and ovaries as weU as chorio carcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal, and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as weU as Ka
  • Such compounds may also be useful in treating solid tumors arising from hematopoietic malignancies such as leukemias (i.e., chloromas, plasmacytomas and the plaques and tumors of mycosis fungosides and cutaneous T-cell lymphoma/leukemia) as well as in the treatment of lymphomas (both Hodgkin's and non-Hodgkin's lymphomas).
  • leukemias i.e., chloromas, plasmacytomas and the plaques and tumors of mycosis fungosides and cutaneous T-cell lymphoma/leukemia
  • lymphomas both Hodgkin's and non-Hodgkin's lymphomas.
  • these compounds may be useful in the prevention of metastases from the tumors described above either when used alone or in combination with radiotherapy and/or other chemotherapeutic agents.
  • autoimmune diseases such as rheumatoid, immune and degenerative arthritis
  • various ocular diseases such as diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration, hypoxia, angiogenesis in the eye associated with infection or surgical intervention, and other abnormal neovascularization conditions of the eye
  • skin diseases such as psoriasis
  • blood vessel diseases such as hemagiomas, and capillary prohferation within atherosclerotic plaques
  • Osier- Webber Syndrome myocardial angiogenesis
  • plaque neovascularization telangiectasia
  • hemophiliac joints angiofibroma
  • wound granulation such as rheumatoid, immune and degenerative arthritis
  • various ocular diseases such as diabetic retinopathy, retinopathy of pre
  • Other uses include the treatment of diseases characterized by excessive or abnormal stimulation of endotheHal cells, including not limited to intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma, and hypertrophic scars (i.e., keloids).
  • Another use is as a birth control agent, by inhibiting ovulation and estabHshment of the placenta.
  • the compounds of the invention are also useful in the treatment of diseases that have angiogenesis as a pathologic consequence such as cat scratch disease (Rochele minutesalia quintosa) and ulcers (Helicobacter pylori).
  • the compounds of the invention are also useful to reduce bleeding by administration prior to surgery, especially for the treatment of resectable tumors.
  • the compounds of the present invention may be used in combination with other compositions and procedures for the treatment of diseases.
  • a tumor may be treated conventionally with surgery, radiation or chemotherapy combined with a compound of the present invention and then a compound of the present invention may be subsequently administered to the patient to extend the dormancy of micrometastases and to stabilize and inhibit the growth of any residual primary tumor.
  • the compounds of the present invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • a sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution.
  • a sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co- glycoHde (copolymers of lactic acid and glycoHc acid) polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phosphoHpids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
  • biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co- glycoHde (copolymers of lactic acid and glycoHc acid) polyan
  • a preferred biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (co-polymers of lactic acid and glycolic acid).
  • a therapeutically effective amount of one of the compounds of the present invention can be employed as a zwitterion or as a pharmaceutically acceptable salt.
  • a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat an angiogenic disease, (for example, to limit tumor growth or to slow or block tumor metastasis) at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific compound employed; and like factors weU known in the medical arts.
  • pharmaceutically acceptable salt those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, aUergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are weU-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate
  • the basic nitrogen- containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, 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; arylalkyl halides Hke benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as dec
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkaH metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the Hke and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the Hke.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • a compound of the present invention may be administered as a pharmaceutical composition containing a compound of the present invention in combination with one or more pharmaceutically acceptable excipients.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-soHd or Hquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the compositions can be administered parenteraUy, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), rectally, or bucally.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions for parenteral injection comprise pharmaceutically- acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as weU as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the Hke. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the Hke.
  • Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
  • Injectable depot forms are made by forming micro encapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycoHde, poly(ortho esters), poly(anhydrides), and (poly)glycols, such as PEG. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating steriHzing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical administration, including those for inhalation, may be prepared as a dry powder which may be pressurized or non-pressurized.
  • the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceuticaUy-acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter.
  • Suitable inert carriers include sugars such as lactose.
  • at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquified gas propellant.
  • the liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent.
  • the pressurized composition may also contain a surface active agent, such as a Hquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
  • a further form of topical administration is to the eye.
  • a compound of the invention is deHvered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to aUow the compound to penetrate the corneal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina and sclera.
  • the pharmaceuticaUy-acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material.
  • the compounds of the invention may be injected directly into the vitreous and aqueous humour.
  • Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature Hquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature Hquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Compounds of the present invention may also be administered in the form of liposomes.
  • liposomes are generally derived from phosphohpids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physio logicaUy-acceptable and metabolizable lipid capable of forming Hposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabUizers, preservatives, excipients, and the like.
  • the preferred Hpids are the phosphohpids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art.
  • the compounds of the present invention can be administered as the sole active pharmaceutical agent, they may also be used in combination with one or more agents which are conventionally administered to patients for treating angiogenic diseases.
  • the compounds of the invention are effective over the short term to make tumors more sensitive to traditional cytotoxic therapies such as chemicals and radiation.
  • the compounds of the invention also enhance the effectiveness of existing cytotoxic adjuvant anti-cancer therapies.
  • the compounds of the invention may also be combined with other antiangio genie agents to enhance their effectiveness, or combined with other antiangiogenic agents and administered together with other cytotoxic agents.
  • compounds of the invention when used in the treatment of solid tumors, may be administered with IL-12, retinoids, interferons, angiostatin, endostatin, thalidomide, thrombospondin-1, tl rombospondin-2, captopryl, angioinhibins, TNP-470, pentosan polysulfate, platelet factor 4, LM-609, SU-5416, CM-101, Tecogalan, plasminogen-K-5, vasostatin, vitaxin, vasculostatin, squalamine, marimastat or other MMP inhibitors, anti-neoplastic agents such as alpha inteferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethas
  • Total daily dose of the compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daUy and more usuaUy 1 to 300 mg/kg body weight.
  • the dose, from 0.0001 to 300 mg/kg body may be given twice a day.
  • agents which can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of angiogenic diseases are not limited to those Hsted above, include in principle any agents useful for the treatment or prophylaxis of angiogenic diseases.
  • methods for preparing compounds of the present invention comprise the sequential addition of one amino acid or suitably protected amino acid to another amino acid or a growing amino acid chain.
  • either the amino or carboxyl group of the first amino acid is protected by a suitable protecting group.
  • the protected or derivatized amino acid can then be either attached to an inert solid support or utilized in solution by adding the next amino acid in the sequence having the complimentary (amino or carboxyl) group suitably protected, under conditions suitable for forming the amide linkage.
  • the protecting group is then removed from this newly added amino acid residue and the next amino acid (suitably protected) is then added, and so forth. After all the desired amino acids have been linked in the proper sequence, any remaining protecting groups (and any soHd support) are removed sequentially or concurrently, to afford the final desired product.
  • Solid phase synthesis incorporates amino acids protected by an acid or base sensitive group.
  • Such protecting groups have the properties of being stable to the conditions of amide bond coupHng, whUe being readUy removable without destruction of the growing amino acid chain or racemization of any of the chiral centers contained therein.
  • Suitable protecting groups are 9-fluorenylmethyloxycarbonyl (Fmoc), t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), biphenylisopropyl-oxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, ( ⁇ , ⁇ )-dimethyl-3,5-dimethoxybenzyloxycarbonyl, O- nitrophenylsulfenyl, 2-cyano-t-butyloxycarbonyl, and the Hke.
  • Side chain protecting groups are: for arginine: 2,2,5,7, 8-pentamethylchroman-6- sulfonyl (Pmc), and 2,2,4, 6,7-pentamethyldihydrobenzofuran-S-sulfonyl (Pbf); for asparagine: trityl (Trt); for glutamine: trityl (Trt); for lysine: t-butoxycarbonyl (Boc); for seryl: t-butyl (t-Bu); for threonine and allothreonine: t-butyl (t-Bu); for tryptophan: t- butoxycarbonyl (Boc); and for tyrosine: t-butyl (t-Bu).
  • soHd phase method the carboxy group of the amino acid is attached to a suitable solid support or resin.
  • Suitable soHd supports useful for the above synthesis are those materials which are inert to the reagents and reaction conditions of the stepwise condensation-deprotection reactions, as well as being insoluble in the media used.
  • the resin is deprotected using secondary amines such as piperidine when the soHd support protecting group is Fmoc.
  • An amino acid is coupled to the resin using coupHng reagents such as O-benzotriazol-l-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate (HBTU, 1 equiv.) with 1-hydroxybenzotriazole (HOBT, 1 equiv.), or [O-(7-azabenzotriazol- l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate] (HATU, 1 equiv.) with N- methylmorphoHne (1 equiv.) in a solvent such as DMF.
  • coupHng reagents such as O-benzotriazol-l-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate (HBTU, 1 equiv.) with 1-hydroxybenzotriazole (HOBT, 1 equiv.), or [O-(7-
  • reagents can be used to accomplish the coupHng, for example, N,N-dicyclohexylcarbodiimide (DCC), N,N'- dnsopropylcarbodiimide (DIC), [O-(7-azabenzotriazol- 1 -yl)- 1,1,3 ,3 -tetramethyluronium hexafluorophosphate] (HATU), or O-benzotriazol-l-yl-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HBTU), with or without 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole (HOBT), N-methylmorpholine (NMM), benzotriazol-1- yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate (BOP) or bis(2-oxo-3- oxazoHdinyl)phosphine chloride (BOPC1)
  • the coupHng of successive protected amino acids can be carried out in a solid phase synthesizer as is well known in the art.
  • Fmoc is removed from the nitrogen of the growing amino acid sequence by treatment with a secondary amine such as piperidine.
  • Each protected amino acid is then introduced and the coupHng is carried out in a solvent such as DMF.
  • the coupling agent is normally O-benzotriazol-l-yl-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HBTU, 1 equiv.) or [O-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate] (HATU, 1 equiv.) in the presence of N- methylmorphoHne (NMM, 1 equiv.). At the end of the soHd phase synthesis, the resin is cleaved.
  • HBTU O-benzotriazol-l-yl-N,N,N',N'- tetramethyluroniumhexafluorophosphate
  • NMM N- methylmorphoHne
  • Conditions necessary for cleavage for example trifluoro acetic acid containing thianisole, water, or ethanedithiol, can result in deprotection of any remaining protecting groups.
  • compounds of the present invention are purified by chromatography including, but not Hmited to: ion exchange on a weakly basic resin in the acetate form; hydrophobic adsorption chromatography on underivitized polystyrene- divinylbenzene (for example, AMBERLITE ® XAD); silica gel adsorption chromatography; ion exchange chromatography on carboxymethylcellulose; partition chromatography, e.g., on SEPHADEX ® G-25, LH-20 or countercurrent distribution; high performance Hquid chromatography (HPLC), especially reverse-phase HPLC on octyl- or octadecylsilyl-silica bonded phase column packing.
  • HPLC high performance Hquid chromatography
  • the compounds of the present invention can be prepared without the use of soHd phase methodology.
  • Amino acids can be coupled under conditions described herein except without the use of a resin.
  • Reagents, resins, amino acids, and amino acid derivatives are commerciaUy available and can be purchased from Chem-Impex International, Inc. (Wood Dale, EL, U.S.A.) or Calbiochem-Novabiochem Corp. (San Diego, CA, U.S.A.) unless otherwise noted herein.
  • AM for aminomethyl
  • Bn for benzyl
  • Boc for tert-butoxycarbonyl
  • Cbz for benzyloxycarbonyl
  • DCC for 1,3-dicyclohexylcarbodiimide
  • DIEA for diisopropylethylamine
  • DMA for dimethylacetamide
  • DMF for N,N-dimethylformamide
  • EDCI or EDC for l-ethyl-3-[3- (dimethylamino)propyl]-carbodiimide hydrochloride
  • Fmoc for fluorenylmethoxycarbonyl
  • HATU for O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTU for O-benzotriazol-l-yl-N j N j N' j N'-tetramethyluronium
  • Compounds of formula (6) wherein L, Ri, R 9 , R 10 , Rn, and R 12 are as defined in Formula (I), can be prepared as described in Scheme 1.
  • Compounds of formula (1) wherein PG is a nitroge protecting group such as Boc, Bn, Cbz, or Fmoc can be purchased or prepared using chemistry known to those of skill in the art.
  • Compounds of formula (1) can be treated with HOBt, carbodumides such as EDCI or DCC, a base such as DIEA or NMM or TEA, and compounds of formula (2), purchased or prepared using chemistry known to those of skill in the art, to provide compounds of formula (3).
  • Compounds of formula (1) can also be treated with HATU and a base such as NMM and compounds of formula (2) to provide compounds of formula (3).
  • Compounds of formula (3) can be treated with reagents/conditions that are well known to those of skUl in the art in order to remove the nitrogen protecting group to provide compounds of formula (4), for example, Boc can be removed by treatment with acid such as HCl or TFA in a solvent such as THF or CH 2 C1 2 , Fmoc can be removed by treatment with a secondary amine such as piperidine in DMF as solvent, Cbz or Bn can be removed by treatment with a metal catalyst such as palladium (Pd/C) under a hydrogen atmosphere.
  • Boc can be removed by treatment with acid such as HCl or TFA in a solvent such as THF or CH 2 C1 2
  • Fmoc can be removed by treatment with a secondary amine such as piperidine in DMF as solvent
  • Cbz or Bn can be removed by treatment with a metal
  • Compounds of formula (16), wherein L, R l5 R 9 , R 10 , and R 12 are as defined in Formula (I), can be prepared using soHd phase techniques known to those of skill in the art.
  • Compounds of formula (8) wherein PG is a nitroge protecting group such as Boc, Bn, Cbz, or Fmoc can be purchased and deprotected using procedures described herein or using procedures known to those of skill in the art to provide compounds of formula (9).
  • Compounds of formula (9) can be treated with compounds of formula (10), HATU and a base such as NMM in a solvent such as DMF to provide compounds of formula (11).
  • Compounds of formula (10) can also be treated with HOBt, carbodumides such as EDCI or DCC, a base such as DIEA or NMM or TEA, and compounds of formula (9) in a solvent such as DMF or CH 2 C1 2 to provide compounds of formula (11).
  • Compounds of formula (11) can be deprotected using procedures described herein or using procedures known to those of skUl in the art to provide compounds of formula (12).
  • Compounds of formula (12) can be treated with compounds of formula (1), HATU, and a base such as NMM in a solvent such as DMF to provide compounds of formula (13).
  • Compounds of formula (12) can also be treated with HOBt, carbodumides such as EDCI or DCC, a base such as DEEA or NMM or TEA, and compounds of formula (1) in a solvent such as DMF or CH 2 C1 2 to provide compounds of formula (13).
  • Compounds of formula (13) can be deprotected using procedures described herein or using procedures known to those of skiU in the art to provide compounds of formula (14).
  • Compounds of formula (14) can be treated with compounds of formula (5), HATU, and a base such as NMM in a solvent such as DMF to provide compounds of formula (15).
  • Compounds of formula (14) can also be treated with HOBt, carbodumides such as EDCI or DCC, a base such as DIEA or NMM or TEA, and compounds of formula (5) in a solvent such as DMF or CH 2 C1 2 to provide compounds of formula (15).
  • Compounds of formula (15) can be treated under conditions known to those of skill in the art to cleave resins such as a TFA, water, and anisole mixture (95:2.5:2.5) to provide compounds of formula (16).
  • Example 2 (3S)-3-[( ⁇ l-[(2S)-2-(acetylamino)-6-aminohexanoyl]-4-phenylpiperidin-4- yl) carbonyl)aminol-4-amino-4-oxobutanoic acid
  • the procedure described in example 1 was used, foUowed by deprotection and sequential coupHngs with Fmoc-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1.
  • Example 3 (2S)-2-[( ⁇ l-[(2S)-2-(acetylaminoV6-aminohexanoyl]-4-phenylpiperidin-4- yl ⁇ carbonyl)amino]succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential couplingswith Fmoc-4-phenylpiperidine-4-carboxyHc acid, Fmoc-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1.
  • Example 4 l-[(2S)-2-(acetylamino)-6-aminohexanoyl]-4-phenylpiperidine-4-carboxylic acid
  • the procedure described in example 1 was used but substituting Wang-resin for Rink amide MBHA resin and coupling with Fmoc-4-phenylpiperidine-4-carboxylic acid, foUowed by deprotection and sequential couphngs with Fmoc-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1.
  • Example 5 (2S)-2-( ⁇ [l-(6-aminohexanoyl)-4-phenylpiperidin-4-yl]carbonyl ⁇ amino)succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential coupling with Fmoc-4-phenylpiperidine-4-carboxylic acid and then with Fmoc-4-aminohexanoic acid using the same synthetic protocols described in example 1.
  • Example 6 (3S)-4-amino-3-( ⁇ [l-(5-aminopentanoyl)-4-phenylpiperidin-4-yl]carbonyl ⁇ amino)-4- oxobutanoic acid
  • the procedure described in example 1 was used, followed by deprotection and sequential coupling with Fmoc-5-aminopentanoic acid using the same synthetic protocols described in example 1.
  • After TFA cleavage and work-up the obtained residue was purified by HPLC using C-18 reverse phase column (7.8x300 mm) using a solvent mixture varying in gradient from 5% to 100% acetonitrile/water over a period of 55 min.
  • Example 7 (3S)-4-amino-3-( ⁇ [l-(4-aminobutanoyl -4-phenylpiperidin-4-yl]carbonyl) amino V4- oxobutanoic acid
  • the procedure described in example 1 was used, followed by deprotection and sequential coupling with Fmoc-4-aminobutyric acid using the same synthetic protocols described in example 1.
  • After TFA cleavage and work-up the obtained residue was purified by HPLC using C-18 reverse phase column (7.8x300 mm) using a solvent mixture varying in gradient from 5% to 100% acetonitrile/water over a period of 55 min.
  • Example 8 (3S)-3-[( ⁇ l-[(2SV2-racetylamino -6-aminohexanoyllpiperidin-4-yl)acetyl)amino]-4-amino- 4-oxobutanoic acid
  • the procedure described in example 1 was used, followed by Fmoc-deprotection of
  • Example 9 (3S)-3-[( ⁇ l-[(2S)-2-(acetylamino)-6-aminohexanoyl1piperidin-4-yl ⁇ carbonyl)amino]-4- amino-4-oxobutanoic acid
  • the procedure described in example 1 was used, foUowed by Fmoc-deprotection of Asp(OtBu) residue and sequential coupling with Fmoc-isonipecotic acid, Fmoc-Lys(Boc) and acetic acid using the same synthetic protocols described in example 1.
  • Example 10 (2S)-2-( ⁇ [l-(6-aminohexanoyl)piperidin-4-yl]acetyl ⁇ amino)succinic acid
  • the procedure described in example 1 was used, but substituting Fmoc-Asp(OtBu)- Wang resin(p-benzyloxybenzyl ester resin) for Rink amide MBHA resin, followed by Fmoc- deprotection of Asp(OtBu) residue and sequential coupling with Fmoc-(4-carboxymethyl)- piperidine acid and Fmoc-6-aminohexanoic acid followed by Fmoc-deprotection using the same synthetic protocols described in example 1.
  • Example 11 (2S)-2-( ⁇ [l-(6-aminohexanoyl)piperidin-4-yl]carbonyllamino)succinic acid
  • the procedure described in example 1 was used, but substituting Fmoc-Asp(OtBu)- Wang resin(p-benzyloxybenzyl ester resin) for Rink amide MBHA resin, followed by Fmoc- deprotection of Asp(OtBu) residue and sequential coupHng with Fmoc-isonipecotic acid and Fmoc-6-aminohexanoic acid foUowed by Fmoc-deprotection using the same synthetic protocols described in example 1.
  • Example 12 3- ( ⁇ l-[(2S)-2-(acetylamino)-6-aminohexanoyl]-4-phenylpiperidin-4- yl ⁇ carbonyl)amino]propanoic acid
  • the procedure described in example 1 was used, but substituting Fmoc-beta-alanine- Wang resin(p-benzyloxybenzyl ester resin) for Rink amide MBHA resin, followed by Fmoc- deprotection of beta-alanine and sequential coupHng with Fmoc-4-phenylpiperidine-4- carboxylic acid, Fmoc-Lys(Boc) and acetic acid using the same synthetic protocols described in example 1.
  • Example 13 l-[(2S)-2-(acetylamino)-6-aminohexanoyl]piperidine-4-carboxylic acid
  • the procedure described in example 1 was used but substituting Wang-resin for Rink amide MBHA resin and coupling with Fmoc-isonipecotic acid, followed by deprotection and sequential coupHng with Fmoc-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1.
  • After TFA cleavage and work-up the obtained residue was purified by HPLC using C-18 reverse phase column (7.8x300 mm) using a solvent mixture varying in gradient from 5% to 100% acetonitrile/water over a period of 55 min.
  • Example 14 (3 S V4-amino-3 -( ⁇ [ 1 -(6-aminohexanoyl)-4-phenylpiperidin-4-yl] carbonyl) amino)-4- oxobutanoic acid
  • the procedure described in example 1 was used but substituting Fmoc-6- aminohexanoic acid for Fmoc-Lys(Boc) and following the same synthetic protocols described in example 1 with the omission of the acetic acid coupling.
  • After TFA cleavage and work-up the obtained residue was purified by HPLC using C-18 reverse phase column (7.8x300 mm) using a solvent mixture varying in gradient from 5% to 100% acetonitrile/water over a period of 55 min.
  • Example 15 (4SV4-[( ⁇ l-[(2S)-2-(acetylamino)-6-aminohexanoyl]-4-phenylpiperidin-4- yl ⁇ carbonyl)anUno]-5-amino-5-oxopentanoic acid
  • the procedure described in example 1 was used but substituting Fmoc-Glu(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Fmoc-Asp(OtBu)-Wang resin (p- benzyloxybenzyl ester resin) and foUowed by deprotection and sequential coupHng with Fmoc-4-phenylpiperidine-4-carboxylic acid, Fmoc-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1.
  • Example 16 (3 S V4-amino-3 -( ⁇ [ 1 -(3 -aminopropanoyl)-4-phenylpiperidin-4-yl] carbonyl) amino)-4- oxobutanoic acid
  • the procedure described in example 1 was used but substituting Fmoc-3- aminopropionic acid for Fmoc-Lys(Boc) and foUowing the same synthetic protocols described in example 1 with the omission of the acetic acid coupHng.
  • After TFA cleavage and work-up the obtained residue was purified by HPLC using C-18 reverse phase column (7.8x300 mm) using a solvent mixture varying in gradient from 5% to 100% acetonitrile/water over a period of 55 min.
  • Example 17 (2S)-2- ((l-[(2S)-2-(acetylamino)-6-aminohexanoyl]-4-phenylpiperidin-4- yl)carbony ⁇ amino1-4-amino-4-oxobutanoic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asn(Trt)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential coupHng with Fmoc-4-phenylpiperidine-4-carboxylic acid, Fmoc-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1. .
  • Example 20 (2RV2-[( ⁇ l-[(2S)-2-(acetylaminoV6-aminohexanoyl]-4-phenylpiperidin-4- yl)carbonv ⁇ amino]succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-D-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and foUowed by deprotection and sequential coupHng with Fmoc-4-phenylpiperidine-4-carboxylic acid, Fmoc-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1.
  • Example 21 (2S)-2-( ⁇ [4-phenyl-l-(pyridin-3-ylcarbonyl)piperidin-4-yl]carbonyl)amino succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential coupling with Fmoc-4-phenylpiperidine-4-carboxylic acid and then with nicotinic acid using the same synthetic protocols described in example 1.
  • Example 22 (2R)-2-[ (l-[(2R)-2-(acetylaminoV6-aminohexanoyl]-4-phenylpiperidin-4- yl)carbonyl)amino]succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-D-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential coupHng with Fmoc-4-phenylpiperidine-4-carboxylic acid, Fmoc-D-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1.
  • Example 23 (2S)-2-( ⁇ [4-phenyl-l-(piperidin-4-ylacetyl)piperidin-4-yl]carbonyl)amino succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-D-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential couplings with Fmoc-4-phenylpiperidine-4-carboxylic acid, and then with Fmoc-(4-carboxymethyl)-piperidine using the same synthetic protocols described in example 1.
  • Example 24 (2S)-2-( ⁇ [4-phenyl-l-(piperazin-l-ylacetyl)piperidin-4-yl]carbonyl)amino ⁇ succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-D-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential coupHngs with Fmoc-4-phenylpiperidine-4-carboxylic acid, and then with Fmoc-(4-carboxymethyl)-piperazine using the same synthetic protocols described in example 1.
  • Example 25 (3S)-4-amino-3-[( ⁇ l-[(2S)-2.6-diaminohexanoyl]-4-phenylpiperidin-4-yl)carbonyl)amino]-4- oxobutanoic acid
  • the procedure described in example 1 was used, followed by deprotection and sequential coupHng with Fmoc-Lys(Boc) and deprotection using the same synthetic protocols described in example 1.
  • TFA cleavage and work-up the obtained residue was purified by HPLC using C-18 reverse phase column (7.8x300 mm) using a solvent mixture varying in gradient from 5% to 100% acetonitrile/water over a period of 55 min.
  • Example 26 (2S)-2-[( ⁇ l- (2S)-2.6-diaminohexanoyl]-4-phenylpiperidin-4-yl)carbonyl)amino]succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and foUowed by deprotection and sequential coupling with Fmoc-4-phenylpiperidine-4-carboxylic acid and Fmoc-Lys(Boc), then deprotection using the same synthetic protocols described in example 1. .
  • Example 27 (2S)-2-[( ⁇ l-[(2S)-2-(acetylaminoV6-aminohexanoyl1-4-phenylpiperidin-4- yl)carbonyl amino]pentanedioic acid
  • the procedure described in example 1 was used but substituting Fmoc-Glu(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and foUowed by deprotection and sequential coupling with Fmoc-4-phenylpiperidine-4-carboxylic acid, Fmoc-Lys(Boc) and then with acetic acid using the same synthetic protocols described in example 1. .
  • Example 29 (2 S V2- ⁇ [Y 1 - ⁇ (2SV2-[(3R)-3 -amino-2-oxop yrrolidin- 1 - yll-4-methylpentano yll -4- phenylpiperidin-4-yl)carbonyl]aminolsuccinic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential coupling with Fmoc-4-phenylpiperidine-4-carboxylic acid and Fmoc-2-(3-amino-2-oxo-pyrrolidin-l-yl)-4-methylpentanoic acid, followed by deprotection using the same synthetic protocols described in example 1.
  • Example 30 (2S)-2-[( ⁇ l-[(2S)-2-(acetylaminoV6-aminohexanoyl]piperidin-4-yl)carbonyl)amino]succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential couphngs with Fmoc-isonipecotic acid, Fmoc-Lys(Boc) and acetic acid using the same synthetic protocols described in example 1.
  • Example 31 (2SV2-(( l-((2SV6-amino-2-( (6-methylpyridin-3-v carbonyllamino)hexanoylV4- phenylpiperidin-4-yl] carbonyl) amino ⁇ succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and followed by deprotection and sequential couplings with Fmoc-4-phenylpiperidine-4-carboxylic acid, Fmoc-Lys(Boc) and 6-methylnicotinic acid using the same synthetic protocols described in example 1.
  • Example 33 (2S)-2-( ⁇ [l-((2SV2-(acetylamino)-5- ⁇ [amino(imino)methyllamino)pentanoyl)-4- phenylpiperidin-4-yl] carbonyl) amino)succinic acid
  • the procedure described in example 1 was used but substituting Fmoc-Asp(OtBu)- Wang resin (p-benzyloxybenzyl ester resin) for Rink amide MBHA resin and foUowed by deprotection and sequential couplings with Fmoc-4-phenylpiperidine-4-carboxylic acid, Fmoc-Arg(Pbf) and acetic acid using the same synthetic protocols described in example 1.

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Abstract

L'invention concerne des composés représentés par la formule I (I) inhibant l'angiogenèse et utilisés dans le traitement d'états pathologiques causés ou exacerbés par l'angiogenèse. L'invention concerne également des compositions pharmaceutiques contenant les composés représentés par la formule I, des méthodes de traitement dans lesquelles sont utilisés les composés représentés par la formule I, et des méthodes d'inhibition de l'angiogenèse dans lesquelles sont utilisés les composés représentés par la formule I.
PCT/US2005/019128 2004-06-02 2005-05-26 Piperidines substituees a activite antiangiogenique WO2005121090A1 (fr)

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Cited By (17)

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WO2011112685A1 (fr) * 2010-03-10 2011-09-15 Janssen Pharmaceutica Nv Dérivés de pipéridine 4,4-disubstituée utiles en tant qu'inhibiteurs de la dipeptidyle peptidase-1 (dpp-1)
US20120329711A1 (en) * 2009-12-16 2012-12-27 Nordisk A/S Glp-1 receptor agonist compounds with a modified n-terminus
EP2638910A2 (fr) * 2010-11-11 2013-09-18 Korea Research Institute of Bioscience and Biotechnology Composition comprenant des dérivés de benpropérine en tant que principes actifs pour la prévention et le traitement de maladies associées à l'angiogenèse
US8569282B2 (en) 2007-12-11 2013-10-29 Cytopathfinder, Inc. Carboxamide compounds and their use
US8598164B2 (en) 2010-05-06 2013-12-03 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
US8686152B2 (en) 2010-03-10 2014-04-01 Janssen Pharmaceutica Nv 4,4-disubstituted piperidine derivatives useful as inhibitors of dipeptidyl peptidase-1 (DPP-1)
US8828996B2 (en) 2011-03-14 2014-09-09 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US8916565B2 (en) 2011-02-02 2014-12-23 Vertex Pharmaceuticals Incorporated Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
US9266940B2 (en) 2011-04-12 2016-02-23 Novo Nordisk A/S Double-acylated GLP-1 derivatives
US10385070B2 (en) 2011-02-18 2019-08-20 Vertex Pharmaceuticals Incorporated Chroman-spirocyclic piperidine amides as modulators of ion channels
US10933120B2 (en) 2012-03-22 2021-03-02 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US10960052B2 (en) 2010-12-16 2021-03-30 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl) amino) caprylic acid
US11033499B2 (en) 2012-06-20 2021-06-15 Novo Nordisk A/S Tablet formulation comprising a GLP-1 peptide and a delivery agent
US11123296B2 (en) 2012-03-22 2021-09-21 Novo Nordisk A/S Compositions comprising a delivery agent and preparation thereof
US20210363128A1 (en) * 2018-03-14 2021-11-25 H. Lee Moffitt Cancer Center And Research Institute, Inc. Yap1 inhibitors that target the interaction of yap1 with oct4
US11833248B2 (en) 2018-02-02 2023-12-05 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US11999695B2 (en) 2016-09-18 2024-06-04 H. Lee Moffitt Cancer Center And Research Institute, Inc. YAP1 inhibitors that target the interaction of YAP1 with OCT4

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US8569282B2 (en) 2007-12-11 2013-10-29 Cytopathfinder, Inc. Carboxamide compounds and their use
US8815802B2 (en) 2009-12-16 2014-08-26 Novo Nordisk A/S GLP-1 analogues and derivatives
US20120329711A1 (en) * 2009-12-16 2012-12-27 Nordisk A/S Glp-1 receptor agonist compounds with a modified n-terminus
CN102933214A (zh) * 2010-03-10 2013-02-13 詹森药业有限公司 可用作二肽基肽酶-1(dpp-1)抑制剂的4，4-二取代的哌啶衍生物
JP2013522218A (ja) * 2010-03-10 2013-06-13 ヤンセン ファーマシューティカ エヌ．ベー． ジペプチジルペプチダーゼ−１（ｄｐｐ−１）の阻害剤として有用な４，４−二置換されたピペリジン誘導体
WO2011112685A1 (fr) * 2010-03-10 2011-09-15 Janssen Pharmaceutica Nv Dérivés de pipéridine 4,4-disubstituée utiles en tant qu'inhibiteurs de la dipeptidyle peptidase-1 (dpp-1)
US8686152B2 (en) 2010-03-10 2014-04-01 Janssen Pharmaceutica Nv 4,4-disubstituted piperidine derivatives useful as inhibitors of dipeptidyl peptidase-1 (DPP-1)
AU2011224417B2 (en) * 2010-03-10 2015-02-19 Janssen Pharmaceutica Nv 4,4-disubstituted piperidine derivatives useful as inhibitors of dipeptidyl peptidase-1 (DPP-1)
US8598164B2 (en) 2010-05-06 2013-12-03 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
EP2638910A2 (fr) * 2010-11-11 2013-09-18 Korea Research Institute of Bioscience and Biotechnology Composition comprenant des dérivés de benpropérine en tant que principes actifs pour la prévention et le traitement de maladies associées à l'angiogenèse
EP2638910A4 (fr) * 2010-11-11 2014-04-16 Korea Res Inst Of Bioscience Composition comprenant des dérivés de benpropérine en tant que principes actifs pour la prévention et le traitement de maladies associées à l'angiogenèse
US11382957B2 (en) 2010-12-16 2022-07-12 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US10960052B2 (en) 2010-12-16 2021-03-30 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl) amino) caprylic acid
US8916565B2 (en) 2011-02-02 2014-12-23 Vertex Pharmaceuticals Incorporated Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
US9511067B2 (en) 2011-02-02 2016-12-06 Vertex Pharmaceuticals Incorporated Substituted spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]s as modulators of ion channels
US10385070B2 (en) 2011-02-18 2019-08-20 Vertex Pharmaceuticals Incorporated Chroman-spirocyclic piperidine amides as modulators of ion channels
US8828996B2 (en) 2011-03-14 2014-09-09 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US9181273B2 (en) 2011-03-14 2015-11-10 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US9527900B2 (en) 2011-04-12 2016-12-27 Novo Nordisk A/S Double-acylated GLP-1 derivatives
US10005827B2 (en) 2011-04-12 2018-06-26 Novo Nordisk A/S Double-acylated GLP-1 derivatives
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US11117947B2 (en) 2011-04-12 2021-09-14 Novo Nordisk A/S Double-acylated GLP-1 derivatives
US9266940B2 (en) 2011-04-12 2016-02-23 Novo Nordisk A/S Double-acylated GLP-1 derivatives
US11759502B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US10933120B2 (en) 2012-03-22 2021-03-02 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11123296B2 (en) 2012-03-22 2021-09-21 Novo Nordisk A/S Compositions comprising a delivery agent and preparation thereof
US11759503B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11759501B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11033499B2 (en) 2012-06-20 2021-06-15 Novo Nordisk A/S Tablet formulation comprising a GLP-1 peptide and a delivery agent
US11999695B2 (en) 2016-09-18 2024-06-04 H. Lee Moffitt Cancer Center And Research Institute, Inc. YAP1 inhibitors that target the interaction of YAP1 with OCT4
US11833248B2 (en) 2018-02-02 2023-12-05 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US11685725B2 (en) * 2018-03-14 2023-06-27 H. Lee Moffitt Cancer Center And Research Institute, Inc. YAP1 inhibitors that target the interaction of YAP1 with OCT4
US20210363128A1 (en) * 2018-03-14 2021-11-25 H. Lee Moffitt Cancer Center And Research Institute, Inc. Yap1 inhibitors that target the interaction of yap1 with oct4

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